Concussion burden and later-life cardiovascular risk factors in former professional American-style football players.

OBJECTIVE: Mid-life cardiovascular risk factors are associated with later cognitive decline. Whether repetitive head injury among professional athletes impacts cardiovascular risk is unknown. We investigated associations between concussion burden and postcareer hypertension, high cholesterol, and diabetes among former professional American-style football (ASF) players. METHODS: In a cross-sectional study of 4080 professional ASF players conducted between January 2015 and March 2022, we used an mulitsymptom concussion symptom score (CSS) and the number of loss-of-consciousness (LOC) episodes as a single severe symptom to quantify football-related concussion exposure. Primary outcomes were hypertension, dyslipidemia, and diabetes, defined by current or recommended prescription medication use. RESULTS: The prevalence of hypertension, high cholesterol, and diabetes among former players (52 ± 14 years of age) was 37%, 34%, and 9%. Concussion burden was significantly associated with hypertension (lowest vs. highest CSS quartile, odds ratio (OR) = 1.99; 95%CI: 1.33-2.98; p < 0.01) and high cholesterol (lowest vs. moderate CSS, OR = 1.46, 95%CI, 1.11-1.91; p < 0.01), but not diabetes. In fully adjusted models, the prevalence of multiple CVD was associated with CSS. These results were driven by younger former players (≤ 40 year of age) in which the odds of hypertension were over three times higher in those in the highest CSS quartile (OR = 3.29, 95%CI: 1.39-7.61; p = 0.01). Results were similar for LOC analyses. INTERPRETATION: Prior concussion burden is associated with postcareer atherogenic cardiovascular risk profiles among former professional American football players.

Multi-modal 3-Dimensional Visualization of Pediatric Neuroblastoma: Aiding Surgical Planning Beyond Anatomical Information.

BACKGROUND: Patient-specific 3D models of neuroblastoma and relevant anatomy are useful tools for surgical planning. However, these models do not represent the heterogenous biology of neuroblastoma. This heterogeneity is visualized with the ADC and 123I-MIGB-SPECT-CT imaging. Combining these multi-modal data into preoperative 3D heatmaps, may allow differentiation of the areas of vital and non-vital tumor tissue. We developed a workflow to create multi-modal preoperative 3D models for neuroblastoma surgery. METHODS: We included 7 patients who underwent neuroblastoma surgery between 2022 and 2023. We developed 3D models based on the contrast enhanced T1-weighted MRI scans. Subsequently, we aligned the corresponding ADC and 123I-MIBG-SPECT-CT images using rigid transformation. We estimated registration precision using the Dice score and the target registration error (TRE). 3D heatmaps were computed based on ADC and 123I-MIBG uptake. RESULTS: The registration algorithm had a median Dice score of 0.81 (0.75-0.90) for ADC and 0.77 (0.65-0.91) for 123I-MIBG-SPECT. For the ADC registration, the median TRE of renal vessels was 4.90 mm (0.86-10.18) and of the aorta 4.67 mm (1.59-12.20). For the 123I -MIBG-SPECT imaging the TRE of the renal vessels was 5.52 mm (1.71-10.97) and 5.28 mm (3.33-16.77) for the aorta. CONCLUSIONS: We successfully developed a registration workflow to create multi-modal 3D models which allows the surgeon to visualize the tumor and its biological behavior in relation to the surrounding tissue. Future research will include linking of pathological results to imaging data, to validate these multi-modal 3D models. LEVEL OF EVIDENCE: Level IV. TYPE OF STUDY: Clinical Research.

A framework to integrate artificial intelligence training into radiology residency programs: preparing the future radiologist.

