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Traumatic Brain Injury and Genetic Risk for Alzheimer's Disease Impact Cerebrospinal Fluid β-Amyloid Levels in Vietnam War Veterans. 创伤性脑损伤和阿尔茨海默病遗传风险对越战老兵脑脊液 β 淀粉样蛋白水平的影响。
IF 1.8 Q3 CLINICAL NEUROLOGY Pub Date : 2024-08-22 eCollection Date: 2024-01-01 DOI: 10.1089/neur.2024.0048
Jena N Moody, Erica Howard, Kate E Nolan, Sarah Prieto, Mark W Logue, Jasmeet P Hayes

Traumatic brain injuries (TBIs) may increase the risk for Alzheimer's disease (AD) and its neuropathological correlates, although the mechanisms of this relationship are unclear. The current study examined the synergistic effects of TBI and genetic risk for AD on β-amyloid (Aβ) levels among Vietnam War Veterans. We hypothesized that the combination of TBI and higher polygenic risk score (PRS) for AD would be associated with lower cerebrospinal fluid (CSF) Aβ42/40. Data were obtained from the Department of Defense Alzheimer's Disease Neuroimaging Initiative. Participants included Vietnam War Veterans without dementia who identified as White non-Hispanic/Latino and had available demographic, clinical assessment, genetic, and CSF biomarker data. Lifetime TBI history was assessed using The Ohio State University TBI Identification Method. Participants were categorized into those with and without TBI. Among those with a prior TBI, injury severity was defined as either mild or moderate/severe. CSF Aβ42/40 ratios were calculated. Genetic propensity for AD was assessed using PRSs. Hierarchical linear regression models examined the interactive effects of TBI and PRS for AD on Aβ42/40. Exploratory analyses examined the interaction between TBI severity and PRS. The final sample included 88 male Vietnam War Veterans who identified as White non-Hispanic/Latino (M age = 68.3 years), 49 of whom reported a prior TBI. There was a significant interaction between TBI and PRS, such that individuals with TBI and higher PRS for AD had lower Aβ42/40 (B = -0.45, 95% CI: -0.86 to -0.05, p = 0.03). This relationship may be stronger with increasing TBI severity (p = 0.05). Overall, TBI was associated with lower Aβ42/40, indicating greater amyloid deposition in the brain, in the context of greater polygenic risk for AD. These findings highlight who may be at increased risk for AD neuropathology following TBI.

创伤性脑损伤(TBI)可能会增加阿尔茨海默病(AD)及其神经病理学相关疾病的发病风险,但这种关系的机制尚不清楚。本研究探讨了创伤性脑损伤和阿尔茨海默病遗传风险对越战退伍军人体内β淀粉样蛋白(Aβ)水平的协同作用。我们假设,TBI 和较高的 AD 多基因风险评分 (PRS) 将与较低的脑脊液 (CSF) Aβ42/40 相关联。数据来自美国国防部阿尔茨海默病神经影像计划。参与者包括没有痴呆症的越战退伍军人,他们被认定为非西班牙裔/拉美裔白人,并拥有可用的人口统计学、临床评估、遗传学和脑脊液生物标记物数据。采用俄亥俄州立大学 TBI 鉴定方法对终生 TBI 史进行评估。参与者被分为有 TBI 史和无 TBI 史两类。在有过创伤性脑损伤的参与者中,损伤严重程度被定义为轻度或中度/重度。计算脑脊液 Aβ42/40 比率。使用PRSs评估AD的遗传倾向。层次线性回归模型检验了创伤性脑损伤和 AD PRS 对 Aβ42/40 的交互影响。探索性分析检验了 TBI 严重程度与 PRS 之间的交互作用。最终样本包括 88 名男性越战退伍军人,他们被认定为非西班牙裔/拉美裔白人(平均年龄 = 68.3 岁),其中 49 人报告曾有过创伤性脑损伤。创伤性脑损伤与 PRS 之间存在明显的交互作用,即创伤性脑损伤和 AD PRS 较高的个体的 Aβ42/40 值较低 (B = -0.45, 95% CI: -0.86 to -0.05, p = 0.03)。这种关系可能随着创伤性脑损伤严重程度的增加而增强(p = 0.05)。总体而言,创伤性脑损伤与较低的 Aβ42/40相关,表明在多基因AD风险增加的背景下,大脑中的淀粉样蛋白沉积增加。这些发现突显了哪些人在受到创伤性脑损伤后可能会增加罹患注意力缺失症神经病理学的风险。
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引用次数: 0
Acute and Reversible Hypothalamic Symptoms in a Lateral Head Impact Mouse Model of Mild Traumatic Brain Injury. 头部外侧撞击轻度脑外伤小鼠模型中的急性和可逆下丘脑症状
IF 1.8 Q3 CLINICAL NEUROLOGY Pub Date : 2024-08-08 eCollection Date: 2024-01-01 DOI: 10.1089/neur.2024.0071
Julie O'Reilly-Fong, Nick J Simpson, Zahra S Thirouin, Paolo A Bastone, Cristian Zaelzer, Anzala Murtaz, Charles W Bourque

