Lipoprotein (a) Lp(a) serum levels are highly genetically determined and promote atherogenesis. High Lp(a) levels are associated with increased cardiovascular morbidity. Serum Lp(a) levels have ...recently been associated with large artery atherosclerosis (LAA) stroke. We aimed to externally validate this association in an independent cohort.
This study stems from the prospective multicentre CoRisk study (CoPeptin for Risk Stratification in Acute Stroke patients NCT00878813), conducted at the University Hospital Bern, Switzerland, between 2009 and 2011, in which Lp(a) plasma levels were measured within the first 24 hours after stroke onset. We assessed the association of Lp(a) with LAA stroke using multivariable logistic regression and performed interaction analyses to identify potential effect modifiers.
Of 743 patients with ischaemic stroke, 105 (14%) had LAA stroke aetiology. Lp(a) levels were higher for LAA stroke than non-LAA stroke patients (23.0 nmol/l vs 16.3 nmol/l, p = 0.01). Multivariable regression revealed an independent association of log10and#xA0;Lp(a) with LAA stroke aetiology (aOR 1.47 95% CI 1.03and#x2013;2.09, p = 0.03). The interaction analyses showed that Lp(a) was not associated with LAA stroke aetiology among patients with diabetes.
In a well-characterised cohort of patients with ischaemic stroke, we validated the association of higher Lp(a) levels with LAA stroke aetiology, independent of traditional cardiovascular risk factors. These findings may inform randomised clinical trials investigating the effect of Lp(a) lowering agents on cardiovascular outcomes. The CoRisk (CoPeptin for Risk Stratification in Acute Patients) study is registered on ClinicalTrials.gov.
NCT00878813.
Post hoc analyses of clinical trials show that PCSK9 inhibitors might lower lipoprotein(a), but whether this effect contributes to reductions in cardiovascular risk remains unknown. We aimed to ...assess whether genetically proxied PCSK9 inhibition influences lipoprotein(a) (Lp(a)), and whether any such effect could mediate its effects on coronary artery disease (CAD) and ischemic stroke (IS).
To explore associations between the genetic proxies for PCSK9 inhibitors and Lp(a) levels, we used UK Biobank data (310,020 individuals). We identified 10 variants in the PCSK9 gene associated with lower PCSK9 and LDL-C levels as proxies for PCSK9 inhibition. We explored the effects of genetically proxied PCSK9 inhibition on Lp(a) levels, as well as on odds of CAD (60,801 cases, 184,305 controls) and IS (60,341 cases, 454,450 controls) in two-sample Mendelian randomization analyses. In mediation analyses, we assessed the effects of genetically proxied PCSK9 inhibition on CAD and IS mediated through reductions in Lp(a) levels.
Genetically proxied PCSK9 inhibition (1-SD decrement in PCSK9 concentration; corresponding to 20.6 mg/dl decrement in LDL-C levels) was associated with a 4% decrease in log-Lp(a) levels (beta: −0.038, 95%CI: −0.053 to −0.023). We estimated a 0.8% reduction in the odds for CAD (OR: 0.992, 95%CI: 0.989–0.995) and a 0.5% reduction in the odds for atherosclerotic IS (OR: 0.995, 95%CI: 0.992–0.998) due to reductions in Lp(a) levels through genetically proxied PCSK9 inhibition, corresponding to 3.8% and 3.2% of the total effects, respectively.
Genetic proxies for PCSK9 inhibition are associated with lower Lp(a) levels. However, Lp(a) lowering explains only a small proportion of the total effects of genetic proxies for PCSK9 inhibitors on risk of CAD and IS.
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•12 genetic variants in the PCSK9 gene were identified as proxies for PCSK9 inhibition.•Genetically proxied PCSK9 inhibition is associated with lower Lp(a) levels.•Lp(a) lowering explains only a small proportion of the effects of genetically proxied PCSK9 inhibition on cardiovascular risk.
The objective of this study was to assess the efficacy and tolerability of intranasal midazolam (in-MDZ) administration for antiseizure treatment in adults.
Embase and Medline literature databases ...were searched. We included randomized trials and cohort studies (excluding case series) of adult patients (≥ 18 years of age) examining in-MDZ administration for epilepsy, epileptic seizures, or status epilepticus published in English between 1985 and 2022. Studies were screened for eligibility based on predefined criteria. The primary outcome was the efficacy of in-MDZ administration, and the secondary outcome was its tolerability. Extracted data included study design, patient characteristics, intervention details, and outcomes. Risk of bias was assessed using the Cochrane Risk of Bias Tool.
A total of 12 studies with 929 individuals treated with in-MDZ were included. Most studies were retrospective, with their number increasing over time. Administered in-MDZ doses ranged from 2.5 to 20 mg per single dose. The mean proportion of successful seizure termination after first in-MDZ administration was 72.7% (standard deviation SD 18%), and the proportion of seizure recurrence or persistent seizures ranged from 61 to 75%. Most frequent adverse reactions to in-MDZ were dizziness (mean 23.5% SD 38.6%), confusion (one study; 17.4%), local irritation (mean 16.6% SD 9.6%), and sedation (mean 12.7% SD 9.7%).