OBJECTIVES: To present a framework to develop and implement a fast-track artificial intelligence (AI) curriculum into an existing radiology residency program, with the potential to prepare a new generation of AI conscious radiologists. METHODS: The AI-curriculum framework comprises five sequential steps: (1) forming a team of AI experts, (2) assessing the residents' knowledge level and needs, (3) defining learning objectives, (4) matching these objectives with effective teaching strategies, and finally (5) implementing and evaluating the pilot. Following these steps, a multidisciplinary team of AI engineers, radiologists, and radiology residents designed a 3-day program, including didactic lectures, hands-on laboratory sessions, and group discussions with experts to enhance AI understanding. Pre- and post-curriculum surveys were conducted to assess participants' expectations and progress and were analyzed using a Wilcoxon rank-sum test. RESULTS: There was 100% response rate to the pre- and post-curriculum survey (17 and 12 respondents, respectively). Participants' confidence in their knowledge and understanding of AI in radiology significantly increased after completing the program (pre-curriculum means 3.25 ± 1.48 (SD), post-curriculum means 6.5 ± 0.90 (SD), p-value = 0.002). A total of 75% confirmed that the course addressed topics that were applicable to their work in radiology. Lectures on the fundamentals of AI and group discussions with experts were deemed most useful. CONCLUSION: Designing an AI curriculum for radiology residents and implementing it into a radiology residency program is feasible using the framework presented. The 3-day AI curriculum effectively increased participants' perception of knowledge and skills about AI in radiology and can serve as a starting point for further customization. CRITICAL RELEVANCE STATEMENT: The framework provides guidance for developing and implementing an AI curriculum in radiology residency programs, educating residents on the application of AI in radiology and ultimately contributing to future high-quality, safe, and effective patient care. KEY POINTS: • AI education is necessary to prepare a new generation of AI-conscious radiologists. • The AI curriculum increased participants' perception of AI knowledge and skills in radiology. • This five-step framework can assist integrating AI education into radiology residency programs.

Artificial CT images can enhance variation of case images in diagnostic radiology skills training.

OBJECTIVES: We sought to investigate if artificial medical images can blend with original ones and whether they adhere to the variable anatomical constraints provided. METHODS: Artificial images were generated with a generative model trained on publicly available standard and low-dose chest CT images (805 scans; 39,803 2D images), of which 17% contained evidence of pathological formations (lung nodules). The test set (90 scans; 5121 2D images) was used to assess if artificial images (512 × 512 primary and control image sets) blended in with original images, using both quantitative metrics and expert opinion. We further assessed if pathology characteristics in the artificial images can be manipulated. RESULTS: Primary and control artificial images attained an average objective similarity of 0.78 ± 0.04 (ranging from 0 [entirely dissimilar] to 1[identical]) and 0.76 ± 0.06, respectively. Five radiologists with experience in chest and thoracic imaging provided a subjective measure of image quality; they rated artificial images as 3.13 ± 0.46 (range of 1 [unrealistic] to 4 [almost indistinguishable to the original image]), close to their rating of the original images (3.73 ± 0.31). Radiologists clearly distinguished images in the control sets (2.32 ± 0.48 and 1.07 ± 0.19). In almost a quarter of the scenarios, they were not able to distinguish primary artificial images from the original ones. CONCLUSION: Artificial images can be generated in a way such that they blend in with original images and adhere to anatomical constraints, which can be manipulated to augment the variability of cases. CRITICAL RELEVANCE STATEMENT: Artificial medical images can be used to enhance the availability and variety of medical training images by creating new but comparable images that can blend in with original images. KEY POINTS: • Artificial images, similar to original ones, can be created using generative networks. • Pathological features of artificial images can be adjusted through guiding the network. • Artificial images proved viable to augment the depth and broadening of diagnostic training.

The Impact of Dual Antiplatelet Therapy Duration on Unruptured Aneurysm Occlusion After Flow Diversion: A Multicenter Study.

OBJECTIVE: Endoluminal flow diversion reduces blood flow into intracranial aneurysms, promoting thrombosis. Postprocedural dual antiplatelet therapy (DAPT) is necessary for the prevention of thromboembolic complications. The purpose of this study is to therefore assess the impact that the type and duration of DAPT has on aneurysm occlusion rates and iatrogenic complications after flow diversion. METHODS: A retrospective review of a multicenter aneurysm database was performed from 2012 to 2020 to identify unruptured intracranial aneurysms treated with single device flow diversion and ≥12-month follow-up. Clinical and radiologic data were analyzed with aneurysm occlusion as a function of DAPT duration serving as a primary outcome measure. RESULTS: Two hundred five patients underwent flow diversion with a single pipeline embolization device with 12.7% of treated aneurysms remaining nonoccluded during the study period. There were no significant differences in aneurysm morphology or type of DAPT used between occluded and nonoccluded groups. Nonoccluded aneurysms received a longer mean duration of DAPT (9.4 vs 7.1 months, P = 0.016) with a significant effect of DAPT duration on the observed aneurysm occlusion rate (F(2, 202) = 4.2, P = 0.016). There was no significant difference in the rate of complications, including delayed ischemic strokes, observed between patients receiving short (≤6 months) and prolonged duration (>6 months) DAPT (7.9% vs 9.3%, P = 0.76). CONCLUSIONS: After flow diversion, an abbreviated duration of DAPT lasting 6 months may be most appropriate before transitioning to low-dose aspirin monotherapy to promote timely aneurysm occlusion while minimizing thromboembolic complications.