Central autonomic and endocrine dysfunctions following traumatic brain injury (TBI) are believed to involve the hypothalamus; however, underlying mechanisms are unknown. Although chronic deficits might be caused by irreversible tissue damage, various neuroendocrine and autonomic symptoms are only observed transiently, suggesting they might result from a temporary alteration in the activity of hypothalamic neurons. We therefore examined if a mouse model of mild TBI could induce reversible autonomic phenotypes and cause acute changes in c-Fos expression within corresponding regions of the hypothalamus. Adult C57Bl/6 male mice were lightly anesthetized with isoflurane and subjected to TBI by lateral head impact using a Gothenburg impactor. Mice treated the same way, but without the head impact served as controls (shams). We monitored body weight and core body temperature by infrared thermography and performed immunohistochemistry against c-Fos in various regions of the hypothalamus. We determined that a projectile velocity of 9 m/s significantly delayed recovery from the anesthesia without inducing skull fractures and signs of discomfort disappeared within 3 h, as assessed by grimace scale. Compared with shams, TBI mice displayed a rapid decrease in core body temperature which resolved within 48 h. Daily body weight gain was also significantly lower in TBI mice on the day following injury but recovered thereafter. c-Fos analysis revealed a significantly higher density of c-Fos-positive cells in the paraventricular nucleus and a significantly lower density in the median preoptic nucleus and medial preoptic area. We conclude that mild TBI induced by a single lateral head impact in mice at 9 m/s produces acute and reversible symptoms associated with hypothalamic dysfunction accompanied by significant changes in c-Fos expression within relevant areas of the hypothalamus. These findings support the hypothesis that a temporary alteration of neuronal activity may underlie the expression of reversible central autonomic and neuroendocrine symptoms.

创伤性脑损伤(TBI)后出现的中枢自律神经和内分泌功能障碍被认为涉及下丘脑,但其潜在机制尚不清楚。虽然慢性功能障碍可能是由不可逆的组织损伤引起的,但各种神经内分泌和自律神经症状只是短暂出现,这表明它们可能是由下丘脑神经元活动的暂时性改变引起的。因此,我们研究了轻度创伤性脑损伤小鼠模型能否诱发可逆的自律神经表型,并引起下丘脑相应区域内c-Fos表达的急性变化。用异氟烷对成年 C57Bl/6 雄性小鼠进行轻度麻醉,然后用哥德堡撞击器对其头部进行侧面撞击,使其受到创伤性脑损伤。以同样的方法处理但不进行头部撞击的小鼠作为对照组(shams)。我们通过红外热成像监测体重和核心体温,并在下丘脑的不同区域进行了针对 c-Fos 的免疫组化。我们发现,9 米/秒的射弹速度可显著延迟麻醉的恢复,但不会导致颅骨骨折,而且根据面无表情量表的评估,不适症状在 3 小时内消失。c-Fos分析显示,脑室旁核中c-Fos阳性细胞的密度明显较高,而视前核中线和视前区内侧的c-Fos阳性细胞密度则明显较低。我们的结论是,小鼠头部单侧受到 9 米/秒速度的撞击而诱发的轻度创伤性脑损伤会产生与下丘脑功能障碍相关的急性和可逆症状,同时下丘脑相关区域的 c-Fos 表达也会发生显著变化。这些研究结果支持这样一种假设,即神经元活动的暂时性改变可能是可逆的中枢自主神经和神经内分泌症状表现的基础。
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引用次数: 0
Exercise Volume Can Modulate the Regenerative Response to Spinal Cord Injury in Mice. 运动量可调节小鼠脊髓损伤的再生反应
IF 1.8 Q3 CLINICAL NEUROLOGY Pub Date : 2024-07-31 eCollection Date: 2024-01-01 DOI: 10.1089/neur.2024.0023
Anne Caroline Rodrigues Dos Santos, Renata Pereira Laurindo, Fernanda Marques Pestana, Luiza Dos Santos Heringer, Nathalie Henrique Silva Canedo, Ana Maria Blanco Martinez, Suelen Adriani Marques

