In this cross-sectional study, we tested the construct validity of a "total SVD score," which combines individual MRI features of small-vessel disease (SVD) in one measure, by testing associations ...with vascular risk factors and stroke subtype.
We analyzed data from patients with lacunar or nondisabling cortical stroke from 2 prospective stroke studies. Brain MRI was rated for the presence of lacunes, white matter hyperintensities, cerebral microbleeds, and perivascular spaces independently. The presence of each SVD feature was summed in an ordinal "SVD score" (range 0-4). We tested associations with vascular risk factors, stroke subtype, and cerebral atrophy using ordinal regression analysis.
In 461 patients, multivariable analysis found that age (odds ratio OR 1.10, 95% confidence interval CI 1.08-1.12), male sex (OR 1.58, 95% CI 1.10-2.29), hypertension (OR 1.50, 95% CI 1.02-2.20), smoking (OR 2.81, 95% CI 1.59-3.63), and lacunar stroke subtype (OR 2.45, 95% CI 1.70-3.54) were significantly and independently associated with the total SVD score. The score was not associated with cerebral atrophy.
The total SVD score may provide a more complete estimate of the full impact of SVD on the brain, in a simple and pragmatic way. It could have potential for patient or risk stratification or early efficacy assessment in clinical trials of interventions to prevent SVD progression and may (after further testing) have a useful role in clinical practice.
Enlarged perivascular spaces in the brain are common but generally overlooked and of uncertain pathophysiology. They may reflect underlying cerebral small vessel disease. We determined whether ...enlarged perivascular spaces were associated with lacunar stroke subtype and white matter hyperintensities, markers of established small vessel disease.
We prospectively recruited patients with acute ischemic lacunar or cortical stroke. Age-matched nonstroke control subjects were also recruited. We rated basal ganglia and centrum semiovale enlarged perivascular spaces 0 to 4 (0=none, 4=>40) on T2-weighted MRI and white matter hyperintensities. We compared enlarged perivascular spaces between stroke subtypes and control subjects and assessed associations with vascular risk factors and white matter hyperintensities.
We recruited 350 patients; 129 lacunar, 124 cortical stroke, and 97 age-matched control subjects. Adjusting for vascular risk factors and white matter hyperintensities, total enlarged perivascular spaces were associated with lacunar stroke subtype (P=0.04) in the acute stroke group (n=253); basal ganglia enlarged perivascular spaces were associated with lacunar stroke subtype (P=0.003), deep (P=0.02) and periventricular white matter hyperintensities (P=0.01); in all 350 subjects, total enlarged perivascular spaces were associated with deep (P<0.001) and periventricular (P<0.001) white matter hyperintensities.
Although prevalent in patients with vascular risk factors and stroke, enlarged perivascular spaces are specifically associated with lacunar ischemic stroke and white matter hyperintensities. Further studies should determine the mechanism of this association while including adequate controls to account for stroke and vascular risk factors. Enlarged perivascular spaces should not be overlooked in studies of small vessel disease.
To assess for the first time the safety and pharmacokinetics of an antiprogrammed cell death-ligand 1 immune checkpoint inhibitor (BMS-936559; Bristol-Myers Squibb, Princeton, NJ) and its effect on ...immune biomarkers in participants with sepsis-associated immunosuppression.
Randomized, placebo-controlled, dose-escalation.
Seven U.S. hospital ICUs.
Twenty-four participants with sepsis, organ dysfunction (hypotension, acute respiratory failure, and/or acute renal injury), and absolute lymphocyte count less than or equal to 1,100 cells/μL.
Participants received single-dose BMS-936559 (10-900 mg; n = 20) or placebo (n = 4) infusions. Primary endpoints were death and adverse events; key secondary endpoints included receptor occupancy and monocyte human leukocyte antigen-DR levels.
The treated group was older (median 62 yr treated pooled vs 46 yr placebo), and a greater percentage had more than 2 organ dysfunctions (55% treated pooled vs 25% placebo); other baseline characteristics were comparable. Overall mortality was 25% (10 mg dose: 2/4; 30 mg: 2/4; 100 mg: 1/4; 300 mg: 1/4; 900 mg: 0/4; placebo: 0/4). All participants had adverse events (75% grade 1-2). Seventeen percent had a serious adverse event (3/20 treated pooled, 1/4 placebo), with none deemed drug-related. Adverse events that were potentially immune-related occurred in 54% of participants; most were grade 1-2, none required corticosteroids, and none were deemed drug-related. No significant changes in cytokine levels were observed. Full receptor occupancy was achieved for 28 days after BMS-936559 (900 mg). At the two highest doses, an apparent increase in monocyte human leukocyte antigen-DR expression (> 5,000 monoclonal antibodies/cell) was observed and persisted beyond 28 days.
In this first clinical evaluation of programmed cell death protein-1/programmed cell death-ligand 1 pathway inhibition in sepsis, BMS-936559 was well tolerated, with no evidence of drug-induced hypercytokinemia or cytokine storm, and at higher doses, some indication of restored immune status over 28 days. Further randomized trials on programmed cell death protein-1/programmed cell death-ligand 1 pathway inhibition are needed to evaluate its clinical safety and efficacy in patients with sepsis.
