Neuroimaging with Rotterdam Scoring System and long-term outcomes in severe traumatic brain injury patients.

PURPOSE: The Rotterdam Scoring System (RSS) attempts to prognosticate early mortality and early functional outcome in patients with traumatic brain injury (TBI) based on non-contrast head computed tomography (CT) imaging findings. The purpose of this study was to identify the relationship between RSS scores and long-term outcomes in patients with severe TBI. METHODS: Consecutively treated patients with severe TBI enrolled between 2008 and 2011, in the prospective, observational, Brain Trauma Research Center database were included. The Glasgow Outcome Scale (GOS) was used to measure long-term functional outcomes at three, six, 12, and 24 months. GOS scores were categorized into favorable (GOS = 4-5) and unfavorable (GOS = 1-3) outcomes. RSS scores were calculated at the time of image acquisition. RESULTS: Of the 89 patients included, 74 (83.4%) were male, 81 (91.0%) were Caucasian, and the mean age of the cohort was 41.9 ± 18.5 years old. Patients with an RSS score of 3 and lower were more likely to have a favorable outcome with increased survival rates than patients with RSS scores greater than 3. CONCLUSIONS: The RSS score determined on the head CT scan acquired at admission in a cohort of patients with severe TBI correlated with long-term survival and functional outcomes up to two years following injury.

Percutaneous glycerol rhizolysis of the trigeminal ganglion for the treatment of idiopathic and classic trigeminal neuralgia: Outcomes and complications.

BACKGROUND AND PURPOSE: Patients with idiopathic trigeminal neuralgia (TN) with absent arterial contact or venous contact only and classic TN with morphological changes of the trigeminal nerve secondary to venous compression are not routinely recommended microvascular decompression at our institution. In patients with these anatomical subtypes of TN, limited data exists describing the outcomes of percutaneous glycerol rhizolysis (PGR) of the trigeminal ganglion (TG). METHODS: We performed a retrospective single-center cohort study and analyzed outcomes and complications after PGR of the TG. Clinical outcome after PGR of the TG was assessed via the Barrow Neurological Institute (BNI) Pain Scale. RESULTS: Forty-five patients underwent a total of 66 PGRs of the TG. At short-term follow-up, 58 procedures (87.9%) resulted in a BNI score of I (i.e., freedom from pain without medication). At a median follow-up of 3.07 years, 18 procedures (27.3%) resulted in a BNI score of I, 12 procedures (18.1%) resulted in BNI score of IIIa, and 36 procedures (54.5%) resulted in a BNI score of IIIb-V. The median length of freedom from pain without medication was 1.5 years. Eighteen procedures (27.3%) caused hypesthesia and two (3.0%) caused paresthesias. There were no serious complications. CONCLUSION: In patients with these anatomical subtypes of TN there was a high rate of short-term pain relief for the first 1-2 years and thereafter a large proportion of patients experienced pain relapse. In this patient group, PGR of the TG represents a safe procedure that is efficacious in the short term.

The Cardiovascular Cost of Silence: Relationships Between Self-silencing and Carotid Atherosclerosis in Midlife Women.

BACKGROUND: Individuals engage in a range of behaviors to maintain close relationships. One behavior is self-silencing or inhibiting self-expression to avoid relationship conflict or loss. Self-silencing is related to poor mental health and self-reported physical health in women but has not been examined in relation to cardiovascular health, particularly using direct measures of the vasculature. PURPOSE: To test associations between self-silencing and carotid atherosclerosis in midlife women; secondary analyses examined moderation by race/ethnicity. METHODS: Women (N = 290, ages 40-60) reported on self-silencing in intimate relationships and underwent physical measurements, blood draw, and ultrasound assessment of carotid intima-media thickness (IMT) and plaque. Associations between self-silencing and mean IMT and plaque index (0, 1, ≥2) were tested in linear regression and multinomial logistic regression models, respectively, followed by interaction terms between self-silencing and race, adjusted for demographic factors, CVD risk factors, partner status, depression, physical activity, and diet. RESULTS: Forty-seven percent of women demonstrated carotid plaque. Greater self-silencing was related to increased odds of plaque index ≥2 (e.g., for each additional point, odds ratio [95% confidence interval] = 1.16 [1.03-1.31], p = .012), relative to no plaque). Moderation analyses indicated that self-silencing was related to odds of plaque index ≥2 in non-white women (1.15 [1.05-1.26], p = .004), but there was no significant relationship in white women (1.01 [0.97-1.06], p = .550). No associations emerged for IMT. CONCLUSIONS: Among midlife women, self-silencing was associated with carotid plaque, independent of CVD risk factors, depression, and health behaviors. Emotional expression in relationships may be important for women's cardiovascular health.