Traumatic spinal cord injury (SCI) causes debilitating motor and sensory deficits that impair functional performance, and physical rehabilitation is currently the only established therapeutic reality in the clinical setting. In this study, we aimed to assess the effect of exercise of different volume and timing of intervention on functional recovery and neuromuscular regeneration in a mouse model of compressive SCI. Mice were assigned to one of four groups: laminectomy only (SHAM); injured, without treadmill training (SCI); injured, treadmill trained for 10 min until day 56 postinjury (TMT1); and injured, treadmill trained for two 10-min cycles with a 10-min pause between them until day 28 postinjury followed by the TMT1 protocol until day 56 postinjury (TMT3). On day 7 postinjury, animals started an eight-week treadmill-training exercise protocol and were trained three times a week. TMT3 mice had the best results in terms of neuroregeneration, functional recovery, and muscle plasticity as measured by functional and morphometric parameters. In conclusion, the volume of exercise can modulate the quality of the regenerative response to injury, when started in the acute phase and adjusted according to the inflammatory window.

创伤性脊髓损伤(SCI)会导致衰弱的运动和感觉障碍,从而影响功能表现,而物理康复是目前临床上唯一确定的治疗方法。在这项研究中,我们旨在评估不同运动量和干预时机对压迫性脊髓损伤小鼠模型的功能恢复和神经肌肉再生的影响。小鼠被分配到四组中的一组:仅椎板切除术组(SHAM);受伤,未进行跑步机训练组(SCI);受伤,进行10分钟跑步机训练,直至伤后第56天组(TMT1);受伤,进行两次10分钟跑步机训练,中间停顿10分钟,直至伤后第28天,然后进行TMT1方案训练,直至伤后第56天组(TMT3)。受伤后第 7 天,动物开始为期八周的跑步机训练运动方案,每周训练三次。通过功能和形态参数测量,TMT3 小鼠在神经再生、功能恢复和肌肉可塑性方面的效果最好。总之,如果在急性期开始运动并根据炎症窗口期进行调整,运动量可以调节损伤再生反应的质量。
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引用次数: 0
Change in Enlarged Perivascular Spaces over Time and Associations with Outcomes After Traumatic Brain Injury. 扩大的血管周围间隙随时间的变化及与创伤性脑损伤后疗效的关系
IF 1.8 Q3 CLINICAL NEUROLOGY Pub Date : 2024-07-31 eCollection Date: 2024-01-01 DOI: 10.1089/neur.2024.0026
Alexa E Walter, Krupa Savalia, Jason Yoon, Justin Morrison, Andrea L C Schneider, Ramon Diaz-Arrastia, Danielle K Sandsmark

Enlarged perivascular spaces (EPVs) can be seen on magnetic resonance imaging (MRI) scans in various neurological diseases, including traumatic brain injury (TBI). EPVs have been associated with cognitive dysfunction and sleep disturbances; however, their clinical significance remains unclear. The goal of this study was to identify MRI burden of EPVs over time following TBI and to explore their relationship with postinjury outcomes. Individuals with TBI underwent postinjury data collection at Day 1 (blood), 2 weeks (blood, MRI, outcomes), and 6 months (blood, MRI, outcomes). EPV burden was assessed using T1 and FLAIR sequences on representative slices in the centrum semiovale, basal ganglia, and midbrain. Serum blood was assayed to measure concentrations of neurofilament light (NfL) and glial fibrillary acidic protein (GFAP). Thirty-two participants with TBI were included (mean age 36.8 years, 78% male, 50% White). Total EPVs count did not significantly change from 2 weeks (23.5 [95% confidence interval or CI = 22.0-32.0]) to 6 months (26.0 [95% CI = 22.0-30.0], p = 0.16). For self-reported measures of sleep, there were no significant associations between EPVs count and Insomnia Severity Index (2 weeks: β = -0.004; 95% CI = -0.094, 0.086; 6 months: β = 0.002; 95% CI = -0.122, 0.125) or the subset of sleep questions on the Rivermead Post-Concussion Symptoms Questionnaire (2 weeks: β = -0.005; 95% CI = -0.049, 0.039; 6 months: β = -0.019; 95% CI = -0.079, 0.042). Functional outcome, determined by 6 months incomplete recovery (Glasgow Outcome Scale-Extended [GOS-E < 8]) versus complete recovery (GOS-E = 8), was significantly associated with a higher number of EPVs at 2 weeks (odds ratio = 0.94, 95% CI = 0.88-0.99). Spearman correlations showed no significant relationship between EPVs count and GFAP or NfL. This study used commonly acquired MRI sequences to quantify EPVs and investigated their utility as a potential imaging biomarker in TBI. Given the minimal change in EPVs over time, this period may not be long enough for potential recovery or may indicate that EPVs are structural findings that do not significantly change over time.