Administration of in-MDZ seems promising for the treatment of prolonged epileptic seizures and seizure clusters in adults. Limited evidence suggests that intranasal administration is safe. Further research is warranted because of the heterogeneity of cohorts, the variation in dosages, and the lack of uniformity in defining successful seizure termination.
Background
We investigate the frequency and diagnostic yield of cerebrospinal fluid (CSF) analysis in adult patients with status epilepticus (SE) and its impact on the outcome.
Methods
From 2011 to ...2018, adult patients treated at the University Hospital Basel were included. Primary outcomes were defined as the frequency of lumbar puncture and results from chemical, cellular, and microbiologic CSF analyses. Secondary outcomes were differences between patients receiving and not receiving lumbar puncture in the context of SE.
Results
In 18% of 408 patients, a lumbar puncture was performed. Of those, infectious pathogens were identified in 21% with 15% detected ± 24 h around SE diagnosis. 74% of CSF analyses revealed abnormal chemical or cellular components without infectious pathogens. Screening for autoimmune diseases was only performed in 22%. In 8%, no or late (i.e., > 24 after SE diagnosis) lumbar puncture was performed despite persistent unknown SE etiology in all, transformation into refractory SE in 78%, and no recovery to premorbid neurologic function in 66%. Withholding lumbar puncture was associated with no return to premorbid neurologic function during hospital stay independent of potential confounders. Not receiving a lumbar puncture was associated with presumed known etiology and signs of systemic infectious complications.
Conclusions
Withholding lumbar puncture in SE patients is associated with increased odds for no return to premorbid neurologic function, and CSF analyses in SE detect infectious pathogens frequently. These results and pathologic chemical and cellular CSF findings in the absence of infections call for rigorous screening to confirm or exclude infectious or autoimmune encephalitis in this context which should not be withheld.
We assessed the efficacy and safety of mechanical thrombectomy (MT) in adult stroke patients with anterior circulation large vessel occlusion presenting in the late time window not fulfilling the ...DEFUSE-3 (Thrombectomy for Stroke at 6 to 16 Hours With Selection by Perfusion Imaging trial) and DAWN (Thrombectomy 6 to 24 Hours After Stroke With a Mismatch Between Deficit and Infarct trial) inclusion criteria.
Cohort study of adults with anterior circulation large vessel occlusion admitted between 6 and 24 hours after last-seen-well at 5 participating Swiss stroke centers between 2014 and 2021. Mismatch was assessed by computer tomography or magnetic resonance imaging perfusion with automated software (RAPID or OLEA). We excluded patients meeting DEFUSE-3 and DAWN inclusion criteria and compared those who underwent MT with those receiving best medical treatment alone by inverse probability of treatment weighting using the propensity score. The primary efficacy end point was a favorable functional outcome at 90 days, defined as a modified Rankin Scale score shift toward lower categories. The primary safety end point was symptomatic intracranial hemorrhage within 7 days of stroke onset; the secondary was all-cause mortality within 90 days.
Among 278 patients with anterior circulation large vessel occlusion presenting in the late time window, 190 (68%) did not meet the DEFUSE-3 and DAWN inclusion criteria and thus were included in the analyses. Of those, 102 (54%) received MT. In the inverse probability of treatment weighting analysis, patients in the MT group had higher odds of favorable outcomes compared with the best medical treatment alone group (modified Rankin Scale shift: acOR, 1.46 1.02-2.10;
=0.04) and lower odds of all-cause mortality within 90 days (aOR, 0.59 0.37-0.93;
=0.02). There were no significant differences in symptomatic intracranial hemorrhage (MT versus best medical treatment alone: 5% versus 2%,
=0.63).
Two out of 3 patients with anterior circulation large vessel occlusion presenting in the late time window did not meet the DEFUSE-3 and DAWN inclusion criteria. In these patients, MT was associated with higher odds of favorable functional outcomes without increased rates of symptomatic intracranial hemorrhage. These findings support the enrollment of patients into ongoing randomized trials on MT in the late window with more permissive inclusion criteria.