Prevalence and severity of neurovascular compression in hemifacial spasm patients.

Hemifacial spasm is typically caused by vascular compression of the proximal intracranial facial nerve. Although the prevalence of neurovascular compression has been investigated in a cohort of patients with classical trigeminal neuralgia, the prevalence and severity of neurovascular compression has not been well characterized in patients with hemifacial spasm. We aimed to investigate whether presence and severity of neurovascular compression are correlated to the symptomatic side in patients with hemifacial spasm. All patients in our study were evaluated by a physician who specializes in the management of cranial nerve disorders. Once hemifacial spasm was diagnosed on physical exam, the patient underwent a dedicated cranial nerve protocol magnetic resonance imaging study on a 3 T scanner. Exams were retrospectively reviewed by a neuroradiologist blinded to the symptomatic side. The presence, severity, vessel type, and location of neurovascular compression along the facial nerve was recorded. Neurovascular compression was graded as contact alone (vessel touching the facial nerve) versus deformity (indentation or deviation of the nerve by the culprit vessel). A total of 330 patients with hemifacial spasm were included. The majority (232) were female while the minority (98) were male. The average age was 55.7 years. Neurovascular compression (arterial) was identified on both the symptomatic (97.88%) and asymptomatic sides (38.79%) frequently. Neurovascular compression from an artery along the susceptible/proximal portion of the nerve was much more common on the symptomatic side (96.36%) than on the asymptomatic side (12.73%), odds ratio = 93.00, P < 0.0001. When we assessed severity of arterial compression, the more severe form of neurovascular compression, deformity, was noted on the symptomatic side (70.3%) much more frequently than on the asymptomatic side (1.82%) (odds ratio = 114.00 P < 0.0001). We conclude that neurovascular compression that results in deformity of the susceptible portion of the facial nerve is highly associated with the symptomatic side in hemifacial spasm.

Mutant huntingtin disrupts mitochondrial proteostasis by interacting with TIM23.

Mutant huntingtin (mHTT), the causative protein in Huntington's disease (HD), associates with the translocase of mitochondrial inner membrane 23 (TIM23) complex, resulting in inhibition of synaptic mitochondrial protein import first detected in presymptomatic HD mice. The early timing of this event suggests that it is a relevant and direct pathophysiologic consequence of mHTT expression. We show that, of the 4 TIM23 complex proteins, mHTT specifically binds to the TIM23 subunit and that full-length wild-type huntingtin (wtHTT) and mHTT reside in the mitochondrial intermembrane space. We investigated differences in mitochondrial proteome between wtHTT and mHTT cells and found numerous proteomic disparities between mHTT and wtHTT mitochondria. We validated these data by quantitative immunoblotting in striatal cell lines and human HD brain tissue. The level of soluble matrix mitochondrial proteins imported through the TIM23 complex is lower in mHTT-expressing cell lines and brain tissues of HD patients compared with controls. In mHTT-expressing cell lines, membrane-bound TIM23-imported proteins have lower intramitochondrial levels, whereas inner membrane multispan proteins that are imported via the TIM22 pathway and proteins integrated into the outer membrane generally remain unchanged. In summary, we show that, in mitochondria, huntingtin is located in the intermembrane space, that mHTT binds with high-affinity to TIM23, and that mitochondria from mHTT-expressing cells and brain tissues of HD patients have reduced levels of nuclearly encoded proteins imported through TIM23. These data demonstrate the mechanism and biological significance of mHTT-mediated inhibition of mitochondrial protein import, a mechanism likely broadly relevant to other neurodegenerative diseases.

Clinical outcomes of reverse total shoulder arthroplasty for elective indications versus acute 3- and 4-part proximal humeral fractures: a systematic review and meta-analysis.