在包括创伤性脑损伤(TBI)在内的各种神经系统疾病的磁共振成像(MRI)扫描中均可看到扩大的血管周围间隙(EPV)。EPV 与认知功能障碍和睡眠障碍有关,但其临床意义尚不清楚。本研究的目的是确定 TBI 后随着时间推移 EPV 的 MRI 负荷,并探讨其与伤后结果的关系。创伤性脑损伤患者在受伤后第 1 天(血液)、2 周(血液、核磁共振成像、结果)和 6 个月(血液、核磁共振成像、结果)接受了数据收集。使用 T1 和 FLAIR 序列对半脑中心、基底节和中脑的代表性切片进行 EPV 负荷评估。对血清进行化验,以测量神经丝光(NfL)和胶质纤维酸性蛋白(GFAP)的浓度。研究对象包括 32 名患有创伤性脑损伤的患者(平均年龄 36.8 岁,78% 为男性,50% 为白人)。从两周(23.5 [95% 置信区间或 CI = 22.0-32.0])到 6 个月(26.0 [95% CI = 22.0-30.0],p = 0.16),EPVs 总计数无明显变化。在自我报告的睡眠测量中,EPVs 计数与失眠严重程度指数(2 周:β = -0.004;95% CI = -0.094,0.086;6 个月:β = 0.002;95% CI = -0.094,0.086)或失眠严重程度指数(2 周:β = -0.004;95% CI = -0.094,0.086)之间没有显著关联。122,0.125)或 Rivermead 脑震荡后症状问卷中的睡眠问题子集(2 周:β = -0.005;95% CI = -0.049,0.039;6 个月:β = -0.019;95% CI = -0.079,0.042)。根据 6 个月未完全恢复(格拉斯哥结果量表扩展版 [GOS-E < 8])与完全恢复(GOS-E = 8)来判定的功能结果与 2 周时 EPV 数量较多有显著相关性(几率比 = 0.94,95% CI = 0.88-0.99)。斯皮尔曼相关性显示 EPVs 数量与 GFAP 或 NfL 之间无明显关系。本研究使用常见的 MRI 序列对 EPVs 进行量化,并研究其作为 TBI 潜在影像生物标记物的效用。鉴于EPV随时间的变化极小,这一时期可能不够长,不足以实现潜在的恢复,也可能表明EPV是结构性结果,不会随时间发生显著变化。
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引用次数: 0
Response of Central Nervous System Biomolecules and Systemic Biomarkers to Aerobic Exercise Following Concussion: A Scoping Review of Human and Animal Research. 脑震荡后中枢神经系统生物分子和系统生物标志物对有氧运动的反应:人类和动物研究范围综述》。
IF 1.8 Q3 CLINICAL NEUROLOGY Pub Date : 2024-07-29 eCollection Date: 2024-01-01 DOI: 10.1089/neur.2024.0062
Dean M Cordingley, Izabella Marquez, Serena C L Buchwald, Frederick A Zeiler

The purpose of this study was to identify the response of biomolecules and biomarkers that are associated with the central nervous system to aerobic exercise in human and pre-clinical models of concussion or mild traumatic brain injury (TBI), and to highlight the knowledge gaps in the literature. A systematic scoping review was conducted following a search of EMBASE, MEDLINE, SCOPUS, BIOSIS, and Cochrane Libraries performed on September 8, 2023 (from data base inception). The scoping review was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews. Duplicates were removed and article screening was performed using an online systematic review management system. The search resulted in a total of 2,449 articles being identified, with 14 articles meeting the inclusion/exclusion criteria and having their data extracted. One study was conducted in humans, while the remainder of identified studies utilized murine models. The current literature is limited and evaluated many different biomolecules and biomarkers with brain-derived neurotrophic factor being the most researched. Further studies on this topic are needed to better understand the biomarker response to exercise after concussion and mild TBI, especially in the human population.