Trp-ing out on cytosolic [Fe-S]-cluster delivery Dean, Dennis R; Martin Del Campo, Julia S
Proceedings of the National Academy of Sciences - PNAS,
11/2023, Volume:
120, Issue:
48
Journal Article
Coordination between visual and motor processes is critical for the selection of stable footholds when walking in uneven terrains. While recent work (Matthis et al. in Curr Biol 8(28):1224-1233, ...2018) demonstrates a tight link between gaze (visual) and gait (motor), it remains unclear which aspects of visual information play a role in this visuomotor control loop, and how the loss of this information affects that relationship. Here we examine the role of binocular information in the visuomotor control of walking over complex terrain. We recorded eye and body movements while normally-sighted participants walked over terrains of varying difficulty, with intact vision or with vision in one eye blurred to disrupt binocular vision. Gaze strategy was highly sensitive to the complexity of the terrain, with more fixations dedicated to foothold selection as the terrain became more difficult. The primary effect of increased sensory uncertainty due to disrupted binocular vision was a small bias in gaze towards closer footholds, indicating greater pressure on the visuomotor control process. Participants with binocular vision losses due to developmental disorders (i.e., amblyopia, strabismus), who have had the opportunity to develop alternative strategies, also biased their gaze towards closer footholds. Across all participants, we observed a relationship between an individual's typical level of binocular visual function and the degree to which gaze is shifted toward the body. Thus the gaze-gait relationship is sensitive to the level of sensory uncertainty, and deficits in binocular visual function (whether transient or long-standing) have systematic effects on gaze strategy in complex terrains. We conclude that binocular vision provides useful information for locating footholds during locomotion. Furthermore, we have demonstrated that combined eye/body tracking in natural environments can be used to provide a more detailed understanding of the impact of a type of vision loss on the visuomotor control process of walking, a vital everyday task.
Abstract Introduction Small vessel disease (SVD) is a common contributor to dementia. Subtle blood-brain barrier (BBB) leakage may be important in SVD-induced brain damage. Methods We assessed ...imaging, clinical variables, and cognition in patients with mild (i.e., nondisabling) ischemic lacunar or cortical stroke. We analyzed BBB leakage, interstitial fluid, and white matter integrity using multimodal tissue-specific spatial analysis around white matter hyperintensities (WMH). We assessed predictors of 1 year cognition, recurrent stroke, and dependency. Results In 201 patients, median age 67 (range 34–97), BBB leakage, and interstitial fluid were higher in WMH than normal-appearing white matter; leakage in normal-appearing white matter increased with proximity to WMH ( P < .0001), with WMH severity ( P = .033), age ( P = .03), and hypertension ( P < .0001). BBB leakage in WMH predicted declining cognition at 1 year. Discussion BBB leakage increases in normal-appearing white matter with WMH and predicts worsening cognition. Interventions to reduce BBB leakage may prevent SVD-associated dementia.
To determine the magnitude of potentially causal relationships among vascular risk factors (VRFs), large-artery atheromatous disease (LAD), and cerebral white matter hyperintensities (WMH) in 2 ...prospective cohorts.
We assessed VRFs (history and measured variables), LAD (in carotid, coronary, and leg arteries), and WMH (on structural MRI, visual scores and volume) in: (a) community-dwelling older subjects of the Lothian Birth Cohort 1936, and (b) patients with recent nondisabling stroke. We analyzed correlations, developed structural equation models, and performed mediation analysis to test interrelationships among VRFs, LAD, and WMH.
In subjects of the Lothian Birth Cohort 1936 (n = 881, mean age 72.5 years SD ±0.7 years, 49% with hypertension, 33% with moderate/severe WMH), VRFs explained 70% of the LAD variance but only 1.4% to 2% of WMH variance, of which hypertension explained the most. In stroke patients (n = 257, mean age 74 years SD ±11.6 years, 61% hypertensive, 43% moderate/severe WMH), VRFs explained only 0.1% of WMH variance. There was no direct association between LAD and WMH in either sample. The results were the same for all WMH measures used.
The small effect of VRFs and LAD on WMH suggests that WMH have a large "nonvascular," nonatheromatous etiology. VRF modification, although important, may be limited in preventing WMH and their stroke and dementia consequences. Investigation of, and interventions against, other suspected small-vessel disease mechanisms should be addressed.
Background and aims
Enlarged perivascular spaces (also known as Virchow-Robin spaces) on T2-weighted brain magnetic resonance imaging are common, but their etiology, and specificity to small vessel ...as opposed to general cerebrovascular disease or ageing, is unclear. We tested the association between enlarged perivascular spaces and ischemic stroke subtype, other markers of small vessel disease, and common vascular risk factors.