Race differences in pain and pain-related risk factors among former professional American-style football players.

ABSTRACT: The burden of pain is unequal across demographic groups, with broad and persisting race differences in pain-related outcomes in the United States. Members of racial and ethnic minorities frequently report more pervasive and severe pain compared with those in the majority, with at least some disparity attributable to differences in socioeconomic status. Whether race disparities in pain-related health outcomes exist among former professional football players is unknown. We examined the association of race with pain outcomes among 3995 former professional American-style football players who self-identified as either Black or White. Black players reported more intense pain and higher levels of pain interference relative to White players, even after controlling for age, football history, comorbidities, and psychosocial factors. Race moderated associations between several biopsychosocial factors and pain; higher body mass index was associated with more pain among White but not among Black players. Fatigue and psychosocial factors were more strongly related to pain among Black players relative to White players. Collectively, the substantial social and economic advantages of working as a professional athlete did not seem to erase race-related disparities in pain. We highlight an increased burden of pain among elite Black professional football players and identify race-specific patterns of association between pain and biopsychosocial pain risk factors. These findings illuminate potential future targets of interventions that may serve to reduce persistent disparities in the experience and impact of pain.

Regulation of cerebrovascular compliance compared with forearm vascular compliance in humans: a pharmacological study.

Increasing evidence indicates that cerebrovascular compliance contributes to the dynamic regulation of cerebral blood flow but the mechanisms regulating cerebrovascular compliance in humans are unknown. This retrospective study investigated the impact of neural, endothelial, and myogenic mechanisms on the regulation of vascular compliance in the cerebral vascular bed compared with the forearm vascular bed. An index of vascular compliance (Ci) was assessed using a Windkessel model applied to blood pressure waveforms (finger photoplethysmography) and corresponding middle cerebral artery blood velocity or brachial artery blood velocity waveforms (Doppler ultrasound). Data were analyzed during a 5-min baseline period (10 waveforms) under control conditions and during distinct sympathetic blockade (experiment 1, phentolamine; 10 adults), cholinergic blockade (experiment 2, glycopyrrolate; 9 adults), and myogenic blockade (experiment 3, nicardipine; 14 adults). In experiment 1, phentolamine increased Ci similarly in the cerebral vascular bed (131 ± 135%) and forearm vascular bed (93 ± 75%; P = 0.45). In experiment 2, glycopyrrolate increased cerebrovascular Ci (72 ± 61%) and forearm vascular Ci (74 ± 64%) to a similar extent (P = 0.88). In experiment 3, nicardipine increased Ci but to a greater extent in the cerebral vascular bed (88 ± 88%) than forearm vascular bed (20 ± 45%; P = 0.01). Therefore, adrenergic, cholinergic, and myogenic mechanisms contribute to the regulation of cerebrovascular and forearm vascular compliance. However, myogenic mechanisms appear to exert more specific control over vascular compliance in the brain relative to the forearm.NEW & NOTEWORTHY Vascular compliance represents an important determinant in the dynamics and regulation of blood flow through a vascular bed. However, the mechanisms that regulate vascular compliance remain poorly understood. This study examined the impact of neural, endothelial, and myogenic mechanisms on cerebrovascular compliance compared with forearm vascular compliance. Distinct pharmacological blockade of α-adrenergic, endothelial muscarinic, and myogenic inputs altered cerebrovascular and forearm vascular compliance. These results further our understanding of vascular control and blood flow regulation in the brain.

Intracerebral Hemorrhage Segmentation on Noncontrast Computed Tomography Using a Masked Loss Function U-Net Approach.

