Endovascular thrombectomy plus medical care versus medical care alone for large ischaemic stroke: 1-year outcomes of the SELECT2 trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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]). INTERPRETATION: 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. FUNDING: Stryker Neurovascular.

Fazirsiran for Adults with Alpha-1 Antitrypsin Deficiency Liver Disease: A Phase 2 Placebo Controlled Trial (SEQUOIA).

BACKGROUND & AIMS: Homozygous ZZ alpha-1 antitrypsin (AAT) deficiency produces mutant AAT (Z-AAT) proteins in hepatocytes, leading to progressive liver fibrosis. We evaluated the safety and efficacy of an investigational RNA interference therapeutic, fazirsiran, that degrades Z-AAT mRNA, reducing deleterious protein synthesis. METHODS: This ongoing, phase 2 study randomized 40 patients to subcutaneous placebo or fazirsiran 25/100/200 mg. The primary endpoint was percentage change in serum Z-AAT concentration from baseline to Week 16. Patients with fibrosis on baseline liver biopsy received treatment on Day 1, Week 4, and then every 12 weeks, and had a second liver biopsy at or after Weeks 48, 72, or 96. Patients without fibrosis received two doses on Day 1 and Week 4. RESULTS: At Week 16, least-squares mean percent declines in serum Z-AAT concentration were -61%, -83% and -94% with fazirsiran 25/100/200 mg, respectively, versus placebo (all P< .0001). Efficacy was sustained through Week 52. At post-dose liver biopsy, fazirsiran reduced median liver Z-AAT concentration by 93% compared with an increase of 26% with placebo. All fazirsiran-treated patients had histological reduction from baseline in hepatic globule burden. Portal inflammation improved in 5/12 and 0/8 patients with baseline score >0 in the fazirsiran and placebo groups, respectively. Histological METAVIR score improved by >1 point in 7/14 and 3/8 patients with fibrosis >F0 at baseline in the fazirsiran and placebo groups, respectively. No adverse events led to discontinuation and pulmonary function tests remained stable. CONCLUSIONS: Fazirsiran reduced serum and liver concentrations of Z-AAT in a dose dependent manner and reduced hepatic globule burden (NCT03945292).

ARISE I Consensus Statement on the Management of Chronic Subdural Hematoma.

ARISE (Aneurysm/AVM/cSDH Roundtable Discussion With Industry and Stroke Experts) organized a one-and-a-half day meeting and workshop and brought together representatives from academia, industry, and government to discuss the most promising approaches to improve outcomes for patients with chronic subdural hematoma (cSDH). The emerging role of middle meningeal artery embolization in clinical practice and the design of current and potential future trials were the primary focuses of discussion. Existing evidence for imaging, indications, agents, and techniques was reviewed, and areas of priority for study and key questions surrounding the development of new and existing treatments for cSDH were identified. Multiple randomized, controlled trials have met their primary efficacy end points, providing high-level evidence that middle meningeal artery embolization is a potent adjunctive therapy to the standard (surgical and nonsurgical) management of neurologically stable cSDH patients in terms of reducing rates of disease recurrence. Pooled data analyses following the formal conclusion and publication of these trials will form a robust foundation upon which guidelines can be strengthened for cSDH treatment modalities and optimal patient selection, as well as delineate future lines of investigation.

Dysregulation of circadian clock gene expression patterns in a treatment-resistant animal model of depression.

Circadian rhythm (CR) disturbances are among the most commonly observed symptoms during major depressive disorder, mostly in the form of disrupted sleeping patterns. However, several other measurable parameters, such as plasma hormone rhythms and differential expression of circadian clock genes (ccgs), are also present, often referred to as circadian phase markers. In the recent years, CR disturbances have been recognized as an essential aspect of depression; however, most of the known animal models of depression have yet to be evaluated for their eligibility to model CR disturbances. In this study, we investigate the potential of adrenocorticotropic hormone (ACTH)-treated animals as a disease model for research in CR disturbances in treatment-resistant depression. For this purpose, we evaluate the changes in several circadian phase markers, including plasma concentrations of corticosterone, ACTH, and melatonin, as well as gene expression patterns of 13 selected ccgs at 3 different time points, in both peripheral and central tissues. We observed no impact on plasma corticosterone and melatonin concentrations in the ACTH rats compared to vehicle. However, the expression pattern of several ccgs was affected in the ACTH rats compared to vehicle. In the hippocampus, 10 ccgs were affected by ACTH treatment, whereas in the adrenal glands, 5 ccgs were affected and in the prefrontal cortex, hypothalamus and liver 4 ccgs were regulated. In the blood, only 1 gene was affected. Individual tissues showed changes in different ccgs, but the expression of Bmal1, Per1, and Per2 were most generally affected. Collectively, the results presented here indicate that the ACTH animal model displays dysregulation of a number of phase markers suggesting the model may be appropriate for future studies into CR disturbances.

