The role of endovascular thrombectomy is uncertain for patients presenting beyond 24 hours of the time they were last known well.
To evaluate functional and safety outcomes for endovascular ...thrombectomy (EVT) vs medical management in patients with large-vessel occlusion beyond 24 hours of last known well.
This retrospective observational cohort study enrolled patients between July 2012 and December 2021 at 17 centers across the United States, Spain, Australia, and New Zealand. Eligible patients had occlusions in the internal carotid artery or middle cerebral artery (M1 or M2 segment) and were treated with EVT or medical management beyond 24 hours of last known well.
Endovascular thrombectomy or medical management (control).
Primary outcome was functional independence (modified Rankin Scale score 0-2). Mortality and symptomatic intracranial hemorrhage (sICH) were safety outcomes. Propensity score (PS)-weighted multivariable logistic regression analyses were adjusted for prespecified clinical characteristics, perfusion parameters, and/or Alberta Stroke Program Early CT Score (ASPECTS) and were repeated in subsequent 1:1 PS-matched cohorts.
Of 301 patients (median IQR age, 69 years 59-81; 149 female), 185 patients (61%) received EVT and 116 (39%) received medical management. In adjusted analyses, EVT was associated with better functional independence (38% vs control, 10%; inverse probability treatment weighting adjusted odds ratio IPTW aOR, 4.56; 95% CI, 2.28-9.09; P < .001) despite increased odds of sICH (10.1% for EVT vs 1.7% for control; IPTW aOR, 10.65; 95% CI, 2.19-51.69; P = .003). This association persisted after PS-based matching on (1) clinical characteristics and ASPECTS (EVT, 35%, vs control, 19%; aOR, 3.14; 95% CI, 1.02-9.72; P = .047); (2) clinical characteristics and perfusion parameters (EVT, 35%, vs control, 17%; aOR, 4.17; 95% CI, 1.15-15.17; P = .03); and (3) clinical characteristics, ASPECTS, and perfusion parameters (EVT, 45%, vs control, 21%; aOR, 4.39; 95% CI, 1.04-18.53; P = .04). Patients receiving EVT had lower odds of mortality (26%) compared with those in the control group (41%; IPTW aOR, 0.49; 95% CI, 0.27-0.89; P = .02).
In this study of treatment beyond 24 hours of last known well, EVT was associated with higher odds of functional independence compared with medical management, with consistent results obtained in PS-matched subpopulations and patients with presence of mismatch, despite increased odds of sICH. Our findings support EVT feasibility in selected patients beyond 24 hours. Prospective studies are warranted for confirmation.
Despite the presence of CTLs in the tumor microenvironment, the majority of immunogenic human colon cancer does not respond to immune checkpoint inhibitor immunotherapy, and microsatellite instable ...(MSI) tumors are not naturally eliminated. The molecular mechanism underlying the inactivity of tumor-infiltrating CTLs is unknown. We report here that CTLs were present in both MSI and microsatellite stable colon tumors. The expression of the H3K9me3-specific histone methyltransferase SUV39H1 was significantly elevated in human colon carcinoma compared with normal colon tissues. Using a mouse colon carcinoma model, we further determined that tumor-infiltrating CTLs in the colon tumor microenvironment have high expression of SUV39H1. To target SUV39H1 in the tumor microenvironment, a virtual chemical library was screened on the basis of the SET (suppressor of variegation 3-9, enhancer of zeste and trithorax) domain structure of the human SUV39H1 protein. Functional enzymatic activity assays identified a small molecule that inhibits SUV39H1 enzymatic activity. On the basis of the structure of this small molecule, we modified it and chemically synthesized a small molecule, termed F5446, which has an EC
of 0.496 μmol/L for SUV39H1 enzymatic activity. H3K9me3 was enriched in the promoters of
, and
in quiescent T cells. F5446 inhibited H3K9me3, thereby upregulating expression of these effectors in tumor-infiltrating CTLs and suppressing colon carcinoma growth in a CD8
CTL-dependent manner
Our data indicate that SUV39H1 represses CTL effector gene expression and, in doing so, confers colon cancer immune escape.
Multiple randomised trials have shown efficacy and safety of endovascular thrombectomy in patients with large ischaemic stroke. The aim of this study was to evaluate long-term (ie, at 1 year) ...evidence of benefit of thrombectomy for these patients.