OBJECTIVE: Intracerebral hemorrhage (ICH) volume is a strong predictor of outcome in patients presenting with acute hemorrhagic stroke. It is necessary to segment the hematoma for ICH volume estimation and for computerized extraction of features, such as spot sign, texture parameters, or extravasated iodine content at dual-energy computed tomography. Manual and semiautomatic segmentation methods to delineate the hematoma are tedious, user dependent, and require trained personnel. This article presents a convolutional neural network to automatically delineate ICH from noncontrast computed tomography scans of the head. METHODS: A model combining a U-Net architecture with a masked loss function was trained on standard noncontrast computed tomography images that were down sampled to 256 × 256 size. Data augmentation was applied to prevent overfitting, and the loss score was calculated using the soft Dice loss function. The Dice coefficient and the Hausdorff distance were computed to quantitatively evaluate the segmentation performance of the model, together with the sensitivity and specificity to determine the ICH detection accuracy. RESULTS: The results demonstrate a median Dice coefficient of 75.9% and Hausdorff distance of 2.65 pixels in segmentation performance, with a detection sensitivity of 77.0% and specificity of 96.2%. CONCLUSIONS: The proposed masked loss U-Net is accurate in the automatic segmentation of ICH. Future research should focus on increasing the detection sensitivity of the model and comparing its performance with other model architectures.

Dynamic effects of cholinergic blockade upon cerebral blood flow autoregulation in healthy adults.

Background: Cerebral flow autoregulation (CFA) is a homeostatic mechanism critical for survival. The autonomic nervous system (ANS) plays a key role in maintaining proper CFA function. More quantitative studies of how the ANS influences CFA are desirable. Objective: To discover and quantify the dynamic effects of cholinergic blockade upon CFA in response to changes of arterial blood pressure and blood CO2 tension in healthy adults. Methods: We analyzed time-series data of spontaneous beat-to-beat mean arterial blood pressure (ABP) and cerebral blood flow velocity in the middle cerebral arteries (CFV), as well as breath-to-breath end-tidal CO2 (CO2), collected in 9 adults before and after cholinergic blockade, in order to obtain subject-specific predictive input-output models of the dynamic effects of changes in ABP and CO2 (inputs) upon CFV (output). These models are defined in convolutional form using "kernel" functions (or, equivalently, Transfer Functions in the frequency domain) that are estimated via the robust method of Laguerre expansions. Results: Cholinergic blockade caused statistically significant changes in the obtained kernel estimates (and the corresponding Transfer Functions) that define the linear dynamics of the ABP-to-CFV and CO2-to-CFV causal relations. The kernel changes due to cholinergic blockade reflect the effects of the cholinergic mechanism and exhibited, in the frequency domain, resonant peaks at 0.22 Hz and 0.06 Hz for the ABP-to-CFV and CO2-to-CFV dynamics, respectively. Conclusion: Quantitative estimates of the dynamics of the cholinergic component in CFA are found as average changes of the ABP-to-CFV and CO2-to-CFV kernels, and corresponding Transfer Functions, before and after cholinergic blockade.

"All-in-one" window/level whole-body computed tomography scan - A faster way to evaluate trauma cases.

PURPOSE: To investigate the accuracy and total assessment time (TAT) of the "All-in-one" (AIO)-window/level setting for whole-body computed tomography (CT) image compared to multiple tissue-specific window/level settings conventionally used for detection of traumatic injuries. METHOD: Contrast-enhanced chest, abdomen, and pelvic CT scans of 50 patients who presented to our emergency department (ED) for major trauma were retrospectively selected. In a simulation of a "wet read" performed at the CT scanner console, 6 readers with different levels of experience had up to 3 min to describe any traumatic finding identified on the CTs. The readers reviewed each patient in two different sessions separated by a washout period to suppress any recall bias from one session to the next. Each scan was reviewed once using the AIO-window/level setting and another time using the conventional bone, lung, and soft tissue window/level display settings, in a randomized order. The CT reports were used as reference standard. RESULTS: Overall, there was no statistically significant difference in the assessment accuracy of the review based on the AIO or the conventional window/level settings (0.89 ± 0.09 vs 0.90 ± 0.08). Using the AIO-window/level settings, TAT was 14.3 s faster when compared with the conventional window/level settings (2.33 ± 0.63 vs 2.57 ± 0.51 min; p < 0.001). CONCLUSIONS: In a time-delimited image review, similar diagnostic accuracy was reached faster using the AIO vs the conventional window/level settings. When providing a "wet read" at the CT console, the ability to identify traumatic injury using a single AIO-window/level may help expedite patient management.

Cerebrovascular regulation in patients with vasovagal syncope and autonomic failure due to familial amyloidotic polyneuropathy.