BACKGROUND: Reverse total shoulder arthroplasty (RTSA) has continued to increase in clinical utility and popularity as an effective treatment for cuff tear arthropathy (CTA), irreparable rotator cuff tears (RCTs), osteoarthritis, and acute 3- and 4-part proximal humeral fractures. Performing RTSA for acute proximal humeral fractures presents the unique challenges of tuberosity management, bone loss, and instability compared with elective indications such as CTA or irreparable RCTs. The purpose of this study was to compare the clinical outcomes, active range of motion (ROM), radiographic outcomes, and complications between patients undergoing elective RTSA (RTSA-E) and those undergoing RTSA for fracture (RTSA-F). METHODS: A systematic review of the literature was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. We queried 3 electronic databases (Embase, Cochrane, and PubMed) using the search term "reverse" AND "shoulder" AND "arthroplasty." Studies investigating the clinical outcomes of RTSA for traumatic and/or elective indications were included. Studies were excluded if they included RTSA performed for fracture sequelae, inflammatory arthritis, post-traumatic osteoarthritis, or avascular necrosis. Data collected included patient demographic characteristics, subjective outcome measurements, ROM, and complications. The pooled means and proportions along with their 95% confidence intervals were generated by a random-effects model that incorporated the between-study variations in weighting. RESULTS: A total of 134 studies (11,651 shoulders) investigating the clinical outcomes of RTSA-E patients and 66 studies (3117 shoulders) investigating RTSA-F patients were included in this systematic review. Analysis of patient-reported outcomes demonstrated that RTSA-F patients experienced significantly lower Constant scores than RTSA-E patients; however, relative Constant scores, Simple Shoulder Test scores, Disabilities of the Arm, Shoulder and Hand scores, American Shoulder and Elbow Surgeons scores, and visual analog scale pain scores were similar. RTSA-F patients also had significantly lower forward elevation, abduction, and external rotation. RTSA-F patients experienced tuberosity complications at a significantly higher rate than RTSA-E patients (25.9% vs. 4.1%). There was no significant difference between the 2 groups in terms of other complications such as heterotopic ossification, radiographic loosening, revision, nerve injury, postoperative stiffness, infection, dislocation, and component loosening. DISCUSSION: RTSA performed for acute 3- and 4-part proximal humeral fractures yields overall worse clinical outcomes and active ROM compared with RTSA performed for elective indications including CTA, massive irreparable RCTs, and osteoarthritis with deformity. Tuberosity healing may be a major contributing factor to the difference in clinical outcomes. In the setting of RTSA-F, patient and surgeon expectations may need to be tempered and appropriate measures undertaken to optimize tuberosity healing.

Cardiac-induced cerebral pulsatility, brain structure, and cognition in middle and older-aged adults.

Changes of cardiac-induced regional pulsatility can be associated with specific regions of brain volumetric changes, and these are related with cognitive alterations. Thus, mapping of cardiac pulsatility over the entire brain can be helpful to assess these relationships. A total of 108 subjects (age: 66.5 ± 8.4 years, 68 females, 52 healthy controls, 11 subjective cognitive decline, 17 impaired without complaints, 19 MCI and 9 AD) participated. The pulsatility map was obtained directly from resting-state functional MRI time-series data at 3T. Regional brain volumes were segmented from anatomical MRI. Multidomain neuropsychological battery was performed to test memory, language, attention and visuospatial construction. The Montreal Cognitive Assessment (MoCA) was also administered. The sparse partial least square (SPLS) method, which is desirable for better interpreting high-dimensional variables, was applied for the relationship between the entire brain voxels of pulsatility and 45 segmented brain volumes. A multiple holdout SPLS framework was used to optimize sparsity for assessing the pulsatility-volume relationship model and to test the reliability by fitting the models to 9 different splits of the data. We found statistically significant associations between subsets of pulsatility voxels and subsets of segmented brain volumes by rejecting the omnibus null hypothesis (any of 9 splits has p < 0.0056 (=0.05/9) with the Bonferroni correction). The pulsatility was positively associated with the lateral ventricle, choroid plexus, inferior lateral ventricle, and 3rd ventricle and negatively associated with hippocampus, ventral DC, and thalamus volumes for the first pulsatility-volume relationship. The pulsatility had an additional negative relationship with the amygdala and brain stem volumes for the second pulsatility-volume relationship. The spatial distribution of correlated pulsatility was observed in major feeding arteries to the brain regions, ventricles, and sagittal sinus. The indirect mediating pathways through the volumetric changes were statistically significant between the pulsatility and multiple cognitive measures (p < 0.01). Thus, the cerebral pulsatility, along with volumetric measurements, could be a potential marker for better understanding of pathophysiology and monitoring disease progression in age-related neurodegenerative disorders.