本研究旨在确定人类和脑震荡或轻度脑损伤(TBI)临床前模型中与中枢神经系统相关的生物分子和生物标志物对有氧运动的反应,并强调文献中的知识空白。在 2023 年 9 月 8 日(从数据库开始)对 EMBASE、MEDLINE、SCOPUS、BIOSIS 和 Cochrane 图书馆进行检索后,进行了系统的范围界定综述。该范围界定综述按照《系统综述和元分析首选报告项目》(Preferred Reporting Items for Systematic Reviews and Meta-Analyses,PRISMA)的范围界定综述扩展标准进行报告。删除了重复内容,并使用在线系统综述管理系统进行了文章筛选。搜索结果共发现 2,449 篇文章,其中 14 篇符合纳入/排除标准并提取了数据。其中一项研究是在人体中进行的,其余已确定的研究则使用了小鼠模型。目前的文献有限,而且评估了许多不同的生物分子和生物标志物,其中研究最多的是脑源性神经营养因子。为了更好地了解生物标志物对脑震荡和轻度创伤性脑损伤后运动的反应,尤其是在人类人群中的反应,还需要对这一主题进行进一步的研究。
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引用次数: 0
Bayesian Methods: A Means of Improving Statistical Power in Preclinical Neurotrauma? 贝叶斯方法:提高临床前神经创伤统计能力的手段?
IF 1.8 Q3 CLINICAL NEUROLOGY Pub Date : 2024-07-16 eCollection Date: 2024-01-01 DOI: 10.1089/neur.2024.0028
Peyton M Mueller, Abel Torres-Espín, Cole Vonder Haar

The field of neurotrauma is grappling with the effects of the recently identified replication crisis. As such, care must be taken to identify and perform the most appropriate statistical analyses. This will prevent misuse of research resources and ensure that conclusions are reasonable and within the scope of the data. We anticipate that Bayesian statistical methods will see increasing use in the coming years. Bayesian methods integrate prior beliefs (or prior data) into a statistical model to merge historical information and current experimental data. These methods may improve the ability to detect differences between experimental groups (i.e., statistical power) when used appropriately. However, researchers need to be aware of the strengths and limitations of such approaches if they are to implement or evaluate these analyses. Ultimately, an approach using Bayesian methodologies may have substantial benefits to statistical power, but caution needs to be taken when identifying and defining prior beliefs.

神经创伤领域正在努力应对最近发现的复制危机的影响。因此,必须谨慎确定并执行最合适的统计分析。这将防止滥用研究资源,并确保结论合理且在数据范围之内。我们预计,贝叶斯统计方法将在未来几年得到越来越多的应用。贝叶斯方法将先验信念(或先验数据)整合到统计模型中,将历史信息和当前实验数据融合在一起。如果使用得当,这些方法可以提高检测实验组之间差异的能力(即统计能力)。不过,研究人员在实施或评估这些分析时,需要了解这些方法的优势和局限性。最终,使用贝叶斯方法可能会大大提高统计能力,但在确定和定义先验信念时需要谨慎。
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引用次数: 0
Predictors of 30-Day Mortality and Morbidity Following Craniotomy for Traumatic Brain Injury: An ACS NSQIP Database Analysis. 创伤性脑损伤开颅手术后 30 天死亡率和发病率的预测因素:ACS NSQIP 数据库分析。
IF 1.8 Q3 CLINICAL NEUROLOGY Pub Date : 2024-07-16 eCollection Date: 2024-01-01 DOI: 10.1089/neur.2024.0039
Jawad Turfa, Ali Hijazi, Yasser Fadlallah, Melhem El-Harati, Hani Dimassi, Marwan El Najjar

Traumatic brain injury (TBI) is the leading cause of death among trauma patients. Identifying preoperative factors that predict postoperative outcomes in such patients can guide surgical decision-making. The aim of this study was to develop a predictive model using preoperative variables that predicts 30-day mortality and morbidity in patients undergoing neurosurgery following TBI. The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database was queried between 2005 and 2017 for patients aged 18 years or older who underwent TBI-specific surgery. The primary outcome was 30-day mortality, and the secondary outcome was a composite morbidity score. Significant variables on univariate analysis with Chi-squared test were used to compute multivariable logistic regression models for both outcomes, and Hosmer-Lemeshow test was used. A total of 1634 patients met the inclusion criteria. Most patients were elderly aged >60 years (74.48%), male (63.59%), of White race (73.62%), and non-Hispanic ethnicity (82.44%). The overall 30-day mortality rate was 20.3%. Using multivariate logistic regression, 11 preoperative variables were significantly associated with 30-day mortality, including (aOR, 95% CI) age 70-79 years (3.38, 2.03-5.62) and age >80 years (7.70, 4.74-12.51), ventilator dependency (6.04, 4.21-8.67), receiving dialysis (4.97, 2.43-10.18), disseminated cancer (4.42, 1.50-13.0), and coma >24 hours (3.30, 1.40-7.80), among others. Similarly, 12 preoperative variables were found to be significantly associated with 30-day morbidity, including acute renal failure (7.10, 1.91-26.32), return to OR (3.82, 2.77-5.27), sepsis (3.27, 1.11-9.66), prior operation within 30 days (2.55, 1.06-4.95), and insulin-dependent diabetes (1.60, 1.06-2.40), among others. After constructing receiver operating characteristic curve, the model for mortality had an area under the curve (AUC) of 0.843, whereas composite morbidity had an AUC of 0.716. This model can aid in clinical decision-making for triaging patients based on prognosis in cases of mass casualty events.