INTRODUCTION: While there is strong evidence for autonomic involvement in cerebrovascular function acutely, long-term role of autonomic nervous system in cerebrovascular function has been controversial. We assessed autoregulation in 10 healthy individuals, nine patients with vasovagal syncope (VVS), and nine with Familial Amyloidotic Polyneuropathy (FAP), in response to head-up tilt test (HUTT). METHODS: Arterial blood pressure heart rate, cardiac output, and bilateral cerebral blood flow velocity (CBFV) at the M1 segment of middle cerebral artery (transcranial Doppler ultrasound) were recorded during supine rest and 70° HUTT. Autoregulation was quantified using a validated nonlinear and nonparametric approach based on projection pursuit regression. Plasma adrenaline and noradrenaline were also measured at rest and during HUTT. RESULTS: During supine rest and HUTT, plasma noradrenaline content was lower in FAP patients. During HUTT, VVS patients had a hyperadrenergic status; CBFV decreased in all groups, which was greater in FAP patients (p < 0.01). Healthy controls responded to HUTT with a reduction in CBFV responses to increases (p = 0.01) and decreases (p < 0.01) in arterial pressure without any change in the range or effectiveness of autoregulation. VVS patients responded to HUTT with a reduction in falling (p = 0.02), but not rising slope (p = 0.40). Autoregulatory range (p < 0.01) and effectiveness increased (p = 0.09), consistent with the rapid increase in levels of catecholamines. In FAP patients, the level of increase in range of autoregulation was significantly related to the magnitude of increase in plasma noradrenaline in response to HUTT (R2 = 0.26, p = 0.05). CONCLUSION: Autonomic dysfunction affects the cerebral autoregulatory response orthostatic to challenge.

Intracranial Blood Flow Quantification by Accelerated Dual-venc 4D Flow MRI: Comparison With Transcranial Doppler Ultrasound.

BACKGROUND: Dual-venc 4D flow MRI, recently introduced for the assessment of intracranial hemodynamics, may provide a promising complementary approach to well-established tools such as transcranial Doppler ultrasound (TCD) and overcome some of their disadvantages. However, data comparing intracranial flow measures from dual-venc 4D flow MRI and TCD are lacking. PURPOSE: To compare cerebral blood flow velocity measures derived from dual-venc 4D flow MRI and TCD. STUDY TYPE: Prospective cohort. SUBJECTS: A total of 25 healthy participants (56 ± 4 years old, 44% female). FIELD STRENGTH/SEQUENCE: A 3 T/dual-venc 4D flow MRI using a time-resolved three-dimensional phase-contrast sequence with three-dimensional velocity encoding. ASSESSMENT: Peak velocity measurements in bilateral middle cerebral arteries (MCA) were quantified from dual-venc 4D flow MRI and TCD. The MRI data were quantified by two independent observers (S.M and Y.M.) and TCD was performed by a trained technician (A.L.M.). We assessed the agreement between 4D flow MRI and TCD measures, and the interobserver agreement of 4D flow MRI measurements. STATISTICAL TESTS: Peak velocity from MRI and TCD was compared using Bland-Altman analysis and coefficient of variance. Intraclass correlation coefficient (ICC) was used to assess MRI interobserver agreement. A P value < 0.05 was considered statistically significant. RESULTS: There was excellent interobserver agreement in dual-venc 4D flow MRI-based measurements of peak velocity in bilateral MCA (ICC = 0.97 and 0.96 for the left and right MCA, respectively). Dual-venc 4D flow MRI significantly underestimated peak velocity in the left and right MCA compared to TCD (bias = 0.13 [0.59, -0.33] m/sec and 0.15 [0.47, -0.17] m/sec, respectively). The coefficient of variance between dual-venc 4D flow MRI and TCD measurements was 26% for the left MCA and 22% for the right MCA. DATA CONCLUSION: There was excellent interobserver agreement for the assessment of MCA peak velocity using dual-venc 4D flow MRI, and ≤20% under-estimation compared with TCD. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Dizziness, Psychosocial Function, and Postural Stability Following Sport-Related Concussion.