Association of Preoperative Visual Hallucinations With Cognitive Decline After Deep Brain Stimulation for Parkinson's Disease.

OBJECTIVE: Deep brain stimulation (DBS) is effective for the motor symptoms of Parkinson's disease (PD). Although most patients benefit with minimal cognitive side effects, cognitive decline is a risk, and there is little available evidence to guide preoperative risk assessment. Visual illusions or visual hallucinations (VHs) and impulse-control behaviors (ICBs) are relatively common complications of PD and its treatment and may be a marker of more advanced disease, but their relationship with postoperative cognition has not been established. The authors aimed to determine whether any preoperative history of VHs or ICBs is associated with cognitive change after DBS. METHODS: Retrospective chart review identified 54 patients with PD who received DBS of the subthalamic nucleus or globus pallidus internus and who completed both pre- and postoperative neuropsychological testing. Linear regression models were used to assess whether any preoperative history of VHs or ICBs was associated with changes in attention, executive function, language, memory, or visuospatial cognitive domains while controlling for surgical target and duration between evaluations. RESULTS: The investigators found that a history of VHs was associated with declines in attention (b=-4.04, p=0.041) and executive function (b=-4.24, p=0.021). A history of ICBs was not associated with any significant changes. CONCLUSIONS: These results suggest that a history of VHs may increase risk of cognitive decline after DBS; thus, specific preoperative counseling and targeted remediation strategies for these patients may be indicated. In contrast, a history of ICBs does not appear to be associated with increased cognitive risk.

Everyday Discrimination Prospectively Predicts Blood Pressure Across 10 Years in Racially/Ethnically Diverse Midlife Women: Study of Women's Health Across the Nation.

BACKGROUND: Interpersonal discrimination is linked to greater risk for cardiovascular disease (CVD) and this association varies by race/ethnicity. PURPOSE: To examine whether exposure to everyday discrimination prospectively predicts elevated blood pressure (BP), whether this association differs by race/ethnicity, and is mediated by adiposity indices. METHODS: Using data for 2,180 self-identified White, Black, Chinese, Japanese, and Hispanic participants from the Study of Women's Health Across the Nation, we examined associations among exposure to (higher vs. lower) everyday discrimination at baseline and BP and hypertension (HTN; systolic blood pressure [SBP] ≥ 140 mmHg; diastolic blood pressure [DBP] ≥ 90 mmHg; or self-reported HTN medication use) risk over a 10 year period. Additionally, we used the bootstrap method to assess repeated, time-varying markers of central and overall adiposity (waist circumference and body mass index [BMI] (kg/m2), respectively) as potential mediators. RESULTS: Exposure to everyday discrimination predicted increases in SBP and DBP over time, even after adjusting for known demographic, behavioral, or medical risk factors. However, greater waist circumference or BMI (examined separately) mediated these observations. Notably, there were no racial/ethnic differences in the observed association and HTN risk was not predicted. CONCLUSIONS: The current findings suggest that everyday discrimination may contribute to elevated BP over time in U.S. women, in part, through increased adiposity. These findings demonstrate the complexity of the linkage of discrimination to CVD risk and raise the need to closely examine biobehavioral pathways that may serve as potential mediators.

Comparison of Quantitative and Qualitative Oxygen Extraction Fraction (OEF) in Acute Stroke Patients with Large Vessel Occlusion.

The superficial temporal artery-middle cerebral artery bypass (STA-MCA) bypass surgery developed by Donaghy and Yarsagil in 1967 provided relief for patients with acute stroke and large vessel occlusive vascular disease. Early reports showed low morbidity and good outcomes. However, a large clinical trial in 1985 reported a failure of extracranial-intracranial (EC/IC) bypass to show benefit in reducing the risk of stroke compared to best medical treatment. Problems with the study included cross overs to surgery from best medical treatment, patients unwilling to be randomized and chose EC/IC surgery, and loss of patients to follow-up. Most egregious is the fact that the study did not attempt to identify and select the patients at high risk for a second stroke. Based on these shortcomings of the EC/IC bypass study, a carotid occlusion surgery study (COSS) was proposed by Dr. William Powers and colleagues using qualitative hemispheric oxygen extraction fraction (OEF) by positron emission tomography (PET) between the contralateral and ipsilateral hemispheres with a ratio of 1.16 indicative of hemodynamic compromise. To increase patient enrollment, several compromises were made mid study. First. The ratio threshold was lowered to 1.12 and the level of occlusion in the carotid reduced from 70% to 60%. Despite these compromises the study was closed for futility, apparently because the stroke rate in the medically treated group was too low. Thus, the question as to the benefit of EC/IC bypass surgery remains unresolved. In our NIH funded study Quantitative Occlusive Vascular Disease Study (QUOVADIS), we used quantitative OEF to evaluate stroke risk and compared it to the qualitative count-rate ratio method used in the COSS study and found that these two methods did not identify the same patients at increased risk for stroke, which may explain the reason for the failure of the COSS study as our results show that qualitative OEF ratios do not identify the same patients as quantitative OEF.