Alpha-1 Antitrypsin Augmentation and the Liver Phenotype of Adults With Alpha-1 Antitrypsin Deficiency (Genotype Pi∗ZZ).

BACKGROUND & AIMS: α1-Antitrypsin (AAT) is a major protease inhibitor produced by hepatocytes. The most relevant AAT mutation giving rise to AAT deficiency (AATD), the 'Pi∗Z' variant, causes harmful AAT protein accumulation in the liver, shortage of AAT in the systemic circulation, and thereby predisposes to liver and lung injury. Although intravenous AAT augmentation constitutes an established treatment of AATD-associated lung disease, its impact on the liver is unknown. METHODS: Liver-related parameters were assessed in a multinational cohort of 760 adults with severe AATD (Pi∗ZZ genotype) and available liver phenotyping, of whom 344 received augmentation therapy and 416 did not. Liver fibrosis was evaluated noninvasively via the serum test AST-to-platelet ratio index and via transient elastography-based liver stiffness measurement. Histologic parameters were compared in 15 Pi∗ZZ adults with and 35 without augmentation. RESULTS: Compared with nonaugmented subjects, augmented Pi∗ZZ individuals displayed lower serum liver enzyme levels (AST 71% vs 75% upper limit of normal, P < .001; bilirubin 49% vs 58% upper limit of normal, P = .019) and lower surrogate markers of fibrosis (AST-to-platelet ratio index 0.34 vs 0.38, P < .001; liver stiffness measurement 6.5 vs 7.2 kPa, P = .005). Among biopsied participants, augmented individuals had less pronounced liver fibrosis and less inflammatory foci but no differences in AAT accumulation were noted. CONCLUSIONS: The first evaluation of AAT augmentation on the Pi∗ZZ-related liver disease indicates liver safety of a widely used treatment for AATD-associated lung disease. Prospective studies are needed to confirm the beneficial effects and to demonstrate the potential efficacy of exogenous AAT in patients with Pi∗ZZ-associated liver disease.

Risk of adjacent level fracture after percutaneous vertebroplasty and kyphoplasty vs natural history for the management of osteoporotic vertebral compression fractures: a network meta-analysis of randomized controlled trials.

OBJECTIVES: Percutaneous vertebroplasty and kyphoplasty are common interventions for osteoporotic vertebral compression fractures. However, there is concern about an increased risk of adjacent-level fractures after treatment. This study aimed to compare the risk of adjacent-level fractures after vertebroplasty and kyphoplasty with the natural history after osteoporotic vertebral compression fractures. MATERIALS AND METHODS: A network meta-analysis of randomized controlled trials (RCTs) was conducted to evaluate the risk of adjacent-level fractures after vertebroplasty and kyphoplasty compared to the natural history after osteoporotic vertebral compression fractures. Frequentist network meta-analysis was conducted using the "netmeta" package, and heterogeneity was assessed using Q statistics. The pooled risk ratio (RR) and 95% confidence intervals (CI) were calculated using random effects. RESULTS: Twenty-three RCTs with a total of 2838 patients were included in the analysis. The network meta-analysis showed comparable risks of adjacent-level fractures between vertebroplasty, kyphoplasty, and natural history after osteoporotic vertebral compression fractures with a mean follow-up of 21.2 (range: 3-49.4 months). The pooled RR for adjacent-level fractures after kyphoplasty compared to natural history was 1.35 (95% CI, 0.78-2.34, p = 0.23) and for vertebroplasty compared to natural history was 1.16 (95% CI, 0.62-2.14) p = 0.51. The risk of bias assessment showed a low to moderate risk of bias among included RCTs. CONCLUSION: There was no difference in the risk of adjacent-level fractures after vertebroplasty and kyphoplasty compared to natural history after osteoporotic vertebral compression fractures. The inclusion of a large patient number and network meta-analysis of RCTs serve evidence-based clinical practice. CLINICAL RELEVANCE STATEMENT: The risk of adjacent-level fracture following percutaneous vertebroplasty or kyphoplasty is similar to that observed in the natural history after osteoporotic vertebral compression fractures. KEY POINTS: RCTs have examined the risk of adjacent-level fracture after intervention for osteoporotic vertebral compression fractures. There was no difference between vertebroplasty and kyphoplasty patients compared to the natural disease history for adjacent compression fractures. This is strong evidence that interventional treatments for these fractures do not increase the risk of adjacent fractures.