SELECT2 was a phase 3, open-label, international, randomised controlled trial with blinded endpoint assessment, conducted at 31 hospitals in the USA, Canada, Spain, Switzerland, Australia, and New Zealand. Patients aged 18–85 years with ischaemic stroke due to proximal occlusion of the internal carotid artery or of the first segment of the middle cerebral artery, showing large ischaemic core on non-contrast CT (Alberta Stroke Program Early Computed Tomographic Score of 3–5 range 0–10, with lower values indicating larger infarctions) or measuring 50 mL or more on CT perfusion and MRI, were randomly assigned, within 24 h of ischaemic stroke onset, to thrombectomy plus medical care or to medical care alone. The primary outcome for this analysis was the ordinal modified Rankin Scale (range 0–6, with higher scores indicating greater disability) at 1-year follow-up in an intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT03876457) and is completed.
The trial was terminated early for efficacy at the 90-day follow-up after 352 patients had been randomly assigned (178 to thrombectomy and 174 to medical care only) between Oct 11, 2019, and Sept 9, 2022. Thrombectomy significantly improved the 1-year modified Rankin Scale score distribution versus medical care alone (Wilcoxon-Mann-Whitney probability of superiority 0·59 95% CI 0·53–0·64; p=0·0019; generalised odds ratio 1·43 95% CI 1·14–1·78). At the 1-year follow-up, 77 (45%) of 170 patients receiving thrombectomy had died, compared with 83 (52%) of 159 patients receiving medical care only (1-year mortality relative risk 0·89 95% CI 0·71–1·11).
In patients with ischaemic stroke due to a proximal occlusion and large core, thrombectomy plus medical care provided a significant functional outcome benefit compared with medical care alone at 1-year follow-up.
Stryker Neurovascular.
Severe acute stroke patients with critical carotid stenosis or occlusion without intracranial thrombus typically do not undergo emergent carotid thromboendarterectomy (CEA) because of the risk of ...reperfusion-related intracranial hemorrhage. Past studies have not consistently demonstrated benefit of early operative intervention. Cerebral computed tomography (CT), cervical and cerebral CT angiography (CTA), and cerebral CT perfusion (CTP) imaging may identify a subset of acute stroke patients without intracranial thrombus who may benefit from emergent CEA. Acute stroke patients underwent unenhanced brain CT imaging to exclude pathology that would contraindicate emergent therapy. Emergent CTAs of the intracranial and extracranial vessels were utilized to identify patients who presented with stroke symptoms based on the presence of isolated extracranial carotid disease in the absence of intracranial thromboembolism. CTP was then used to assess the extent of potentially reversible cerebral ischemia (penumbral tissue). Patients with isolated extracranial carotid lesions with significant reversible ischemia in the absence of large areas of irreversible cerebral damage underwent emergent CEA to salvage ischemic penumbra. In 1 year, 3 patients presented with large acute strokes in which CTA disclosed symptomatic extracranial internal carotid artery preocclusive or occlusive lesions without intracranial thromboembolic occlusions. CTP indicated a large area of ischemic penumbra with limited permanent injury. Mean age, time to presentation, and National Institutes of Health stroke score (NIHSS) were 66 years, 4.2 hr, and 19.3. All patients underwent emergent CEA with cervical carotid thrombectomy. Average time from stroke symptom onset to revascularization was 12.5 (range 5.9-19.0) hr. There were no perioperative deaths. At day 5, the mean NIHSS decreased to 7.6 and at day 30 was 4.7. The modified Rankin scale score dropped from a poststroke, preoperative level of 5 to 2.3 by day 30. Emergent CEA should be considered in patients presenting with large acute strokes based on favorable CT, CTA, and CTP findings. Emergent clot localization and physiological assessment of brain "tissue at risk" relative to irreversible cerebral infarction using CT, CTA, and CTP is now available. Utilization of this information by an experienced stroke team of neurologists, radiologists, and surgeons may aid in the recognition of a select group of patients in which emergent CEA may drive to improved outcomes.
Background
Accumulating evidence indicates that the pathological changes of AD begin 15 years prior to symptom onset. There is an unmet need for accessible, affordable, and accurate means to screen ...cognitively normal individuals for preclinical AD. We previously developed the Percepts of Odor Episodic Memory (POEM) test battery, which assesses identification, memory and discrimination of odor percepts. In a pilot study, we demonstrated that elderly individuals with odor memory scores that fell below the 50% confidence intervals of the memory scores predicted by their odor discrimination and odor identification scores; these individuals were deemed “at risk” for progression to mild cognitive impairment and AD based on an enrichment in biomarkers for AD.