Are Optimism and Cynical Hostility Associated with Smoking Cessation in Older Women?

BACKGROUND: Optimism and cynical hostility independently predict morbidity and mortality in Women's Health Initiative (WHI) participants and are associated with current smoking. However, their association with smoking cessation in older women is unknown. PURPOSE: The purpose of this study is to test whether optimism (positive future expectations) or cynical hostility (mistrust of others) predicts smoking cessation in older women. METHODS: Self-reported smoking status was assessed at years 1, 3, and 6 after study entry for WHI baseline smokers who were not missing optimism or cynical hostility scores (n = 10,242). Questionnaires at study entry assessed optimism (Life Orientation Test-Revised) and cynical hostility (Cook-Medley, cynical hostility subscale). Generalized linear mixed models adjusted for sociodemographics, lifestyle factors, and medical and psychosocial characteristics including depressive symptoms. RESULTS: After full covariate adjustment, optimism was not related to smoking cessation. Each 1-point increase in baseline cynical hostility score was associated with 5% lower odds of cessation over 6 years (OR = 0.95, CI = 0.92-0.98, p = 0.0017). CONCLUSIONS: In aging postmenopausal women, greater cynical hostility predicts lower smoking cessation over time. Future studies should examine whether individuals with this trait may benefit from more intensive cessation resources or whether attempting to mitigate cynical hostility itself may aid smoking cessation.

Outcomes of Spoke-Retained Telestroke Patients Versus Hub-Treated Patients After Intravenous Thrombolysis: Telestroke Patient Outcomes After Thrombolysis.

BACKGROUND AND PURPOSE: The outcomes of patients remaining at a community spoke hospital after tissue-type plasminogen activator treatment via telemedicine are unclear. Our aim was to compare medical outcomes between these patients and those treated at a hub stroke center. METHODS: We retrospectively examined patient medical records from 2006 to 2014 of 272 consecutive patients treated with intravenous tissue-type plasminogen activator at University of Pittsburgh Medical Center (UPMC) Presbyterian Hospital, a telestroke hub, and 134 consecutive patients treated after telemedicine consultation at 5 UPMC spoke hospitals, who then remained at these hospitals (drip-and-stay). Complications included mortality, length of stay, and common poststroke medical complications. We performed multivariate analysis to identify complications that are independently increased or decreased in the drip-and-stay population. We also performed a Cox proportional hazards regression to compare long-term survival. RESULTS: The drip-and-stay patients had less severe strokes (National Institutes of Health Stroke Scale score, 9.5±5.9 versus 12.7±7.1; P<0.001) and fewer large vessel occlusions (11.9% versus 36%; P<0.001). After controlling for all variables with multivariate analysis, we found that the drip-and-stay patients had an increased risk of adjusted in-hospital mortality (adjusted odds ratio 11.046; 95% confidence interval, 2.785­43.810) and having a length of stay >6 days (adjusted odds ratio, 4.696, 95% confidence interval, 2.428­9.083) [corrected]. Furthermore, the drip-and-stay patients had significantly decreased long-term survival compared with the hub patients (P<0.001). CONCLUSIONS: Despite having less severe strokes, the drip-and-stay patients had an increased adjusted risk of in-hospital mortality, longer length of stay, and lower long-term survival than hub hospital patients. Further studies are needed to confirm the findings and address differences in post-tissue-type plasminogen activator medical care.

Pediatric Cranial Vault Fractures: Analysis of Demographics, Injury Patterns, and Factors Predictive of Mortality.