Detachment forces during parallel-plate gap separation mediated by a simple yield-stress fluid.

In this work we have monitored the multiple stages of the normal traction force response of a yield-stress fluid confined between two circular parallel plates that are separated at constant velocity. At narrow initial gaps, the air-fluid interface suffers from the Saffman-Taylor instability, confirmed by visual inspection of fingering patterns imprinted on the fluid. At larger initial gaps, the fluid preserves the initially imposed circular symmetry of the confining plates, indicating the absence of instability. Due to the system characteristics and experimental environment, the multiple traction force contributions occurred in cascade, permitting us to isolate the adhesion responses associated with viscosity, capillarity, and yield stress. Employing a standard Herschel-Bulkley model, we assessed the scaling of the traction force in multiple regimes-specifically, evaluating the dependencies of the fingering to yield-stress transitions.

Cost-Effectiveness of Late Endovascular Thrombectomy vs. Best Medical Management in a Clinical Trial Setting and Real-World Setting.

BACKGROUND AND PURPOSE: To assess cost-effectiveness of late time-window endovascular treatment (EVT) in a clinical trial setting and a "real-world" setting. METHODS: Data are from the randomized ESCAPE trial and a prospective cohort study (ESCAPE-LATE). Anterior circulation large vessel occlusion patients presenting > 6 hours from last-known-well were included, whereby collateral status was an inclusion criterion for ESCAPE but not ESCAPE-LATE. A Markov state transition model was built to estimate lifetime costs and quality-adjusted life-years (QALYs) for EVT in addition to best medical care vs. best medical care only in a clinical trial setting (comparing ESCAPE-EVT to ESCAPE control arm patients) and a "real-world" setting (comparing ESCAPE-LATE to ESCAPE control arm patients). We performed an unadjusted analysis, using 90-day modified Rankin Scale(mRS) scores as model input and analysis adjusted for baseline factors. Acceptability of EVT was calculated using upper/lower willingness-to-pay thresholds of 100,000 USD/50,000 USD/QALY. RESULTS: Two-hundred and forty-nine patients were included (ESCAPE-LATE:n = 200, ESCAPE EVT-arm:n = 29, ESCAPE control-arm:n = 20). Late EVT in addition to best medical care was cost effective in the unadjusted analysis both in the clinical trial and real-world setting, with acceptability 96.6%-99.0%. After adjusting for differences in baseline variables between the groups, late EVT was marginally cost effective in the clinical trial setting (acceptability:49.9%-61.6%), but not the "real-world" setting (acceptability:32.9%-42.6%). CONCLUSION: EVT for LVO-patients presenting beyond 6 hours was cost effective in the clinical trial setting and "real-world" setting, although this was largely related to baseline patient differences favoring the "real-world" EVT group. After adjusting for these, EVT benefit was reduced in the trial setting, and absent in the real-world setting.

Thrombectomy alone versus intravenous alteplase plus thrombectomy in patients with stroke: an open-label, blinded-outcome, randomised non-inferiority trial.