创伤性脑损伤(TBI)是导致创伤患者死亡的主要原因。确定能预测此类患者术后结果的术前因素可以为手术决策提供指导。本研究旨在利用术前变量建立一个预测模型,以预测接受神经外科手术的 TBI 患者 30 天的死亡率和发病率。研究人员查询了美国外科学院国家外科质量改进计划(ACS NSQIP)数据库,该数据库在 2005 年至 2017 年期间收录了年龄在 18 岁以上、接受 TBI 特异性手术的患者。主要结果是30天死亡率,次要结果是综合发病率评分。通过卡方检验进行单变量分析后发现的显著变量被用于计算这两项结果的多变量逻辑回归模型,并使用Hosmer-Lemeshow检验。共有 1634 名患者符合纳入标准。大多数患者为年龄大于 60 岁的老年人(74.48%)、男性(63.59%)、白人(73.62%)和非西班牙裔(82.44%)。30 天总死亡率为 20.3%。通过多变量逻辑回归,11 个术前变量与 30 天死亡率显著相关,包括(aOR,95% CI)年龄 70-79 岁(3.38,2.03-5.62)和年龄大于 80 岁(7.70,4.74-12.51)、呼吸机依赖(6.04,4.21-8.67)、接受透析(4.97,2.43-10.18)、播散性癌症(4.42,1.50-13.0)和昏迷 >24 小时(3.30,1.40-7.80)等。同样,有 12 个术前变量与 30 天内的发病率显著相关,包括急性肾功能衰竭(7.10,1.91-26.32)、重返手术室(3.82,2.77-5.27)、败血症(3.27,1.11-9.66)、30 天内曾做过手术(2.55,1.06-4.95)和胰岛素依赖型糖尿病(1.60,1.06-2.40)等。构建接收者操作特征曲线后,死亡率模型的曲线下面积(AUC)为 0.843,而复合发病率的曲线下面积(AUC)为 0.716。该模型有助于在大规模伤亡事件中根据预后对患者进行分流的临床决策。
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引用次数: 0
The Influence of CYP2B6 Variants and Administration of Propofol on Patient Outcomes after Traumatic Brain Injury. CYP2B6 变异和丙泊酚的施用对创伤性脑损伤后患者预后的影响。
IF 1.8 Q3 CLINICAL NEUROLOGY Pub Date : 2024-07-16 eCollection Date: 2024-01-01 DOI: 10.1089/neur.2024.0025
Katherine O'Meara, Ava M Puccio, Dianxu Ren, Sandra Deslouches, Ruchira Jha, David O Okonkwo, Yvette P Conley

Management of severe traumatic brain injury (sTBI) typically involves the use of sedation, which inherently results in benefits and risks. The cytochrome P450 enzyme CYP2B6 is involved in the biotransformation of particular drug classes, including many intravenous sedatives. Variants of the CYP2B6 gene can lead to decreased systemic clearance of some sedatives, including propofol. This study aimed to investigate the relationship of CYP2B6 gene variation and patient outcomes after TBI while also considering propofol administration. Patients who sustained a non-penetrating sTBI and admitted to a single-center Level 1 trauma hospital were included in this study (n = 440). The *6 functional allele of CYP2B6 that leads to reduced enzyme expression and activity required genotyping two single nucleotide polymorphisms, rs3745274 and rs2279343. Patient outcomes were evaluated using the Glasgow Outcome Scale (GOS) and Disability Rating Scale (DRS) at 3 and 6 months post-injury. Data on sedative administration were abstracted from medical records. Individuals homozygous for the alleles coding for the reduced enzyme expression and activity were more likely to have worse outcomes. A relationship between propofol administration and 3-month GOS and 6-month DRS was noted when controlling for CYP2B6 genotype. These findings suggest that genetic variation in CYP2B6 may influence the impact of intravenous sedation on patient outcomes after TBI and warrants further investigation.