Objectives This review examined studies regarding the implementation and translation of patients' advance directives (AD) in intensive care units (ICUs), focusing on practical difficulties and ...obstacles. Methods The digital PubMed and Medline databases were screened using predefined keywords to identify relevant prospective and retrospective studies published until 2022. Results Seventeen studies from the United States, Europe, and South Africa (including 149,413 patients and 1210 healthcare professionals) were identified. The highest prevalence of ADs was described in a prospective study in North America (49%), followed by Central Europe (13%), Asia (4%), Australia and New Zealand (4%), Latin America (3%), and Northern and Southern Europe (2.6%). While four retrospective studies reported limited effects of ADs, four retrospective studies, one survey and one systematic review indicated significant effects on provision of intensive care, higher rates of do-not-resuscitate orders, and care withholding in patients with ADs. Four of these studies showed shorter ICU stays, and lower treatment costs in patients with ADs. One prospective and two retrospective studies reported issues with loss, delayed or no transmission of ADs. One survey revealed that 91% of healthcare workers did not regularly check for ADs. Two retrospective studies and two survey revealed that the implementation of directives is further challenged by issues with their applicability, phrasing, and compliance by the critical care team and family members. Conclusions Although ADs may improve intensive- and end-of-life care, insufficient knowledge, lack of awareness, poor communication between healthcare providers and patients or surrogates, lack of standardization of directives, as well as ethical and legal concerns challenge their implementation. Keywords: Advance directives, Patients' will, Intensive care, Neurocritical illness
Background
Cerebral microbleeds (CMBs) may have a differential impact on clinical outcome in stroke patients with atrial fibrillation (AF) treated with different types of oral anticoagulation (OAC).
...Methods
Observational single-center study on AF-stroke-patients treated with OAC. Magnetic-resonance-imaging was performed to assess CMBs. Outcome measures consisted of recurrent ischemic stroke (IS), intracranial hemorrhage (ICH), death, and their combined analysis. Functional disability was assessed by mRS. Using adjusted logistic regression and Cox proportional-hazards models, we assessed the association of the presence of CMBs and OAC type (vitamin K antagonists VKAs vs. direct oral anticoagulants DOACs) with clinical outcome.
Results
Of 310 AF-stroke patients treated with OAC DOACs:
n
= 234 (75%); VKAs:
n
= 76 (25%), CMBs were present in 86 (28%) patients; of these, 66 (77%) received DOACs. In both groups, CMBs were associated with an increased risk for the composite outcome: VKAs: HR 3.654 1.614; 8.277;
p
= 0.002; DOACs: HR 2.230 1.233; 4.034;
p
= 0.008. Patients with CMBs had ~50% higher absolute rates of the composite outcome compared to the overall cohort, with a comparable ratio between treatment groups VKAs 13/20(65%) vs. DOACs 19/66(29%);
p
< 0.01. The VKA-group had a 2-fold higher IS VKAs:4 (20%) vs. DOACs:6 (9%);
p
= 0.35 and a 10-fold higher ICH rate VKAs: 3 (15%) vs. DOACs: 1 (1.5%);
p
= 0.038. No significant interaction was observed between type of OAC and presence of CMBs. DOAC-patients showed a significantly better functional outcome (OR 0.40 0.17; 0.94;
p
= 0.04).
Conclusions
In AF-stroke patients treated with OAC, the presence of CMBs was associated with an unfavorable composite outcome for both VKAs and DOACs, with a higher risk for recurrent IS than for ICH. Strokes were numerically higher under VKAs and increased in the presence of CMBs.
Clinical trial registration
http://www.clinicaltrials.gov
, Unique identifier: NCT03826927.
Background:
The DEFUSE-3 and DAWN trials showed that mechanical thrombectomy (MT) improves the outcome of selected patients with anterior circulation large vessel occlusions (LVO) up to 24 h after ...stroke onset. However, it is unknown whether only those patients fulfilling the trial inclusion criteria benefit, or whether benefit is seen in a broader range of patients presenting between 6 and 24 h.
Aims:
We determined whether fulfilling the DEFUSE-3 and DAWN selection criteria affects outcomes in MT patients in clinical practice.
Methods:
We reviewed adult patients with LVO treated with MT between 6 and 24 h after stroke onset at five Swiss stroke centers between 2014 and 2021. We compared two groups: (1) patients who satisfied neither DEFUSE-3 nor DAWN criteria (NDND) and (2) those who satisfied DEFUSE-3 or DAWN criteria (DOD). We used logistic regression to examine the impact of trial eligibility on two safety outcomes (symptomatic intracranial hemorrhage sICH and all-cause mortality at 3 months) and two efficacy outcomes (modified Rankin Score mRS shift toward lower categories and mRS of 0–2 at 3 months).
Results:
Of 174 patients who received MT, 102 (59%) belonged to the NDND group. Rates of sICH were similar between the NDND group and the DOD group (3% vs. 4%, p = 1.00). Multivariable regression revealed no differences in 3-month all-cause mortality (aOR 2.07, 95% CI 0.64–6.84, p = 0.23) or functional outcomes (mRS shift: acOR 0.81, 95% CI 0.37–1.79, p = 0.60; mRS 0–2: aOR 0.91, 95% CI 0.31–2.57, p = 0.85).
Conclusion:
Among adult patients with LVO treated with MT between 6 and 24 h, safety and efficacy outcomes were similar between DEFUSE-3/DAWN eligible and ineligible patients. Our data provide a compelling rationale for randomized trials with broader inclusion criteria for MT.
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