BACKGROUND: Whether thrombectomy alone is equally as effective as intravenous alteplase plus thrombectomy remains controversial. We aimed to determine whether thrombectomy alone would be non-inferior to intravenous alteplase plus thrombectomy in patients presenting with acute ischaemic stroke. METHODS: In this multicentre, randomised, open-label, blinded-outcome trial in Europe and Canada, we recruited patients with stroke due to large vessel occlusion confirmed with CT or magnetic resonance angiography admitted to endovascular centres. Patients were randomly assigned (1:1) via a centralised web server using a deterministic minimisation method to receive stent-retriever thrombectomy alone or intravenous alteplase plus stent-retriever thrombectomy. In both groups, thrombectomy was initiated as fast as possible with any commercially available Solitaire stent-retriever revascularisation device (Medtronic, Irvine, CA, USA). In the combined treatment group, intravenous alteplase (0·9 mg/kg bodyweight, maximum dose 90 mg per patient) was administered as early as possible after randomisation for 60 min with 10% of the calculated dose given as an initial bolus. Personnel assessing the primary outcome were masked to group allocation; patients and treating physicians were not. The primary binary outcome was a score of 2 or less on the modified Rankin scale at 90 days. We assessed the non-inferiority of thrombectomy alone versus intravenous alteplase plus thrombectomy in all randomly assigned and consenting patients using the one-sided lower 95% confidence limit of the Mantel-Haenszel risk difference, with a prespecified non-inferiority margin of 12%. The main safety endpoint was symptomatic intracranial haemorrhage assessed in all randomly assigned and consenting participants. This trial is registered with ClinicalTrials.gov, NCT03192332, and is closed to new participants. FINDINGS: Between Nov 29, 2017, and May 7, 2021, 5215 patients were screened and 423 were randomly assigned, of whom 408 (201 thrombectomy alone, 207 intravenous alteplase plus thrombectomy) were included in the primary efficacy analysis. A modified Rankin scale score of 0-2 at 90 days was reached by 114 (57%) of 201 patients assigned to thrombectomy alone and 135 (65%) of 207 patients assigned to intravenous alteplase plus thrombectomy (adjusted risk difference -7·3%, 95% CI -16·6 to 2·1, lower limit of one-sided 95% CI -15·1%, crossing the non-inferiority margin of -12%). Symptomatic intracranial haemorrhage occurred in five (2%) of 201 patients undergoing thrombectomy alone and seven (3%) of 202 patients receiving intravenous alteplase plus thrombectomy (risk difference -1·0%, 95% CI -4·8 to 2·7). Successful reperfusion was less common in patients assigned to thrombectomy alone (182 [91%] of 201 vs 199 [96%] of 207, risk difference -5·1%, 95% CI -10·2 to 0·0, p=0·047). INTERPRETATION: Thrombectomy alone was not shown to be non-inferior to intravenous alteplase plus thrombectomy and resulted in decreased reperfusion rates. These results do not support omitting intravenous alteplase before thrombectomy in eligible patients. FUNDING: Medtronic and University Hospital Bern.

Non-invasive Brain Stimulation Can Reduce Unilateral Spatial Neglect after Stroke: ELETRON Trial.

OBJECTIVE: Rehabilitation top-down techniques based on brain stimulation present variable outcomes in unilateral spatial neglect (USN) after stroke. This study aimed to examine the effects of physical therapy after anodal and cathodal transcranial direct current stimulation (A-tDCS and C-tDCS, respectively) to improve visuospatial and functional impairments in individuals with USN after stroke. METHODS: This double-blinded, pilot randomized clinical trial enrolled patients with USN after ischemic stroke. Randomization was stratified according to the Behavior Inattention Test-Conventional (BIT-C) and Catherine Bergego Scale (CBS). Outpatient physical therapy was conducted for 7.5 weeks after 20 minutes of tDCS. The primary outcome was the USN degree evaluated by the BIT-C. Secondary outcomes were the difference in CBS score, stroke severity (National Institutes of Health Stroke Scale [NIHSS]), disability (modified Rankin Scale), autonomy (Barthel Index, Functional Independence Measure), and quality of life (EuroQol Group 5-Dimension Self-Report Questionnaire). Outcomes were analyzed using an analysis of covariance model corrected by age, baseline NIHSS, and baseline BIT-C. Pairwise post hoc comparisons were performed using Bonferroni correction. RESULTS: In the primary outcomes, A-tDCS led to greater improvement in BIT-C after intervention (mean difference [MD] = 18.4, 95% confidence interval [CI] = 3.9-32.8, p = 0.008) compared to sham. However, no significant differences were observed between A-tDCS and C-tDCS (MD = 13.9, 95% CI = -0.3 to 28.1, p = 0.057), or C-tDCS and sham (MD = 4.5, 95% CI = -9.7 to 18.8, p = 0.99). There were no significant differences between groups in terms of secondary outcomes. INTERPRETATION: A-tDCS associated with physical therapy can decrease the severity of USN after stroke. However, these preliminary findings must be confirmed by collecting additional evidence in a larger phase 3 trial. ANN NEUROL 2022;92:400-410.

