OBJECTIVE: Patients with hypopituitarism are at increased cardiovascular risk, in part because of growth hormone deficiency (GHD), but probably also because of the overuse of glucocorticosteroids in concomitant adrenal insufficiency (AI). We hypothesized that patients with hypopituitarism that were on glucocorticosteroid replacement therapy for concomitant AI would have worse cardiovascular outcomes than those without.
METHODS: Retrospective nationwide cohort study. GHD patients from the Dutch National Registry of Growth Hormone Treatment in adults were grouped by the presence (AI; N = 1836) or absence (non-AI; N = 750) of concomitant AI, and differences between groups were analyzed for baseline characteristics and cardiovascular risk, at baseline and during GHRT.
RESULTS: At baseline, AI patients had higher levels of total and LDL cholesterol (both p < 0.01). During GHRT, AI patients were more likely to use cardiovascular drugs (p ≤ 0.01), but we did not find worse outcomes for blood pressure, body composition, lipid and glucose metabolism. The risk of developing peripheral arterial disease (HR 2.22 [1.06-4.65]) and non-fatal cerebrovascular events (HR 3.47 [1.60-7.52]) was higher in AI patients, but these differences disappeared in the models adjusted for baseline differences.
CONCLUSIONS: We found no clear evidence to support our hypothesis that patients with hypopituitarism and concomitant AI have worse cardiovascular outcomes than non-AI patients. This suggests that glucocorticoid replacement therapy in AI may be safer than previously thought. However, cardiovascular burden, events and medication use at baseline and during GHRT (in unadjusted models) were higher in AI; so the lack of power, the important role of (adjusting for) other risk factors, and the inability to distinguish between glucocorticoid treatment regimens may have influenced the outcomes.

BACKGROUND: Systematic Review and Meta-Analysis (SRMAs) in neurosurgery have significantly increased. With approximately 1 million patients affected by cerebrovascular disease annually, interpreting SRMAs necessitates a systematic approach. The objective of this review is to identify and describe four essential domains for SRMA interpretation.
METHODS: This review outlines the necessities of reviewing existing literature and methodological frameworks essential for interpreting cerebrovascular neurosurgery SRMAs. Each domain is to accurately assess study design variations, heterogeneity assessment methods, outcome comparability strategies, and the impact of technological advancements and time bias on study outcomes.
RESULTS: Study design evaluation distinguishes between randomized controlled trials (RCTs) and non-randomized studies. RCTs provide high internal validity, but as seen in the ARUBA trial, can contain internal flaws that necessitate a deeper understanding before application to clinical practices. Non-randomized studies offer valuable real-world insights. A heterogeneity assessment involves readers and writers accurately using forest plots, Cochrane\'s Q test, Higgins I² statistics, subgroup analysis, and meta-regressions to understand a study\'s clinical findings. The expertise thresholds, as in the NASCET trial, significantly impact a study\'s external validity. Strategies such as the GRADE approach can assist in managing diverse outcome measures. Technological advancements, particularly in endovascular procedures and SRS, influence the accuracy of comparing studies across periods, and thus swiftly outdate older studies, lowering the applicability of SRMAs.
CONCLUSIONS: Effective interpretation of cerebrovascular neurosurgery SRMAs requires attention to study design, heterogeneity, outcome comparability, and technological advancements. These domains collectively enable evidence-based clinical decision-making and optimized patient care in a dynamic field.

UNASSIGNED: African Americans (AA) are widely underrepresented in plasma biomarker studies for Alzheimer\'s disease (AD) and current diagnostic biomarker candidates do not reflect the heterogeneity of AD.
UNASSIGNED: Untargeted proteome measurements were obtained using the SomaScan 7k platform to identify novel plasma biomarkers for AD in a cohort of AA clinically diagnosed as AD dementia (n=183) or cognitively unimpaired (CU, n=145). Machine learning approaches were implemented to identify the set of plasma proteins that yields the best classification accuracy.
UNASSIGNED: A plasma protein panel achieved an area under the curve (AUC) of 0.91 to classify AD dementia vs CU. The reproducibility of this finding was observed in the ANMerge plasma and AMP-AD Diversity brain datasets (AUC=0.83; AUC=0.94).
UNASSIGNED: This study demonstrates the potential of biomarker discovery through untargeted plasma proteomics and machine learning approaches. Our findings also highlight the potential importance of the matrisome and cerebrovascular dysfunction in AD pathophysiology.