BACKGROUND: Pediatric cranial vault fractures are a unique subset of injuries that pose distinct management and treatment challenges. They are anatomically distinct from their adult counterparts with potential implications on the development of the brain and craniofacial skeleton, and require unique considerations for management and treatment outcomes.A detailed analysis of the characteristics and outcomes of pediatric cranial vault fractures remains understudied in this population. Thus, the aim of this study was to characterize the demographics, injury patterns, operative interventions, concomitant injuries, and factors predictive of mortality in pediatric patients sustaining cranial vault fractures. METHODS: A retrospective review of patients less than 18 years of age presenting to the emergency department of a pediatric level I trauma center between 2000 and 2005 with skull fractures was performed. All patients were included regardless of treating specialty, treatment modality, or inpatient status. Patients were stratified into 3 groups (age < = 5 yrs, 5.1-11 yrs, and >11 yrs). ZIP codes were mapped using ArcGIS 10.2 Software (ESRI Inc, Redlands, CA) with ZIP code shapefiles from ESRI's ArcGIS Online. Socioeconomic and demographic variables at the ZIP code level were linked to each geocoded location using the United States Census Bureau summary files, and spatial clusters of injury were performed using GeoDa to conduct a test of local indicator of spatial autocorrelation. Statistical analysis was performed using the SPSS version 17 (SPSS Inc, Chicago, IL). RESULTS: A total of 923 consecutive patients met the inclusion criteria for the study. Caucasian (P < 0.001) males (P = 0.055) were most likely to sustain cranial vault fractures. The average age at injury was 5.97 years. Falls (53.7%) were the most common cause of injury across all age groups, followed by collisions (20.8%), with falls being more common in the youngest age group (< = 5 yrs), and collisions being more common in the older age groups. Direct objects to the head had the highest rate of surgical intervention (P < 0.001). Parietal bone fractures were more frequent in the youngest age group, while frontal and temporal bone fractures were more common in the older age groups. Increasing age was an independent predictor of the need for surgical intervention (P < 0.0001). The overall incidence of blindness and hearing loss was low, and increased with increasing age. Patients with fractures as a result of violent mechanisms were more likely to come from highly impoverished zip codes, compared with patients with nonviolent mechanisms of injury (19.6% versus 8%). Overall mortality was low (2.9%). Temporal bone fractures had the greatest risk of mortality (P < 0.001) with age > = 5 years being an independent predictor of mortality (P < 0.001). Victims of falls, and patients with associated gastrointestinal or musculoskeletal injuries, had a statistically significant increased chance of survival, whereas victims of collisions and patients with concomitant cervical spine, cardiothoracic, or respiratory injuries had a significantly increased risk of death. CONCLUSIONS: Pediatric cranial vault fracture injury patterns are significantly correlated with demographics, mechanisms of injury, presence and type of concomitant injuries, need for surgical intervention, and mortality. Although the need for operative intervention and overall mortality is low, these variables play significant roles in portending prognosis, and an understanding of the metrics presented herein will enable practitioners optimize management and treatment in this unique patient population.

Child abuse is related to inflammation in mid-life women: role of obesity.

OBJECTIVE: Elevated inflammation biomarkers are associated with incident cardiovascular disease. Several studies suggest that childhood abuse may be associated with inflammation later in life. This study examined whether childhood abuse predicted elevated levels of C-reactive protein (CRP) and whether the association was due to body size. METHODS: Participants were 326 (104 Black, 222 White) women from the Pittsburgh site of the Study of Women's Health Across the Nation (SWAN). SWAN included a baseline assessment of pre-menopausal or early peri-menopausal women in mid-life (mean age=45.7), and CRP, depressive symptoms, body mass index (BMI), and other covariates were measured over 7 annual follow-up visits. The Childhood Trauma Questionnaire, a standardized measure that retrospectively assesses abuse and neglect in childhood and adolescence, was administered at year 8 or 9 of follow-up. RESULTS: Approximately 37% of the participants reported a history of abuse or neglect. Generalized estimating equations showed that sexual and emotional abuse, emotional and physical neglect, and the total number of types of abuse were associated with higher CRP levels over 7 years, adjusting for race, age, education, smoking status, use of hormone therapy, depressive symptoms, occurrence of heart attack or stroke, and medications for hypertension. The coefficients for indirect effects for emotional and sexual abuse, physical neglect, and total number of types of abuse on CRP levels through BMI were significant. A history of emotional abuse and neglect was related to percent change in CRP over the 7 years but not through percent change in BMI over the 7 years. CONCLUSION: A history of childhood abuse and neglect retrospectively reported is related to overall elevated inflammation in mid-life women, perhaps through obesity. A history of some types of abuse and neglect (emotional) may be related to change in inflammation, independent of simultaneously measured change in BMI.