OBJECTIVE: To examine if self-reported dizziness is associated with concussion symptoms, depression and/or anxiety symptoms, or gait performance within 2 weeks of postconcussion. DESIGN: Cross-sectional study. SETTING: Research laboratory. PARTICIPANTS: Participants were diagnosed with a concussion within 14 days of initial testing (N = 40). Participants were divided into 2 groups based on their Dizziness Handicap Inventory (DHI) score: 36 to 100 = moderate/severe dizziness and 0 to 35 = mild/no dizziness. INTERVENTIONS: Participants were tested on a single occasion and completed the DHI, hospital anxiety and depression scale (HADS), Patient Health Questionnaire-9 (PHQ-9), and Post-Concussion Symptom Inventory (PCSI). Three different postural control tests were use: modified Balance Error Scoring System, single-/dual-task tandem gait, and a single-/dual-task instrumented steady-state gait analysis. MAIN OUTCOME MEASURES: Comparison of patient-reported outcomes and postural control outcomes between moderate/severe (DHI ≥ 36) and mild/no (DHI < 36) dizziness groups. RESULTS: Participants with moderate/severe dizziness (n = 19; age = 17.1 ± 2.4 years; 63% female) reported significantly higher symptom burden (PSCI: 43.0 ± 20.6 vs 22.8 ± 15.7; P = 0.001) and had higher median HADS anxiety (6 vs 2; P < 0.001) and depression (6 vs 1; P = 0.001) symptom severity than those with no/minimal dizziness (n = 21; age = 16.5 ± 1.9; 38% female). During steady-state gait, moderate/severe dizziness group walked with significantly slower single-task cadence (mean difference = 4.8 steps/minute; 95% confidence interval = 0.8, 8.8; P = 0.02) and dual-task cadence (mean difference = 7.4 steps/minute; 95% confidence interval = 0.7, 14.0; P = 0.04) than no/mild dizziness group. CONCLUSION: Participants who reported moderate/severe dizziness reported higher concussion symptom burden, higher anxiety scores, and higher depression scores than those with no/mild dizziness. Cadence during gait was also associated with the level of dizziness reported.

Predictors of Acute Transfer and Mortality Within 6 Months From Admission to an Inpatient Rehabilitation Facility for Patients With Brain Tumors.

OBJECTIVE: To obtain useful information for clinicians in evaluating patients with brain tumors for transfer to and subsequent care in inpatient rehabilitation facilities (IRFs). DESIGN: Retrospective chart review. SETTING: Inpatient rehabilitation facility. PARTICIPANTS: A total of 208 adults with either initial or recurrent brain tumors who were admitted to an IRF between January 2017 and December 2018 after an acute hospitalization. INTERVENTIONS: None MAIN OUTCOME MEASURES: Transfer from an IRF to an acute care hospital and mortality within 6 months from admission to an IRF. RESULTS: Of the 208 patients who met inclusion criteria, 20.2% were transferred to an acute care hospital during the IRF stay, which was associated with prior chemotherapy, steroid use, and laterality of tumor. In total, 36.9% of patients with brain tumors died within 6 months of an IRF admission that was associated with recurrent tumor diagnosis, prior chemotherapy, prior neurosurgical intervention, prior neurostimulant use, use of steroids, isocitrate dehydrogenase and O6-methyl-guanyl-methyl-transferase biomarkers, and laterality and location of tumor. CONCLUSIONS: Patients with brain tumors have a notable potential for acute hospital transfer and mortality within 6 months of IRF stay, with several tumor- and treatment-related risk factors. This information can help identify functional goals, identify high risk patients, enable closer clinical monitoring, and facilitate focused care discussions at IRFs.

Linear Mixed Effect Models for Rehabilitation Research.

ABSTRACT: The growing emphasis on evidence-based methods in rehabilitation medicine calls for increase in the sophistication of study design and analytic methods across the discipline. To properly evaluate new treatment options, a physiatrist needs to be able to separate treatment effects from parallel changes that occur over time and variations that may be due to subject demographics. Simple t tests may not be appropriate where observations may vary randomly across different institutions participating in a multicenter trial, or the same rehabilitation course may lead to different outcomes because of various factors. In the analysis of any rehabilitation program, these random variations must be accounted for to receive accurate results. In this short review, we focus in one of the most common approaches that are appropriate to account for these variations, namely, linear mixed effect models.

Postconcussion Exercise Volume Associations With Depression, Anxiety, and Dizziness Symptoms, and Postural Stability: Preliminary Findings.