严重创伤性脑损伤(sTBI)的治疗通常需要使用镇静剂,而镇静剂本身既有好处也有风险。细胞色素 P450 酶 CYP2B6 参与了特定药物类别的生物转化,包括许多静脉注射镇静剂。CYP2B6 基因的变异可导致某些镇静剂(包括异丙酚)的全身清除率降低。本研究旨在调查 CYP2B6 基因变异与创伤性脑损伤后患者预后的关系,同时还考虑了异丙酚的用药情况。本研究纳入了在单中心一级创伤医院住院的非穿透性 sTBI 患者(n = 440)。CYP2B6的*6功能等位基因会导致酶的表达和活性降低,因此需要对rs3745274和rs2279343这两个单核苷酸多态性进行基因分型。采用格拉斯哥结果量表(GOS)和残疾评定量表(DRS)对伤后 3 个月和 6 个月的患者结果进行评估。镇静剂用药数据摘自医疗记录。编码酶表达和活性降低的等位基因的同卵个体更有可能出现较差的预后。在控制 CYP2B6 基因型的情况下,丙泊酚用药与 3 个月的 GOS 和 6 个月的 DRS 之间存在关系。这些研究结果表明,CYP2B6的基因变异可能会影响静脉镇静对创伤性脑损伤后患者预后的影响,值得进一步研究。
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引用次数: 0
Effect-Size Discrepancies in Literature Versus Raw Datasets from Experimental Spinal Cord Injury Studies: A CLIMBER Meta-Analysis. 文献与脊髓损伤实验研究原始数据集的效应大小差异:CLIMBER Meta 分析。
IF 1.8 Q3 CLINICAL NEUROLOGY Pub Date : 2024-07-16 eCollection Date: 2024-01-01 DOI: 10.1089/neur.2024.0038
Emma G Iorio, Alireza Khanteymoori, Kenneth A Fond, Anastasia V Keller, Lex Maliga Davis, Jan M Schwab, Adam R Ferguson, Abel Torres-Espin, Ralf Watzlawick

Translation of spinal cord injury (SCI) therapeutics from pre-clinical animal studies into human studies is challenged by effect size variability, irreproducibility, and misalignment of evidence used by pre-clinical versus clinical literature. Clinical literature values reproducibility, with the highest grade evidence (class 1) consisting of meta-analysis demonstrating large therapeutic efficacy replicating across multiple studies. Conversely, pre-clinical literature values novelty over replication and lacks rigorous meta-analyses to assess reproducibility of effect sizes across multiple articles. Here, we applied modified clinical meta-analysis methods to pre-clinical studies, comparing effect sizes extracted from published literature to raw data on individual animals from these same studies. Literature-extracted data (LED) from numerical and graphical outcomes reported in publications were compared with individual animal data (IAD) deposited in a federally supported repository of SCI data. The animal groups from the IAD were matched with the same cohorts in the LED for a direct comparison. We applied random-effects meta-analysis to evaluate predictors of neuroconversion in LED versus IAD. We included publications with common injury models (contusive injuries) and standardized end-points (open field assessments). The extraction of data from 25 published articles yielded n = 1841 subjects, whereas IAD from these same articles included n = 2441 subjects. We observed differences in the number of experimental groups and animals per group, insufficient reporting of dropout animals, and missing information on experimental details. Meta-analysis revealed differences in effect sizes across LED versus IAD stratifications, for instance, severe injuries had the largest effect size in LED (standardized mean difference [SMD = 4.92]), but mild injuries had the largest effect size in IAD (SMD = 6.06). Publications with smaller sample sizes yielded larger effect sizes, while studies with larger sample sizes had smaller effects. The results demonstrate the feasibility of combining IAD analysis with traditional LED meta-analysis to assess effect size reproducibility in SCI.