Thrombectomy versus Medical Management in Mild Strokes due to Large Vessel Occlusion: Exploratory Analysis from the EXTEND-IA Trials and a Pooled International Cohort.

OBJECTIVE: This study was undertaken to evaluate functional and safety outcomes for endovascular thrombectomy (EVT) versus medical management (MM) in patients with large vessel occlusion (LVO) and mild neurological deficits, stratified by perfusion imaging mismatch. METHODS: The pooled cohort consisted of patients with National Institutes of Health Stroke Scale (NIHSS) < 6 and internal carotid artery (ICA), M1, or M2 occlusions from the Extending the Time for Thrombolysis in Emergecy Neurological Deficits - Intra-Arterial (EXTEND-IA) Trial,  Tenecteplase vs Alteplase before Endovascular Thrombectomy in Ischemic Stroke (EXTEND-IA TNK) trials Part I/II and prospective data from 15 EVT centers from October 2010 to April 2020. RAPID software estimated ischemic core and mismatch. Patients receiving primary EVT (EVTpri ) were compared to those who received primary MM (MMpri ), including those who deteriorated and received rescue EVT, in overall and propensity score (PS)-matched cohorts. Patients were stratified by target mismatch (mismatch ratio ≥ 1.8 and mismatch volume ≥ 15ml). Primary outcome was functional independence (90-day modified Rankin Scale = 0-2). Secondary outcomes included safety (symptomatic intracerebral hemorrhage [sICH], neurological worsening, and mortality). RESULTS: Of 540 patients, 286 (53%) received EVTpri and demonstrated larger critically hypoperfused tissue (Tmax > 6 seconds) volumes (median [IQR]: 64 [26-96] ml vs MMpri : 40 [14-76] ml, p < 0.001) and higher presentation NIHSS (median [IQR]: 4 [2-5] vs MMpri : 3 [2-4], p < 0.001). Functional independence was similar (EVTpri : 77.4% vs MMpri : 75.6%, adjusted odds ratio [aOR] = 1.29, 95% confidence interval [CI] = 0.82-2.03, p = 0.27). EVT had worse safety regarding sICH (EVTpri : 16.3% vs MMpri : 1.3%, p < 0.001) and neurological worsening (EVTpri : 19.6% vs MMpri : 6.7%, p < 0.001). In 414 subjects (76.7%) with target mismatch, EVT was associated with improved functional independence (EVTpri : 77.4% vs MMpri : 72.7%, aOR = 1.68, 95% CI = 1.01-2.81, p = 0.048), whereas there was a trend toward less favorable outcomes with primary EVT (EVTpri : 77.4% vs MMpri : 83.3%, aOR = 0.39, 95% CI = 0.12-1.34, p = 0.13) without target mismatch (pinteraction  = 0.06). Similar findings were observed in a propensity score-matched subpopulation. INTERPRETATION: Overall, EVT was not associated with improved clinical outcomes in mild strokes due to LVO, and sICH was increased. However, in patients with target mismatch profile, EVT was associated with increased functional independence. Perfusion imaging may be helpful to select mild stroke patients for EVT. ANN NEUROL 2022;92:364-378.

Sex Differences in Functional Outcomes Following Endovascular Treatment for Acute Ischemic Stroke.

BACKGROUND: Sex disparities have been reported across many aspects of acute ischemic stroke (AIS) care; however, there is a relative paucity of research examining sex differences in outcomes following endovascular treatment (EVT). Some studies report worse functional independence for females following EVT. Few, if any of these studies account for differences in age, baseline function, and comorbidity burden. This retrospective cohort study aimed to assess for sex differences in functional outcomes following EVT by comparing 90-day modified Rankin Scale (mRS) of males and females while controlling for baseline function and comorbidity burden. METHODS: Baseline demographic and clinical data, and stroke severity were compared for 230 consecutive patients undergoing EVT for AIS between October 2014 and July 2019 at a tertiary stroke centre in Toronto, Canada. Effect of sex on likelihood of functional independence post-EVT was assessed using regression analysis with and without correction for age, baseline mRS, and Charlson Comorbidity Index (CCI). RESULTS: Females undergoing EVT for AIS were older (75 ± 13 vs. 66 ± 15, p < 0.0001), with worse clinical and functional baselines. Unadjusted, males were more functionally independent (90-day mRS < 3) [OR = 1.831, 95%CI 1.082-3.098]. After controlling for age, baseline mRS and CCI, there was no difference between groups [OR 1.21, 95%CI 0.61-2.37]. CONCLUSIONS: This study provides evidence that prior findings of sex disparities in function after EVT may be accounted for by differences in age, baseline clinical status and functional independence between males and females when a comprehensive measure of comorbidity burden is utilized.