OBJECTIVE: To examine the association between postconcussion exercise volume and changes in depression, anxiety, dizziness, and postural stability. DESIGN: Secondary analysis of a single-site prospective clinical trial. SETTING: Cerebrovascular research laboratory. PARTICIPANTS: Participants completed questionnaires and underwent tests of gait and balance within 2 weeks of a concussion (mean = 11 ± 3 days postconcussion) and approximately 1 month later (mean = 41 ± 7 days postconcussion). Exercise volume was tracked by weekly exercise logs. INTERVENTIONS: On the basis of a previous work classifying exercise volume following concussion, we grouped participants according to self-reported exercise volume between visits as high exercise volume (≥150 min/wk) or low exercise volume (<150 min/wk). MAIN OUTCOME MEASURES: Participants completed assessments evaluating anxiety and depression (Hospital Anxiety and Depression Scale), dizziness (Dizziness Handicap Inventory), and postural stability (tandem gait and modified Balance Error Scoring System). RESULTS: Thirty-eight participants completed the study, of which 22 were in the high exercise volume group (mean = 71 ± 40 min/wk; 16.8 ± 2.1 years; 59% female) and 16 were in the low exercise volume group (mean = 379 ± 187 min/wk; 17.5 ± 2.1 years; 31% female). Although depression symptoms were not significantly different initially (mean difference = 1.5; 95% CI, -0.68 to 3.68; P = .24), the high exercise volume group had significantly lower depression symptom scores at follow-up (mean difference = 3.0; 95% CI, 1.40 to 4.47; P < .001). Anxiety symptoms (mean difference = 2.8; 95% CI, 0.3 to 5.4; P = 0.03), dizziness symptoms (mean difference = 10.9; 95% CI, 0.2 to 21.5; P = .047), single-task tandem gait (mean difference = 3.1 seconds; 95% CI, 0.2 to 6.0; P = .04), and dual-task tandem gait (mean difference = 4.2 seconds; 95% CI, 0.2 to 8.2; P = .04) were significantly better among the high exercise volume group. CONCLUSION: Greater exercise volumes were associated with lower depression, anxiety, and dizziness symptoms, and faster tandem gait performance. These preliminary findings suggest a potentially beneficial role for exercise within several different domains commonly affected by concussion.

Clazosentan for Improvement of Time to Peak Perfusion in Patients with Angiographically Confirmed Severe Vasospasm.

BACKGROUND: Clazosentan, an endothelin-1 receptor antagonist, has been shown to prevent the development of large vessel angiographic vasospasm after aneurysmal subarachnoid hemorrhage. We hypothesized that clazosentan can improve cerebral perfusion for territories affected by angiographically confirmed vasospasm. METHODS: The REVERSE study (REversal of Vasospasm with clazosEntan post-aneuRysmal Subarachnoid hEmorrhage) was a prospective multicenter open-label pilot study of adult patients with aneurysmal subarachnoid hemorrhage who received intravenous clazosentan after developing moderate to severe angiographic vasospasm. Using the radiographic data from the REVERSE study and additional retrospective radiographic data from our tertiary medical center, we compared the impact of intravenous clazosentan with intraarterial vasodilator therapy (medical standard of care) on vasospasm reversal using time to peak perfusion (TTPP; the time interval between the peak opacification of contrast dye in the main artery supplying an anatomically defined territory and the parenchymal phase when the dye is diffusely present in the brain parenchyma). RESULTS: Both intravenous clazosentan (n = 7 vessels) and intraarterial vasodilator therapy (n = 11 vessels) resulted in a statistically significant improvement in TTPP at 24 h post intervention, when compared with the TTPP just prior to intervention for territories with angiographically confirmed severe vasospasm in the proximal arteries at baseline (linear mixed-effect model, p = 0.02). The clazosentan and intraarterial vasodilator therapy groups exhibited no statistically significant interaction term [time x treatment group (medical standard of care vs. clazosentan)] in our model (p = 0.71), suggesting similar temporal course of two therapies. CONCLUSIONS: In our small pilot study, intravenous clazosentan administered for at least 24 h had an effect comparable with that of intraarterial vasodilator therapy in reversing angiographically confirmed severe vasospasm. Our results may indicate that clazosentan, in an appropriately selected patient cohort, could offer a noninvasive approach for alleviating vasospasm.

Association of Hemodynamic and Cerebrovascular Responses to Exercise With Symptom Severity in Adolescents and Young Adults With Concussion.