Method
We tested our olfactory “at risk” status as a predictor of future decline by administering the POEM test battery to 61 older individuals who were cognitively normal (CN) or expressed subjective cognitive concerns (SCC) and were followed longitudinally in the Massachusetts Alzheimer’ s Disease Research Center. These individuals were added to our original sample of 140 participants who had undergone olfactory testing. A Cox Proportional Hazards model was used in a subset of this expanded cohort (n=127) who were followed over an average of 4.22 years to determine whether the olfactory “at risk” status predicted a risk of clinical progression to a diagnosis of amnestic MCI or Alzheimer’s disease.
Result
28% of the CN and SCC participants followed longitudinally were deemed “at risk” based on a selective odor memory loss. These “at risk” participants demonstrated a higher risk of progressing to amnestic MCI or AD (HR = 3.45, (95% CI:1.13‐10.72, p=0.0278) over time while controlling for age, education, and sex. The effect of Group (CN vs SCC) and its interaction with “at risk” status were not significant.
Conclusion
Our results indicate that probing olfactory function with a threshold based on personalized identification and discrimination abilities identifies cognitively healthy seniors who progress to amnestic MCI or AD at faster rate over time. Future work is focused on developing a remote version of this test for self‐administration that can be used to screen cognitively healthy individuals for research studies and clinical trials.
Abstract
Background
Accumulating evidence indicates that the pathological changes of AD begin 15 years prior to symptom onset. There is an unmet need for accessible, affordable, and accurate means to ...screen cognitively normal individuals for preclinical AD. We previously developed the Percepts of Odor Episodic Memory (POEM) test battery, which assesses identification, memory and discrimination of odor percepts. In a pilot study, we demonstrated that elderly individuals with odor memory scores that fell below the 50% confidence intervals of the memory scores predicted by their odor discrimination and odor identification scores; these individuals were deemed “at risk” for progression to mild cognitive impairment and AD based on an enrichment in biomarkers for AD.
Method
We tested our olfactory “at risk” status as a predictor of future decline by administering the POEM test battery to 61 older individuals who were cognitively normal (CN) or expressed subjective cognitive concerns (SCC) and were followed longitudinally in the Massachusetts Alzheimer’ s Disease Research Center. These individuals were added to our original sample of 140 participants who had undergone olfactory testing. A Cox Proportional Hazards model was used in a subset of this expanded cohort (n=127) who were followed over an average of 4.22 years to determine whether the olfactory “at risk” status predicted a risk of clinical progression to a diagnosis of amnestic MCI or Alzheimer’s disease.
Result
28% of the CN and SCC participants followed longitudinally were deemed “at risk” based on a selective odor memory loss. These “at risk” participants demonstrated a higher risk of progressing to amnestic MCI or AD (HR = 3.45, (95% CI:1.13‐10.72, p=0.0278) over time while controlling for age, education, and sex. The effect of Group (CN vs SCC) and its interaction with “at risk” status were not significant.
Conclusion
Our results indicate that probing olfactory function with a threshold based on personalized identification and discrimination abilities identifies cognitively healthy seniors who progress to amnestic MCI or AD at faster rate over time. Future work is focused on developing a remote version of this test for self‐administration that can be used to screen cognitively healthy individuals for research studies and clinical trials.
The ABC-ATPase GlcV energizes a binding protein-dependent ABC transporter that mediates glucose uptake in Sulfolobus solfataricus. Here, we report high-resolution crystal structures of GlcV in ...different states along its catalytic cycle: distinct monomeric nucleotide-free states and monomeric complexes with ADP-Mg2+ as a product-bound state, and with AMPPNP-Mg2+ as an ATP-like bound state. The structure of GlcV consists of a typical ABC-ATPase domain, comprising two subdomains, connected by a linker region to a C-terminal domain of unknown function. Comparisons of the nucleotide-free and nucleotide-bound structures of GlcV reveal re-orientations of the ABCα subdomain and the C-terminal domain relative to the ABCα/β subdomain, and switch-like rearrangements in the P-loop and Q-loop regions. Additionally, large conformational differences are observed between the GlcV structures and those of other ABC-ATPases, further emphasizing the inherent flexibility of these proteins. Notably, a comparison of the monomeric AMPPNP-Mg2+-bound GlcV structure with that of the dimeric ATP-Na+-bound LolD-E171Q mutant reveals a ±20° rigid body re-orientation of the ABCα subdomain relative to the ABCα/β subdomain, accompanied by a local conformational difference in the Q-loop. We propose that these differences represent conformational changes that may have a role in the mechanism of energy-transduction and/or allosteric control of the ABC-ATPase activity in bacterial importers.