BACKGROUND: Endovascular treatment with the woven endobridge (WEB) device has been widely utilized for managing intracranial aneurysms. However, predicting the probability of achieving adequate occlusion (Raymond-Roy classification 1 or 2) remains challenging.
OBJECTIVE: Our study sought to develop and validate a predictive calculator for adequate occlusion using the WEB device via data from a large multi-institutional retrospective cohort.
METHODS: We used data from the WorldWide WEB Consortium, encompassing 356 patients from 30 centers across North America, South America, and Europe. Bivariate and multivariate regression analyses were performed on a variety of demographic and clinical factors, from which predictive factors were selected. Calibration and validation were conducted, with variance inflation factor (VIF) parameters checked for collinearity.
RESULTS: A total of 356 patients were included: 124 (34.8%) were male, 108 (30.3%) were elderly (≥65 years), and 118 (33.1%) were current smokers. Mean maximum aneurysm diameter was 7.09 mm (SD 2.71), with 112 (31.5%) having a daughter sac. In the multivariate regression, increasing aneurysm neck size (OR 0.706 [95% CI: 0.535-0.929], p = 0.13) and partial aneurysm thrombosis (OR 0.135 [95% CI: 0.024-0.681], p = 0.016) were found to be the only statistically significant variables associated with poorer likelihood of achieving occlusion. The predictive calculator shows a c-statistic of 0.744. Hosmer-Lemeshow goodness-of-fit test indicated a satisfactory model fit with a p-value of 0.431. The calculator is available at: https://neurodx.shinyapps.io/WEBDEVICE/.
CONCLUSIONS: The predictive calculator offers a substantial contribution to the clinical toolkit for estimating the likelihood of adequate intracranial aneurysm occlusion by WEB device embolization.

To further explore the role of different antipsychotic treatments for cardio-cerebrovascular mortality, we performed several subgroup, sensitivity and meta-regression analyses based on a large previous meta-analysis focusing on cohort studies assessing mortality relative risk (RR) for cardio-cerebrovascular disorders in people with schizophrenia, comparing antipsychotic treatment versus no antipsychotic. Quality assessment through the Newcastle-Ottawa Scale (NOS) and publication bias was measured. We meta-analyzed 53 different studies (schizophrenia patients: n = 2,513,359; controls: n = 360,504,484) to highlight the differential effects of antipsychotic treatment regimens on cardio-cerebrovascular-related mortality in incident and prevalent samples of patients with schizophrenia. We found first generation antipsychotics (FGA) to be associated with higher mortality in incident samples of schizophrenia (oral FGA [RR=2.20, 95 %CI=1.29-3.77, k = 1] and any FGA [RR=1.70, 95 %CI=1.20-2.41, k = 1]). Conversely, second generation antipsychotics (SGAs) and clozapine were associated with reduced cardio-cerebrovascular-related mortality, in prevalent samples of schizophrenia. Subgroup analyses with NOS score ≥7 (higher quality) demonstrated a significantly increased cardio-cerebrovascular disorder-related mortality, among those exposed to FGAs vs SGAs. Meta-regression analyses demonstrated a larger association between antipsychotics and decreased risk of mortality with longer follow-up, recent study year, and higher number of adjustment variables. Overall, this subanalysis of a systematic review contributes to the evolving understanding of the complex role of antipsychotic treatment for cardio-cerebrovascular mortality in schizophrenia, paving the way for more targeted interventions and improved patient outcomes.