A Rational Approach to Meshing Cerebral Venous Geometries for High-Fidelity Computational Fluid Dynamics.

Computational fluid dynamics (CFD) of cerebral venous flows has become popular owing to the possibility of using local hemodynamics and hemoacoustics to help diagnose and plan treatments for venous diseases of the brain. Lumen geometries in low-pressure cerebral veins are different from those in cerebral arteries, often exhibiting fenestrations and flattened or triangular cross section, in addition to constrictions and expansions. These can challenge conventional size-based volume meshing strategies, and the ability to resolve nonlaminar flows. Here we present a novel strategy leveraging estimation of length scales that could be present if flow were to become transitional or turbulent. Starting from the lumen geometry and flow rate boundary conditions, centerlines are used to determine local hydraulic diameters and cross-sectional mean velocities, from which flow length scales are approximated using conventional definitions of local Kolmogorov and Taylor microscales. By inspection of these scales, a user specifies minimum and maximum mesh edge lengths, which are then distributed along the model in proportion to the approximated local Taylor length scales. We demonstrate in three representative cases that this strategy avoids some of the pitfalls of conventional size-based strategies. An exemplary CFD mesh-refinement study shows convergence of high-frequency flow instabilities even starting from relatively coarse edge lengths near the lower bounds of the approximated Taylor length scales. Rational consideration of the length scales in a possibly nonlaminar flow may thus provide a useful and replicable baseline for denovo meshing of complicated or unfamiliar venous lumen geometries.

Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency.

OBJECTIVE: Alpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the 'Pi*Z' variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous 'Pi*Z' carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common 'Pi*S' variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD. DESIGN: Baseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption. RESULTS: Among UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8-53.7)) and primary liver cancer (aOR=44.5 (10.8-183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2-2.2)) and cholelithiasis (aOR=1.3 (1.2-1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1-8.2)) and primary liver cancer (aOR=6.6 (1.6-26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis. CONCLUSION: Our study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.

Repeat Flow Diversion for Cerebral Aneurysms Failing Prior Flow Diversion: Safety and Feasibility From Multicenter Experience.

BACKGROUND: Aneurysmal persistence after flow diversion (FD) occurs in 5% to 25% of aneurysms, which may necessitate retreatment. There are limited data on safety/efficacy of repeat FD-a frequently utilized strategy in such cases. METHODS: A series of consecutive patients undergoing FD retreatment from 15 centers were reviewed (2011-2019), with inclusion criteria of repeat FD for the same aneurysm at least 6 months after initial treatment, with minimum of 6 months post-retreatment imaging. The primary outcome was aneurysmal occlusion, and secondary outcome was safety. A multivariable logistic regression model was constructed to identify predictors of incomplete occlusion (90%-99% and <90% occlusion) versus complete occlusion (100%) after retreatment. RESULTS: Ninety-five patients (median age, 57 years; 81% women) harboring 95 aneurysms underwent 198 treatment procedures. Majority of aneurysms were unruptured (87.4%), saccular (74.7%), and located in the internal carotid artery (79%; median size, 9 mm). Median elapsed time between the first and second treatment was 12.2 months. Last available follow-up was at median 12.8 months after retreatment, and median 30.6 months after the initial treatment, showing complete occlusion in 46.2% and near-complete occlusion (90%-99%) in 20.4% of aneurysms. There was no difference in ischemic complications following initial treatment and retreatment (4.2% versus 4.2%; P>0.99). On multivariable regression, fusiform morphology had higher nonocclusion odds after retreatment (odds ratio [OR], 7.2 [95% CI, 1.97-20.8]). Family history of aneurysms was associated with lower odds of nonocclusion (OR, 0.18 [95% CI, 0.04-0.78]). Likewise, positive smoking history was associated with lower odds of nonocclusion (OR, 0.29 [95% CI, 0.1-0.86]). History of hypertension trended toward incomplete occlusion (OR, 3.10 [95% CI, 0.98-6.3]), similar to incorporated branch into aneurysms (OR, 2.78 [95% CI, 0.98-6.8]). CONCLUSIONS: Repeat FD for persistent aneurysms carries a reasonable success/safety profile. Satisfactory occlusion (100% and 90%-99% occlusion) was encountered in two-thirds of patients, with similar complications between the initial and subsequent retreatments. Fusiform morphology was the strongest predictor of retreatment failure.

