The meibomian glands (MGs) within the eyelids produce a lipid-rich secretion that forms the superficial layer of the tear film. Meibomian gland dysfunction (MGD) results in excessive evaporation of ...the tear film, which is the leading cause of dry eye disease (DED). To develop a research model similar to the physiological situation of MGs, we established a new 3D organotypic slice culture (OSC) of
MGs (mMGs) and investigated the effects of melanocortins on exocrine secretion. Tissue viability, lipid production and morphological changes were analyzed during a 21-day cultivation period. Subsequently, the effects on lipid production and gene expression were examined after stimulation with a melanocortin receptor (MCR) agonist, α-melanocyte-stimulating hormone (α-MSH), and/or an MCR antagonist, JNJ-10229570. The cultivation of mMGs OSCs was possible without impairment for at least seven days. Stimulation with the MCR agonists induced lipid production in a dose-dependent manner, whereas this effect was tapered with the simultaneous incubation of the MCR antagonist. The new 3D OSC model is a promising approach to study the (patho-) physiological properties of MG/MGD while reducing animal studies. Therefore, it may accelerate the search for new treatments for MGD/DED and lead to new insights, such as that melanocortins likely stimulate meibum production.
The probability to receive intravenous thrombolysis (IVT) for treatment of acute ischemic stroke declines with increasing age and is consequently the lowest in very elderly patients. Safety concerns ...likely influence individual IVT treatment decisions. Using data from a large IVT registry, we aimed to provide more evidence on safety of IVT in the very elderly.
In this prospective multicenter study from the TRISP (Thrombolysis in Ischemic Stroke Patients) registry, we compared patients ≥90 years with those <90 years using symptomatic intracranial hemorrhage (ECASS European Cooperative Acute Stroke Study-II criteria), death, and poor functional outcome in survivors (modified Rankin Scale score 3-5 for patients with prestroke modified Rankin Scale score ≤2 and modified Rankin Scale score 4-5 for patients prestroke modified Rankin Scale ≥3) at 3 months as outcomes. We calculated adjusted odds ratio with 95% CI using logistic regression models.
Of 16 974 eligible patients, 976 (5.7%) were ≥90 years. Patients ≥90 years had higher median National Institutes of Health Stroke Scale on admission (12 versus 8) and were more often dependent prior to the index stroke (prestroke modified Rankin Scale score of ≥3; 45.2% versus 7.4%). Occurrence of symptomatic intracranial hemorrhage (5.7% versus 4.4%, odds ratio
1.14 0.83-1.57) did not differ significantly between both groups. However, the probability of death (odds ratio
3.77 3.14-4.53) and poor functional outcome (odds ratio
2.63 2.13-3.25) was higher in patients aged ≥90 years. Results for the sample of centenarians (n=21) were similar.
The probability of symptomatic intracranial hemorrhage after IVT in very elderly patients with stroke did not exceed that of their younger counterparts. The higher probability of death and poor functional outcome during follow-up in the very elderly seems not to be related to IVT treatment. Very high age itself should not be a reason to withhold IVT.
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.
Introduction: Measures of cerebral small vessel disease (cSVD), such as white matter hyperintensities (WMH) and cerebral microbleeds (CMB), are associated with an unfavorable clinical course in ...stroke patients on oral anticoagulation (OAC) for atrial fibrillation (AF). Here, we investigated whether similar findings can be observed for global cortical atrophy (GCA). Methods: Registry-based prospective observational study of 320 patients treated with OAC following AF stroke. Patients underwent magnetic resonance imaging (MRI) allowing assessment of GCA. Using the simplified visual Pasquier scale, the severity of GCA was categorized as follows: 0: no atrophy, 1: mild atrophy; 2: moderate atrophy, and 3: severe atrophy. Using adjusted logistic and Cox regression analysis, we investigated the association of GCA using a composite outcome measure, comprising: (i) recurrent acute ischemic stroke (IS); (ii) intracranial hemorrhage (ICH); and (iii) death. Results: In our time to event analysis after adjusting for potential confounders (i.e., WMH, CMB, age, sex, diabetes, arterial hypertension, coronary heart disease, hyperlipidemia, and antiplatelet use), GCA was associated with an increased risk for the composite outcome in all three degrees of atrophy (grade 1: aHR 3.95, 95% CI 1.34–11.63, p = 0.013; grade 2: aHR 3.89, 95% CI 1.23–12.30, p = 0.021; grade 3: aHR 4.16, 95% CI 1.17–14.84, p = 0.028). Conclusion: GCA was associated with our composite outcome also after adjusting for other cSVD markers (i.e., CMB, WMH) and age, indicating that GCA may potentially serve as a prognostic marker for stroke patients with atrial fibrillation on oral anticoagulation.