The cold pressor test (CPT) involves cold water immersion of either the upper or lower limb(s) and elicits autonomic and hemodynamic increases via stimulation of pain and cutaneous thermoreceptors. It is unclear whether the choice of limb(s) in CPT studies differentially affects systemic and cerebral hemodynamic responses. Herein, we assessed systemic and cerebral hemodynamic and ventilatory responses to different CPT protocols of the hand (CPTH), foot (CPTF), or bilateral feet (CPTBF). We hypothesized CPTBF would elicit greatest physiological responses due to increased exposure area to the cold stimulus. Methods. Twenty-eight (14M;14F) healthy young adults [23.4 (SD: 2.4) years] participated in three 3-minute CPT protocols during a single visit. Mean arterial pressure (MAP), heart rate (HR), middle cerebral artery blood velocity (MCAv) and cerebrovascular conductance index, and end-tidal carbon dioxide (PETCO2), and pain perception were recorded throughout CPT protocols. Results. There was a time-CPT protocol interaction on systolic (p=0.02) and diastolic blood pressure (p<0.01), MAP (p<0.01), HR (p<0.001), presented as mean(SD). MCAv and cerebrovascular conductance index did not change with CPTs. Peak delta HR from baseline occurred in CPTBF (Δ13.6(15.5)BPM) compared to CPTH (Δ4.85(12.6)BPM; p=0.01) and CPTF (Δ4.04(13.3)BPM; p=0.02). Delta MAP was greater in CPTH (Δ12.3(7.95)mmHg) and CPTBF (Δ12.9(9.24)mmHg) compared to CPTF (Δ8.42(7.12)mmHg; p<0.01). Perceived pain was higher in CPTBF compared to single limb protocols (p≤0.01). Conclusion. Our findings suggest choice of limb(s) in CPT protocols affects systemic hemodynamic responses and should be considered when designing CPT studies.

OBJECTIVE: Axel Perneczky is responsible for conceptualizing the \"keyhole\" philosophy as a new paradigm of minimal invasiveness within cranial neurosurgery. Keyhole neurosurgery aims to limit approach-related traumatization and minimize brain retraction while still enabling the neurosurgeon to achieve operative goals. The supraorbital keyhole craniotomy (SOKC) and minipterional (pterional keyhole, PKC) approaches have become mainstays for clipping intracranial aneurysms. While studies have compared these approaches to the traditional pterional craniotomy for clipping cerebral aneurysms, head-to-head comparisons of these workhorse keyhole approaches remain limited.
METHODS: The authors queried three databases per PRISMA guidelines to identify all studies comparing the SOKC to the PKC for microsurgical clipping of cerebral aneurysms. Of 148 unique studies returned on initial query, a total of 5 studies published between 2013 and 2019 met inclusion criteria. Where applicable, quantitative meta-analysis was performed via the Mantel-Haenszel method using Review Manager v5.4 (Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark). Risk of bias (ROB) was assessed using the Cochrane ROBINS-I tool, and all studies were assigned a Level of Evidence (I-V).
RESULTS: Across all five studies, the mean age ranged from 53.0 to 57.5 years old, and the cohort consisted of more females (n = 403, 60.6%) than males. The proportion of patients presenting with ruptured aneurysmal SAH was comparable between the SOKC and PKC cohorts (p = 0.43). Clipping rate [defined as the rate of successful aneurysm clip deployment with successful intraoperative occlusion] (OR 1.52 [0.49, 4.71], I2 = 0%, p = 0.47), final occlusion rates (OR 1.27 [0.37, 4.32], p = 0.70), and operative durations (SMD 0.33 [-0.83. 1.49], I2 = 97%, p = 0.58) were comparable regardless of approach used. Furthermore, rates of intraoperative rupture (OR 1.51 [0.64, 3.55], I2 = 0, p = 0.34), postoperative hemorrhage (OR 1.49 [0.74, 3.01], I2 = 0, p = 0.26), postoperative vasospasm (OR 0.94 [0.49, 1.80], I2 = 63, p = 0.86), and postoperative infection (OR 0.70 [0.16, 2.99], I2 = 0%, p = 0.63) were equivocal across SOKC and PKC cohorts.
CONCLUSIONS: The PKC and SOKC approaches appear to afford comparable outcomes when used for open microsurgical clipping of cerebral aneurysms in select patients with both ruptured and unruptured aneurysms. Both are associated with excellent clipping and occlusion rates, minimal perioperative complication profiles, and favorable postoperative neurologic outcomes. Further investigations are merited so clinicians can further parse out the indications and contraindications for each keyhole approach.