Intermittent versus continuous cerebrospinal fluid drainage management in adult severe traumatic brain injury: assessment of intracranial pressure burden.

INTRODUCTION: There is clinical equipoise regarding whether neurointensive care unit management of external ventricular drains (EVD) in severe traumatic brain injury (TBI) should involve an open EVD, with continuous drainage of cerebrospinal fluid (CSF), versus a closed EVD, with intermittent opening as necessary to drain CSF. In a matched cohort design, we assessed the relative impact of continuous versus intermittent CSF drainage on intracranial pressure in the management of adult severe TBI. METHODS: Sixty-two severe TBI patients were assessed. Thirty-one patients managed by open EVD drainage were matched by age, sex, and injury severity (initial Glasgow Coma Scale (GCS) score) to 31 patients treated with a closed EVD drainage. Patients in the open EVD group also had a parenchymal intracranial pressure (ICP) monitor placed through an adjacent burr hole, allowing real-time recording of ICP. Hourly ICP and other pertinent data, such as length of stay in intensive care unit (LOS-ICU), Injury Severity Score, and survival status, were extracted from our prospective database. RESULTS: With age, injury severity (initial GCS score), and neurosurgical intervention adjusted for, there was a statistically significant difference of 5.66 mmHg in mean ICP (p < 0.0001) between the open and the closed EVD groups, with the closed EVD group exhibiting greater mean ICP. ICP burden (ICP ≥ 20 mmHg) was shown to be significantly higher in the intermittent EVD group (p = 0.0002) in comparison with the continuous EVD group. CONCLUSION: Continuous CSF drainage via an open EVD seemed to be associated with more effective ICP control in the management of adult severe TBI.

Association Between ß-Amyloid Accumulation and Incident Dementia in Individuals 80 Years or Older Without Dementia.

BACKGROUND AND OBJECTIVES: While the highest prevalence of dementia occurs in individuals older than 80 years, most imaging studies focused on younger populations. The rates of ß-amyloid (Aß) accumulation and the effect of Alzheimer disease (AD) pathology on progression to dementia in this age group remain unexplored. In this study, we examined the relationship between changes in Aß deposition over time and incident dementia in nondemented individuals followed during a period of 11 years. METHODS: We examined 94 participants (age 85.9 + 2.8 years) who had up to 5 measurements of Pittsburgh compound-B (PiB)-PET and clinical evaluations from 2009 to 2020. All 94 participants had 2 PiB-PET scans, 76 participants had 3 PiB-PET scans, 18 participants had 4 PiB-PET scans, and 10 participants had 5 PiB-PET scans. The rates of Aß deposition were compared with 120 nondemented individuals younger than 80 years (69.3 ± 5.4 years) from the Australian Imaging, Biomarker, and Lifestyle (AIBL) study who had 3 or more annual PiB-PET assessments. RESULTS: By 2020, 49% of the participants developed dementia and 63% were deceased. There was a gradual increase in Aß deposition in all participants whether they were considered Aß positive or negative at baseline. In a Cox model controlled for age, sex, education level, APOE-4 allele, baseline Mini-Mental State Examination, and mortality, short-term change in Aß deposition was not significantly associated with incident dementia (HR 2.19 (0.41-11.73). However, baseline Aß burden, cortical thickness, and white matter lesions volume were the predictors of incident dementia. Aß accumulation was faster (p = 0.01) in the older cohort (5.6%/year) when compared with AIBL (4.1%/year). In addition, baseline Aß deposition was a predictor of short-term change (mean time 1.88 years). DISCUSSION: There was an accelerated Aß accumulation in cognitively normal individuals older than 80 years. Baseline Aß deposition was a determinant of incident dementia and short-term change in Aß deposition suggesting that an active Aß pathologic process was present when these participants were cognitively normal. Consequently, age may not be a limiting factor for the use of the emergent anti-Aß therapies.

An ERK5-PFKFB3 axis regulates glycolysis and represents a therapeutic vulnerability in pediatric diffuse midline glioma.