BACKGROUND AND OBJECTIVES: Aerobic exercise has become a useful method to assist with postconcussion management. Exercise can exacerbate concussion symptoms even when symptoms are not apparent at rest. Few studies have examined the reasons for symptom exacerbation during exercise following a concussion. We had 2 primary objectives: (1) to delineate cardiopulmonary and cerebrovascular responses to exercise in adolescents and young adults with a concussion and healthy controls and (2) to determine the association between cerebrovascular responses and symptom burden. METHODS: We recruited participants with a recent concussion from a sport concussion clinic between September 1, 2018, and February 22, 2020. They were included if their concussion occurred <3 weeks before initial testing and if they were symptomatic at rest. Participants were excluded if they sustained a concussion in the past year (excluding index injury), reported history of neurologic disorders, or were using medications/devices that may alter neurologic function. Participants completed a progressive, symptom-limited, submaximal exercise protocol on a stationary bicycle. We assessed heart rate, blood pressure, fraction of end tidal CO2 (FETCO2), and middle cerebral artery blood flow velocity (CBF) and cerebrovascular function (vasoactivity and autoregulation) at seated rest and during exercise. RESULTS: We conducted 107 exercise tests (40 concussed, 37 healthy participants initially; 30 concussed at follow-up). Concussed participants were tested initially (mean 17.6 ± 2.2 [SD] years of age; 55% female; mean 12.5 ± 4.7 days postconcussion) and again 8 weeks later (mean 73.3 ± 9.5 days postconcussion). Control participants (mean 18.3 ± 2.4 years; 62% female) were tested once. FETCO2 increased throughout the exercise protocol as heart rate increased, reached a plateau, and declined at higher exercise intensities. CO2 explained >25% of the variation in resting CBF (R 2 > 0.25; p < 0.01) in most (73% individuals). Within the concussion group, resting symptom severity and the heart rate at which FETCO2 reached a plateau explained ∼2/3s of variation in exercise-induced symptom exacerbation (R 2 = 0.65; FETCO2 ß = -1.210 ± 0.517 [SE], p < 0.05). There was a moderate, statistically significant relationship between cerebrovascular responses to CO2 at rest (cerebral vasoactivity) and cerebrovascular responses to exercise-induced changes in FETCO2 (R 2 = 0.13, p = 0.01). DISCUSSION: The arterial CO2 response and symptom exacerbation relationship during postconcussion aerobic exercise may be mediated by increased sensitivity of cerebral vasculature to exercise-related increase in CO2.

Sequential Therapy With Recombinant Human IGF-1 Followed by Risedronate Increases Spine Bone Mineral Density in Women With Anorexia Nervosa: A Randomized, Placebo-Controlled Trial.

Anorexia nervosa is complicated by low bone mineral density (BMD) and increased fracture risk associated with low bone formation and high bone resorption. The lumbar spine is most severely affected. Low bone formation is associated with relative insulin-like growth factor 1 (IGF-1) deficiency. Our objective was to determine whether bone anabolic therapy with recombinant human (rh) IGF-1 used off-label followed by antiresorptive therapy with risedronate would increase BMD more than risedronate or placebo in women with anorexia nervosa. We conducted a 12-month, randomized, placebo-controlled study of 90 ambulatory women with anorexia nervosa and low areal BMD (aBMD). Participants were randomized to three groups: 6 months of rhIGF-1 followed by 6 months of risedronate ("rhIGF-1/Risedronate") (n = 33), 12 months of risedronate ("Risedronate") (n = 33), or double placebo ("Placebo") (n = 16). Outcome measures were lumbar spine (1° endpoint: postero-anterior [PA] spine), hip, and radius aBMD by dual-energy X-ray absorptiometry (DXA), and vertebral, tibial, and radial volumetric BMD (vBMD) and estimated strength by high-resolution peripheral quantitative computed tomography (HR-pCT) (for extremity measurements) and multi-detector computed tomography (for vertebral measurements). At baseline, mean age, body mass index (BMI), aBMD, and vBMD were similar among groups. At 12 months, mean PA lumbar spine aBMD was higher in the rhIGF-1/Risedronate (p = 0.03) group and trended toward being higher in the Risedronate group than Placebo. Mean lateral lumbar spine aBMD was higher, in the rhIGF-1/Risedronate than the Risedronate or Placebo groups (p < 0.05). Vertebral vBMD was higher, and estimated strength trended toward being higher, in the rhIGF-1/Risedronate than Placebo group (p < 0.05). Neither hip or radial aBMD or vBMD, nor radial or tibial estimated strength, differed among groups. rhIGF-1 was well tolerated. Therefore, sequential therapy with rhIGF-1 followed by risedronate increased lateral lumbar spine aBMD more than risedronate or placebo. Strategies that are anabolic and antiresorptive to bone may be effective at increasing BMD in women with anorexia nervosa. © 2021 American Society for Bone and Mineral Research (ASBMR).