Methods
We prospectively recruited patients with acute stroke, diagnosed and subtyped by a stroke physician using clinical features and brain magnetic resonance imaging. A neuroradiologist rated basal ganglia and centrum semiovale enlarged perivascular spaces on a five-point scale, white matter lesions, recent and old infarcts, and cerebral atrophy. We assessed associations between basal ganglia-, centrum semiovale- and total (combined basal ganglia and centrum semiovale) enlarged perivascular spaces, stroke subtype, white matter lesions, atrophy, and vascular risk factors.
Results
Among 298 patients (mean age 68 years), after adjusting for vascular risk factors and white matter lesions, basal ganglia-enlarged perivascular spaces were associated with increasing age (P = 0·001), centrum semiovale-enlarged perivascular spaces (P < 0·001), cerebral atrophy (P = 0·03), and lacunar stroke subtype (P = 0·04). Centrum semiovale- enlarged perivascular spaces were associated mainly with basal ganglia-enlarged perivascular spaces. Total enlarged perivascular spaces were associated with increasing age (P = 0·01), deep white matter lesions (P = 0·005), and previous stroke (P = 0·006).
Conclusions
Enlarged perivascular spaces are associated with age, lacunar stroke subtype and white matter lesions and should be considered as another magnetic resonance imaging marker of cerebral small vessel disease. Further evaluation of enlarged perivascular spaces in studies of ageing, stroke, and dementia is needed to determine their pathophysiological importance.
Anxiety after stroke is common and disabling. Stroke trialists have treated anxiety as a homogenous condition, and intervention studies have followed suit, neglecting the different treatment ...approaches for phobic and generalized anxiety. Using diagnostic psychiatric interviews, we aimed to report the frequency of phobic and generalized anxiety, phobic avoidance, predictors of anxiety, and patient outcomes at 3 months poststroke/transient ischemic attack.
We followed prospectively a cohort of new diagnosis of stroke/transient ischemic attack at 3 months with a telephone semistructured psychiatric interview, Fear Questionnaire, modified Rankin Scale, EuroQol-5D5L, and Work and Social Adjustment Scale.
Anxiety disorder was common (any anxiety disorder, 38 of 175 22%). Phobic disorder was the predominant anxiety subtype: phobic disorder only, 18 of 175 (10%); phobic and generalized anxiety disorder, 13 of 175 (7%); and generalized anxiety disorder only, 7 of 175 (4%). Participants with anxiety disorder reported higher level of phobic avoidance across all situations on the Fear Questionnaire. Younger age (per decade increase in odds ratio, 0.64; 95% confidence interval, 0.45-0.91) and having previous anxiety/depression (odds ratio, 4.38; 95% confidence interval, 1.94-9.89) were predictors for anxiety poststroke/transient ischemic attack. Participants with anxiety disorder were more dependent (modified Rankin Scale score 3-5, anxiety 55% versus no anxiety 29%;
<0.0005), had poorer quality of life on EQ-5D5L, and restricted participation (Work and Social Adjustment Scale: median, interquartile range, anxiety 19.5, 10-27 versus no anxiety 0, 0-5;
<0.001).
Anxiety after stroke/transient ischemic attack is predominantly phobic and is associated with poorer patient outcomes. Trials of anxiety intervention in stroke should consider the different treatment approaches needed for phobic and generalized anxiety.
Purpose
Sepsis-associated immunosuppression increases hospital-acquired infection and viral reactivation risk. A key underlying mechanism is programmed cell death protein-1 (PD-1)-mediated T-cell ...function impairment. This is one of the first clinical safety and pharmacokinetics (PK) assessments of the anti-PD-1 antibody nivolumab and its effect on immune biomarkers in sepsis.
Methods
Randomized, double-blind, parallel-group, Phase 1b study in 31 adults at 10 US hospital ICUs with sepsis diagnosed ≥ 24 h before study treatment, ≥ 1 organ dysfunction, and absolute lymphocyte count ≤ 1.1 × 10
3
cells/μL. Participants received one nivolumab dose 480 mg (
n
= 15) or 960 mg (
n
= 16); follow-up was 90 days. Primary endpoints were safety and PK parameters.
Results
Twelve deaths occurred
n
= 6 per study arm; 40% (480 mg) and 37.5% (960 mg). Serious AEs occurred in eight participants
n
= 1, 6.7% (480 mg);
n
= 7, 43.8% (960 mg). AEs considered by the investigator to be possibly drug-related and immune-mediated occurred in five participants
n
= 2, 13.3% (480 mg);
n
= 3, 18.8% (960 mg). Mean ± SD terminal half-life was 14.7 ± 5.3 (480 mg) and 15.8 ± 7.9 (960 mg) days. All participants maintained > 90% receptor occupancy (RO) 28 days post-infusion. Median (Q1, Q3) mHLA-DR levels increased to 11,531 (6528, 19,495) and 11,449 (6225, 16,698) mAbs/cell in the 480- and 960-mg arms by day 14, respectively. Pro-inflammatory cytokine levels did not increase.
Conclusions
In this sepsis population, nivolumab administration did not result in unexpected safety findings or indicate any ‘cytokine storm’. The PK profile maintained RO > 90% for ≥ 28 days. Further efficacy and safety studies are warranted.
Trial registration number (clinicaltrials.gov)
NCT02960854.
PDF