Metabolic reprogramming in pediatric diffuse midline glioma is driven by gene expression changes induced by the hallmark histone mutation H3K27M, which results in aberrantly permissive activation of oncogenic signaling pathways. Previous studies of diffuse midline glioma with altered H3K27 (DMG-H3K27a) have shown that the RAS pathway, specifically through its downstream kinase, extracellular-signal-related kinase 5 (ERK5), is critical for tumor growth. Further downstream effectors of ERK5 and their role in DMG-H3K27a metabolic reprogramming have not been explored. We establish that ERK5 is a critical regulator of cell proliferation and glycolysis in DMG-H3K27a. We demonstrate that ERK5 mediates glycolysis through activation of transcription factor MEF2A, which subsequently modulates expression of glycolytic enzyme PFKFB3. We show that in vitro and mouse models of DMG-H3K27a are sensitive to the loss of PFKFB3. Multi-targeted drug therapy against the ERK5-PFKFB3 axis, such as with small-molecule inhibitors, may represent a promising therapeutic approach in patients with pediatric diffuse midline glioma.

Predictive value of autoantibody testing for validating self-reported diagnoses of rheumatoid arthritis in the Women's Health Initiative.

Rheumatoid arthritis (RA) research using large databases is limited by insufficient case validity. Of 161,808 postmenopausal women in the Women's Health Initiative, 15,691 (10.2%) reported having RA, far higher than the expected 1% population prevalence. Since chart review for confirmation of an RA diagnosis is impractical in large cohort studies, the current study (2009-2011) tested the ability of baseline serum measurements of rheumatoid factor and anti-cyclic citrullinated peptide antibodies, second-generation assay (anti-CCP2), to identify physician-validated RA among the chart-review study participants with self-reported RA (n = 286). Anti-CCP2 positivity had the highest positive predictive value (PPV) (80.0%), and rheumatoid factor positivity the lowest (44.6%). Together, use of disease-modifying antirheumatic drugs and anti-CCP2 positivity increased PPV to 100% but excluded all seronegative cases (approximately 15% of all RA cases). Case definitions inclusive of seronegative cases had PPVs between 59.6% and 63.6%. False-negative results were minimized in these test definitions, as evidenced by negative predictive values of approximately 90%. Serological measurements, particularly measurement of anti-CCP2, improved the test characteristics of RA case definitions in the Women's Health Initiative.

Long-term survival in adults 65 years and older with white matter hyperintensity: association with performance on the digit symbol substitution test.

OBJECTIVE: White matter hyperintensity (WMH) confers increased mortality risk in patients with cardiovascular diseases. However, little is known about differences in survival times among adults 65 years and older who have WMH and live in the community. To characterize the factors that may reduce mortality risk in the presence of WMH, measures of race, sex, apolipoprotein E4, neuroimaging, and cardiometabolic, physiological, and psychosocial characteristics were examined, with a particular focus on information processing as measured by the Digit Symbol Substitution Test (DSST). METHODS: Cox proportional models were used to estimate mortality risks in a cohort of 3513 adults (74.8 years, 58% women, 84% white) with WMH (0-9 points), DSST (0-90 points), risk factor assessment in 1992 to 1994, and data on mortality and incident stroke in 2009 (median follow-up [range] = 14.2 [0.5-18.1] years). RESULTS: WMH predicted a 48% greater mortality risk (age-adjusted hazard ratio [HR; 95% confidence interval {CI}] for WMH >3 points = 1.48 [1.35-1.62]). This association was attenuated after adjustment for DSST (HR [CI] = 1.38 [1.27-1.51]) or lacunar infarcts (HR [CI] = 1.37 [1.25,1.50]) but not after adjustment for other factors. The interaction between DSST and WMH was significant (p = .011). In fully adjusted models stratified by WMH of 3 or higher, participants with DSST greater than or equal to median had a 34% lower mortality risk among those with WMH of 3 or higher (n = 532/1217) and a 28% lower mortality risk among those with WMH lower than 3 (n = 1364/2296), compared with participants with DSST less than median (HR [95% CI] = 0.66 [0.55-0.81] and 0.72 [0.62-0.83], respectively). CONCLUSIONS: WMH is associated with increased long-term mortality risk in community-dwelling adults 65 years and older. The increased risk is attenuated for those with higher DSST. Assessment of cognitive function with DSST may improve risk stratification of individuals with WMH.