脊髓损伤(SCI)疗法从临床前动物研究转化为人体研究面临着效应大小可变性、不可再现性以及临床前文献与临床文献所用证据不一致的挑战。临床文献重视可重复性,最高级别的证据(1 级)由荟萃分析组成,可在多项研究中重复显示巨大的疗效。相反,临床前文献重视新颖性而非重复性,缺乏严格的荟萃分析来评估多篇文章中效应大小的重复性。在此,我们将修改后的临床荟萃分析方法应用于临床前研究,比较了从已发表文献中提取的效应大小与这些相同研究中的动物个体原始数据。我们将从出版物中报告的数字和图表结果中提取的文献数据(LED)与存放在联邦政府支持的 SCI 数据库中的动物个体数据(IAD)进行了比较。IAD 中的动物组群与 LED 中的相同组群相匹配,以便进行直接比较。我们采用随机效应荟萃分析来评估 LED 与 IAD 中神经转换的预测因素。我们纳入了具有共同损伤模型(挫伤)和标准化终点(开放场地评估)的出版物。从 25 篇已发表的文章中提取的数据得出了 n = 1841 个受试者,而从这些相同的文章中提取的 IAD 数据则得出了 n = 2441 个受试者。我们观察到实验组和每组动物数量的差异、对辍学动物报告的不足以及实验细节信息的缺失。Meta 分析显示,LED 与 IAD 分层的效应大小存在差异,例如,重度损伤在 LED 中的效应大小最大(标准化平均差 [SMD = 4.92]),但轻度损伤在 IAD 中的效应大小最大(SMD = 6.06)。样本量较小的文献产生的效应大小较大,而样本量较大的研究产生的效应较小。结果表明,将IAD分析与传统的LED荟萃分析相结合来评估SCI的效应大小再现性是可行的。
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引用次数: 0
Applying Dynamical Systems Theory to Improve Personalized Medicine Following Mild Traumatic Brain Injury. 应用动态系统理论改进轻度脑外伤后的个性化医疗。
IF 1.8 Q3 CLINICAL NEUROLOGY Pub Date : 2024-07-16 eCollection Date: 2024-01-01 DOI: 10.1089/neur.2024.0040
Shawn R Eagle, Rebecca J Henry

A sizable proportion of patients with mild traumatic brain injury (mTBI) have persistent symptoms and functional impairments months to years following injury. This phenomenon is continually observed despite an explosion of research and interest in improving mTBI clinical outcomes over the last two decades. All pharmacological clinical trials to date have failed to demonstrate improved outcomes for mTBI. One possible explanation for these continued failures is an overly myopic approach to treating mTBI (i.e., testing the effect of a single drug with a specific mechanism on a group of people with highly heterogenous injuries). Clinical presentation and prognosis of mTBI vary considerably between patients, and yet we continue to assess group-level effects of a homogenized treatment. We need to utilize an equally complex treatment approach to match the extraordinary complexity of the human brain. Dynamical systems theory has been used to describe systems composed of multiple subsystems who function somewhat independently but are ultimately interconnected. This theory was popularized in the motor control literature as an overarching framework for how the mind and body connect to interact and move through the environment. However, the human body can be viewed as a dynamical system composed of multiple subsystems (i.e., organ systems) who have isolated functions, which are also codependent on the health and performance of other interconnected organ systems. In this perspective piece, we will use the example of mTBI in the obese patient to demonstrate how broadening our approach to treatment of the individual (and not necessarily the injury) may ultimately yield improved outcomes. Furthermore, we will explore clinical and pre-clinical evidence demonstrating multiple system interactions in the context of obesity and TBI and discuss how expanding our understanding of the mechanistic interplay between multiple organ systems may ultimately provide a more personalized treatment approach for this mTBI patient subpopulation.

相当一部分轻度脑外伤(mTBI)患者在伤后数月至数年仍有持续的症状和功能障碍。尽管在过去二十年中,人们对改善 mTBI 临床疗效的研究和兴趣呈爆炸式增长,但这种现象仍持续存在。迄今为止,所有药物临床试验都未能证明 mTBI 的治疗效果有所改善。对这些持续失败的一个可能解释是,治疗 mTBI 的方法过于近视(即测试具有特定机制的单一药物对具有高度异质性损伤的人群的影响)。不同患者的 mTBI 临床表现和预后差异很大,但我们仍在继续评估同质化治疗的群体效应。我们需要采用同样复杂的治疗方法,以适应人类大脑的非凡复杂性。动态系统理论被用来描述由多个子系统组成的系统,这些子系统在一定程度上独立运行,但最终又相互联系。这一理论在运动控制文献中广为流传,被作为身心如何在环境中互动和运动的总体框架。然而,人体可以被视为一个由多个子系统(即器官系统)组成的动态系统,这些子系统具有各自独立的功能,同时也依赖于其他相互关联的器官系统的健康和性能。在这篇透视文章中,我们将以肥胖患者的 mTBI 为例,说明我们如何拓宽治疗个体(而不一定是损伤)的方法,从而最终改善治疗效果。此外,我们还将探讨肥胖和创伤性脑损伤背景下多系统相互作用的临床和临床前证据,并讨论如何扩大我们对多个器官系统之间机理相互作用的理解,最终为这一创伤性脑损伤患者亚群提供更加个性化的治疗方法。
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引用次数: 0
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