MEWpy: a computational strain optimization workbench in Python.

SUMMARY: Metabolic Engineering aims to favour the overproduction of native, as well as non-native, metabolites by modifying or extending the cellular processes of a specific organism. In this context, Computational Strain Optimization (CSO) plays a relevant role by putting forward mathematical approaches able to identify potential metabolic modifications to achieve the defined production goals. We present MEWpy, a Python workbench for metabolic engineering, which covers a wide range of metabolic and regulatory modelling approaches, as well as phenotype simulation and CSO algorithms. AVAILABILITY AND IMPLEMENTATION: MEWpy can be installed from PyPi (pip install mewpy), the source code being available at https://github.com/BioSystemsUM/mewpy under the GPL license.

Assessment of rSodC, rPknG, rNanH, and rSpaC as Antigens for Diagnostic Tools Against Caseous Lymphadenitis.

Corynebacterium pseudotuberculosis is a bacillus that causes caseous lymphadenitis in small ruminants, leading to great losses to rural producers; thus, an efficient diagnosis is necessary for using disease control measures. This study aimed to evaluate the antigenic potential of four C. pseudotuberculosis recombinant proteins (rSodC, rPknG, rNanH, and rSpaC) against sera of goat and sheep experimentally infected with one of three different C. pseudotuberculosis strains. Goats were infected with CAP76 or CAP21 strain (n = 10), sheep with VD57 strain (n = 6), and a group of not-infected animals (goats and sheep) were kept as a healthy control (healthy n = 12). Sera were collected at 0, 14, 60, 90, 180, or 190 days after inoculation for antigenicity testing using Western blotting and enzyme-linked immunosorbent assay (ELISA) techniques. Cross-reactivity tests with recombinant proteins were performed in goat serum experimentally vaccinated with Nocardia sp. or Rhodococcus equi bacterin. The rSodC protein showed discriminatory antigenic reactivity with a statistically significant difference against three different C. pseudotuberculosis strains evaluated in goats and sheep samples, while rPknG showed statistical significance only against two C. pseudotuberculosis strains evaluated in goats. rSodC was proved to be a strong candidate as a tool for diagnosis of C. pseudotuberculosis infection, once it was able to recognize antibodies against all strains evaluated in goats and sheep.

Histological composition of retrieved emboli in acute ischemic stroke is independent of pre-thrombectomy alteplase use.

BACKGROUND AND PURPOSE: Given recent evidence suggesting the clot composition may be associated with revascularization outcomes and stroke etiology, clot composition research has been a topic of growing interest. It is currently unclear what effect, if any, pre-thrombectomy thrombolysis has on clot composition. Understanding this association is important as it is a potential confounding variable in clot composition research. We retrospectively evaluated the composition of retrieved clots from ischemic stroke patients who did and did not receive pre-treatment tPA to study the effect of tPA on clot composition. MATERIALS AND METHODS: Consecutive patients enrolled in the Stroke Thromboembolism Registry of Imaging and Pathology (STRIP) were included in this study. All patients underwent mechanical thrombectomy and retrieved clots were sent to a central core lab for processing. Histological analysis was performed using Martius Scarlett Blue (MSB) staining and area of the clot was also measured on the gross photos. Student's t test was used for continuous variables and chi-squared test for categorical variables. RESULTS: A total of 1430 patients were included in this study. Mean age was 68.4±13.5 years. Overall rate of TICI 2c/3 was 67%. A total of 517 patients received tPA (36%) and 913 patients did not (64%). Mean RBC density for the tPA group was 42.97±22.62% compared to 42.80±23.18% for the non-tPA group (P=0.89). Mean WBC density for the tPA group was 3.74±2.60% compared to 3.42±2.21% for the non-tPA group (P=0.012). Mean fibrin density for the tPA group was 26.52±15.81% compared to 26.53±15.34% for the non-tPA group (P=0.98). Mean platelet density for the tPA group was 26.22±18.60% compared to 26.55±19.47% for the non-tPA group (P=0.75). tPA group also had significantly smaller clot area compared to non-tPA group. CONCLUSIONS: Our study 1430 retrieved emboli and ischemic stroke patients shows no interaction between tPA administration and clot composition. These findings suggest that tPA does not result in any histological changes in clot composition.