Data on the effectiveness and safety of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) in patients with stroke attributable to atrial fibrillation (AF) who were dependent on ...the daily help of others at hospital discharge are scarce.
Based on prospectively obtained data from the observational Novel-Oral-Anticoagulants-in-Ischemic-Stroke-Patients-longterm registry from Basel, Switzerland, we compared the occurrence of the primary outcome—the composite of recurrent ischemic stroke, major bleeding, and all-cause death—among consecutive patients with AF-stroke treated with either VKAs or DOACs between patients dependent (defined as modified Rankin Scale score, 3–5) and patients independent at discharge. We used simple, adjusted, and weighted Cox proportional hazards regression to account for potential confounders.
We analyzed 801 patients (median age 80 years, 46% female), of whom 391 (49%) were dependent at discharge and 680 (85%) received DOACs. Over a total follow-up of 1216 patient-years, DOAC- compared to VKA-treated patients had a lower hazard for the composite outcome (hazard ratio HR, 0.58 95% CI, 0.42–0.81), as did independent compared to dependent patients (HR, 0.54 95% CI, 0.40–0.71). There was no evidence that the effect of anticoagulant type (DOAC versus VKA) on the hazard for the composite outcome differed between dependent (HRdependent, 0.68 95% CI, 0.45–1.01) and independent patients (HRindependent, 0.44 95% CI, 0.26–0.75) in the simple model (Pinteraction=0.212). Adjusted (HRdependent, 0.74 95% CI, 0.49–1.11 and HRindependent, 0.51 95% CI, 0.30–0.87; Pinteraction=0.284) and weighted models (HRdependent, 0.79 95% CI, 0.48–1.31 and HRindependent, 0.46 95% CI, 0.26–0.81; Pinteraction=0.163) yielded concordant results. Secondary analyses focusing on the individual components of the composite outcome were consistent to the primary analyses.
The benefits of DOACs in patients with atrial fibrillation with a recent stroke were maintained among patients who were dependent on the help of others at discharge.
URL: https://www.clinicaltrials.gov; Unique identifier: NCT03826927.
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.
Objective
To investigate the prognostic value of white blood cell count (WBC) on functional outcome, mortality and bleeding risk in stroke patients treated with intravenous thrombolysis (IVT).
...Methods
In this prospective multicenter study from the TRISP registry, we assessed the association between WBC on admission and 3-month poor outcome (modified Rankin Scale 3–6), mortality and occurrence of symptomatic intracranial hemorrhage (sICH; ECASS-II-criteria) in IVT-treated stroke patients. WBC was used as continuous and categorical variable distinguishing leukocytosis (WBC > 10 × 10
9
/l) and leukopenia (WBC < 4 × 10
9
/l). We calculated unadjusted/ adjusted odds ratios with 95% confidence intervals (OR 95% CI) with logistic regression models. In a subgroup, we analyzed the association of combined leukocytosis and elevated C-reactive protein (CRP > 10 mg/l) on outcomes.
Results
Of 10,813 IVT-treated patients, 2527 had leukocytosis, 112 leukopenia and 8174 normal WBC. Increasing WBC (by 1 × 10
9
/l) predicted poor outcome (OR
adjusted
1.041.02–1.06) but not mortality and sICH. Leukocytosis was independently associated with poor outcome (OR
adjusted
1.481.29–1.69) and mortality (OR
adjusted
1.601.35–1.89) but not with sICH (OR
adjusted
1.170.94–1.45). Leukopenia did not predict any outcome. In a subgroup, combined leukocytosis and elevated CRP had the strongest association with poor outcome (OR
adjusted
2.261.76–2.91) and mortality (OR
adjusted
2.431.86–3.16) when compared to combined normal WBC and CRP.
Conclusion
In IVT-treated patients, leukocytosis independently predicted poor functional outcome and death. Bleeding complications after IVT were not independently associated with leukocytosis.
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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