Summary Background Cognitive decline is a debilitating manifestation of disease progression in Parkinson's disease. We aimed to develop a clinical–genetic score to predict global cognitive impairment ...in patients with the disease. Methods In this longitudinal analysis, we built a prediction algorithm for global cognitive impairment (defined as Mini Mental State Examination MMSE ≤25) using data from nine cohorts of patients with Parkinson's disease from North America and Europe assessed between 1986 and 2016. Candidate predictors of cognitive decline were selected through a backward eliminated Cox's proportional hazards analysis using the Akaike's information criterion. These were used to compute the multivariable predictor on the basis of data from six cohorts included in a discovery population. Independent replication was attained in patients from a further three independent longitudinal cohorts. The predictive score was rebuilt and retested in 10 000 training and test sets randomly generated from the entire study population. Findings 3200 patients with Parkinson's disease who were longitudinally assessed with 27 022 study visits between 1986 and 2016 in nine cohorts from North America and Europe were assessed for eligibility. 235 patients with MMSE ≤25 at baseline and 135 whose first study visit occurred more than 12 years from disease onset were excluded. The discovery population comprised 1350 patients (after further exclusion of 334 with missing covariates) from six longitudinal cohorts with 5165 longitudinal visits over 12·8 years (median 2·8, IQR 1·6–4·6). Age at onset, baseline MMSE, years of education, motor exam score, sex, depression, and β-glucocerebrosidase ( GBA ) mutation status were included in the prediction model. The replication population comprised 1132 patients (further excluding 14 patients with missing covariates) from three longitudinal cohorts with 19 127 follow-up visits over 8·6 years (median 6·5, IQR 4·1–7·2). The cognitive risk score predicted cognitive impairment within 10 years of disease onset with an area under the curve (AUC) of more than 0·85 in both the discovery (95% CI 0·82–0·90) and replication (95% CI 0·78–0·91) populations. Patients scoring in the highest quartile for cognitive risk score had an increased hazard for global cognitive impairment compared with those in the lowest quartile (hazard ratio 18·4 95% CI 9·4–36·1). Dementia or disabling cognitive impairment was predicted with an AUC of 0·88 (95% CI 0·79–0·94) and a negative predictive value of 0·92 (95% 0·88–0·95) at the predefined cutoff of 0·196. Performance was stable in 10 000 randomly resampled subsets. Interpretation Our predictive algorithm provides a potential test for future cognitive health or impairment in patients with Parkinson's disease. This model could improve trials of cognitive interventions and inform on prognosis. Funding National Institutes of Health, US Department of Defense.
Recent neuroimaging studies have converged to show that odorant-induced responses to prolonged stimulation in primary olfactory cortex (POC) are characterized by a rapidly habituating time course. ...Different statistical approaches have effectively modeled this time course. One approach explicitly modeled rapid habituation using an exponentially decaying reference waveform that decreased to baseline levels within 30 to 40 s. A
second approach modeled an early transient response by simply shortening the odorant ‘ON’ period to be less than the actual stimulation period (i.e., 9 of 40 s). The goal of the current study was to validate, compare, and optimize these methodological approaches by applying them to an olfactory fMRI block-design dataset from 10 healthy young subjects presented with odorants for 12 s (ON), alternating with 30 s of clear air (OFF). Both approaches significantly improved sensitivity to odorant-induced signal changes in POC relative to a square-wave model based on the actual stimulation period. Our findings further demonstrate that the ‘optimal’ model fit to the data was achieved by shortening the odorant ‘ON’ period to approximately 6 s. These results suggest that sensitivity to odorant-induced POC activity in block-design experiments can be optimized by modeling an early phasic response followed by a precipitous rather than specific exponential decrease to baseline levels. Notably, whole brain voxel-wise analyses further established that modeling rapid habituation in this way is not only sensitive, but also highly specific to odorant-induced activation in a well-established network of olfactory-related brain areas.
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