Randomized trial of a photography-aided behavioural intervention to reduce risk factors for caries and malocclusion in high-risk infants.

OBJECTIVE: To assess the efficacy of a photography-aided behavioural intervention in reducing risk factors for dental caries and malocclusion in high-risk infants. MATERIALS AND METHODS: In this randomized trial conducted in a maternity hospital, 55 mothers of recently born infants at high risk of developing oral diseases were allocated to either the intervention (n = 28) or usual care (n = 27). The intervention arm received the same usual care plus an enhanced, behaviour-oriented, photography-aided, two-stage (0 and +6 months) educational programme addressing nutritional, behavioural, lifestyle and familial factors that affect child's oral health. The primary outcome was the proportion of children classified as being at a 'low risk' of developing dental caries at the age of 12 months using a modified score based on the Caries-risk Assessment Form of the American Academy of Pediatric Dentistry. Secondary outcomes included risk factors for malocclusion, such as duration of exclusive breastfeeding, pacifier use and bottle-feeding and/or sippy cup usage. RESULTS: At 12 months, the proportion of children considered at low risk for dental caries was significantly higher in the intervention group compared to usual care (71% vs 15%, respectively, relative risk = 4.82, 95% confidence interval = 1.89-12.3, p < 0.001). The median duration of exclusive breastfeeding in the intervention group was 1.7 times higher than in the control arm (5 months vs 3 months, p = 0.03). CONCLUSION: Altogether, our findings provide evidence that a low-cost, two-stage preventive strategy using photographs to deliver a stronger visual impact might significantly reduce the incidence of risk factors for dental caries and malocclusion in 12-month-old children.

Bridging May Increase the Risk of Symptomatic Intracranial Hemorrhage in Thrombectomy Patients With Low Alberta Stroke Program Early Computed Tomography Score.

BACKGROUND AND PURPOSE: Whether intravenous thrombolysis (IVT) increases the risk for symptomatic intracranial hemorrhage (sICH) in patients treated with mechanical thrombectomy (MT) is a matter of debate. Purpose of this study was to evaluate the extent of early ischemia as a possible factor influencing the risk for sICH after IVT+MT versus direct MT. METHODS: An explorative analysis of the BEYOND-SWIFT (Bernese-European Registry for Ischemic Stroke Patients Treated Outside Current Guidelines With Neurothrombectomy Devices Using the SOLITAIRE FR With the Intention for Thrombectomy) multicenter cohort was performed. We hypothesized that the sICH risk between IVT+MT versus direct MT differs across the strata of Alberta Stroke Program Early CT Scores (ASPECTS). For this purpose, all patients with ICA, M1, and M2 vessel occlusions and available noncontrast computed tomography or diffusion-weighed imaging ASPECTS (n=2002) were analyzed. We used logistic regression analysis in subgroups, as well as interaction terms, to address the risk of sICH in IVT+MT versus direct MT patients across the ASPECTS strata. RESULTS: In 2002 patients (median age, 73.7 years; 50.7% women; median National Institutes of Health Stroke Scale score, 16), the overall rate of sICH was 6.5% (95% CI, 5.5%-7.7%). Risk of sICH differed across ASPECTS groups (9-10: 6.3%; 6-8: 5.6% and ≤5 9.8%; P=0.042). With decreasing ASPECTS, the risks of sICH in the IVT+MT versus the direct MT group increased from adjusted odds ratio of 0.61 ([95% CI, 0.24-1.60] ASPECTS 9-10), to 1.72 ([95% CI, 0.69-4.24] ASPECTS 6-8) and 6.31 ([95% CI, 1.87-21.29] ASPECTS ≤5), yielding a positive interaction term (1.91 [95% CI, 1.01-3.63]). Sensitivity analyses regarding diffusion-weighed imaging versus noncontrast computed tomography ASPECTS did not alter the primary observations. CONCLUSIONS: The extent of early ischemia may influence relative risks of sICH in IVT+MT versus direct MT patients, with an excess sICH risk in IVT+MT patients with low ASPECTS. If confirmed in post hoc analyses of randomized controlled trial data, IVT may be administered more carefully in patients with low ASPECTS eligible for and with direct access to MT.