Resting cerebral perfusion metrics can be calculated from the MRI ΔR2* signal during the first passage of an intravascular bolus of a Gadolinium-based contrast agent (GBCA), or more recently, a transient hypoxia-induced change in the concentration of deoxyhemoglobin ([dOHb]). Conventional analysis follows a proxy process that includes deconvolution of an arterial input function (AIF) in a tracer kinetic model. We hypothesized that the step reduction in magnetic susceptibility accompanying a step decrease in [dOHb] that occurs when a single breath of oxygen terminates a brief episode of lung hypoxia permits direct calculation of relative perfusion metrics. The time course of the ΔR2* signal response enables both the discrimination of blood arrival times and the time course of voxel filling. We calculated the perfusion metrics implied by this step signal change in seven healthy volunteers and compared them to those from conventional analyses of GBCA and dOHb using their AIF and indicator dilution theory. Voxel-wise maps of relative cerebral blood flow and relative cerebral blood volume had a high spatial and magnitude congruence for all three analyses (r > 0.9) and were similar in appearance to published maps. The mean (SD) transit times (s) in grey and white matter respectively for the step response (7.4 (1.1), 8.05 (1.71)) were greater than those for GBCA (2.6 (0.45), 3.54 (0.83)) attributable to the nature of their respective calculation models. In conclusion we believe these calculations of perfusion metrics derived directly from ΔR2* have superior merit to calculations via AIF by virtue of being calculated from a direct signal rather than through a proxy model which encompasses errors inherent in designating an AIF and performing deconvolution calculations.

[This corrects the article DOI: 10.3389/fncel.2023.1226580.].

BACKGROUND: Randomized controlled trials (RCTs) provide information on appropriate management protocols in patients with cerebrovascular diseases. Despite growing evidence of race and ethnicity being independent predictors of outcomes, recent literature has drawn attention to inadequate reporting of these demographic profiles across RCTs. To our knowledge, the adherence to reporting race and/or ethnicity in cerebrovascular RCTs remains undescribed. Our study describes trends in the reporting of race and/or ethnicity across cerebrovascular RCTs.
METHODS: Web of Science was searched to identify the top 100-cited cerebrovascular RCTs. Additional articles were retrieved from guidelines issued by the American Heart Association for the management of ischemic stroke, intracerebral hemorrhage, and aneurysmal subarachnoid hemorrhage. Univariate and multivariate analyses were performed to assess for factors influencing reporting of race/ethnicity.
RESULTS: Sixty-five percent of cerebrovascular RCTs lacked reporting of participant race and/or ethnicity. Multivariate regression revealed that studies from North America had a 14.74- fold higher odds (95% CI: 4.574-47.519) of reporting race/ethnicity. Impact factor of the journal was associated with 1.007-fold odds of reporting race/ethnicity (95% CI: 1.000-1.013). Reporting of race and/or ethnicity did not increase with time, or vary according to the number of participating centers, median number of study participants, source of funding, or category of RCT. Among RCTs that reported race, Blacks and Asians were underrepresented compared to Whites.
CONCLUSIONS: Sixty-five percent of prominent cerebrovascular RCTs lack adequate reporting of participant race/ethnicity. Reasons for inadequate reporting of these variables remain unclear and warrant additional investigation.