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BackgroundFirst pass reperfusion (FPR), defined as near complete reperfusion (extended Treatment in Cerebral Ischemia (eTICI) score 2c/3) in a single attempt without rescue therapy has been proposed as a quality metric. However, it remains unclear if the thrombectomy method influences clinical outcome and FPR rate. This study evaluates whether stent retriever and aspiration based thrombectomy differ in FPR rate, technical and clinical outcomes in FPR, and multiple pass reperfusion (MPR).MethodsThis retrospective, nationwide, multicenter registry study included consecutive patients with proximal anterior or posterior circulation stroke, treated between 2018 and 2021 in Sweden. Outcome measures were FPR rate, procedure time, early neurological improvement (≥4 points on National Institutes of Health Stroke Scale (NIHSS) or a score of 0–1 at 24 hours), favorable functional outcome (modified Rankin Scale score of 0–2 or no decline at 90 days), and mortality at 90 days.ResultsOf 3309 patients (median age 75, median NIHSS 16), 1990 underwent stent retriever and 1319 aspiration based thrombectomy as the firstline method. No difference in FPR rate was observed. Aspiration based thrombectomy showed a shorter procedure time in the FPR group (crude OR (cOR) 6.4 min (95% CI 3.4 to 9.3), adjusted OR (aOR) 8.7 min (95% CI 1.8 to 15.6)) and MPR group (cOR 9.7 min (95% CI 4.0 to 15.4), aOR 17.4 min (95% CI 9.6 to 25.2)), and association with early neurological improvement (cOR 1.21 (95% CI 1.03 to 1.42), aOR 1.40 (95% CI 1.18 to 1.67)) and favorable functional outcome (aOR 1.22 (95% CI 1.01 to 1.47)).ConclusionsOur findings suggest that aspiration based thrombectomy was associated with a shorter procedure time and better clinical outcomes than treatment with a stent retriever. No difference was found in FPR rate.

Data on de novo aneurysm formation after treatment for intracranial aneurysms remains scarce. We studied the incidence of de novo aneurysm formation in patients who had undergone aneurysm treatment more than 18 years prior to follow-up. As it is a disease affecting a younger patient population more specific guidelines are needed when planning a follow-up regime. The rate of de novo aneurysm formation was assessed with Magnetic Resonance Angiography (MRA) follow-up >18 years after endovascular or microsurgical treatment for an intracranial aneurysm. Variables associated with de novo aneurysm formation were studied using logistic regression. Missing data were imputed using chained random forests. A data-driven model for the prediction of de novo aneurysm was created to calculate the relative variable importance of ten clinical features. De novo aneurysms were identified in 11/81 (13.6 %) patients, of whom 1 was male, over a median follow-up of 20 years. Sex was the most important variable associated with de novo aneurysm formation. Regarding the development of de novo aneurysm, men displayed an odds ratio (OR) of 0.16 (0.01–0.97), compared with women. OR for mRS score 2 or more was 0.20 (95 % CI 0.01–1.34), and OR for smokers was 3.70 (0.54–31.18). Six out of 11 patients (54.5 %) needed treatment; 1 underwent endovascular treatment (EVT) and 5 underwent microsurgical treatment (MST). The overall annual de novo aneurysm formation rate was 0.92 %. This study highlights the need for a longer follow-up imaging monitoring of patients that have previously undergone treatment for an intracranial aneurysm. These data are useful to take into consideration when planning a follow-up strategy. •The overall annual de novo aneurysm formation rate was 0.92 %.•Sex was the most important variable associated with de novo aneurysm formation rate.•A longer follow-up is deemed necessary especially in the younger population suffering an aneurysmal Subarachnoid haemorrhage.

Plasma flows with enhanced dynamic pressure, known as magnetosheath jets, are often found downstream of collisionless shocks. As they propagate through the magnetosheath, they interact with the surrounding plasma, shaping its properties, and potentially becoming geoeffective upon reaching the magnetopause. In recent years (since 2016), new research has produced vital results that have significantly enhanced our understanding on many aspects of jets. In this review, we summarise and discuss these findings. Spacecraft and ground-based observations, as well as global and local simulations, have contributed greatly to our understanding of the causes and effects of magnetosheath jets. First, we discuss recent findings on jet occurrence and formation, including in other planetary environments. New insights into jet properties and evolution are then examined using observations and simulations. Finally, we review the impact of jets upon interaction with the magnetopause and subsequent consequences for the magnetosphere-ionosphere system. We conclude with an outlook and assessment on future challenges. This includes an overview on future space missions that may prove crucial in tackling the outstanding open questions on jets in the terrestrial magnetosheath as well as other planetary and shock environments.

The structure and function of the anterolateral complex (ALC) of the knee has created much controversy since the ‘re-discovery’ of the anterolateral ligament (ALL) and its proposed role in aiding control of anterolateral rotatory laxity in the anterior cruciate ligament (ACL) injured knee. A group of surgeons and researchers prominent in the field gathered to produce consensus as to the anatomy and biomechanical properties of the ALC. The evidence for and against utilisation of ALC reconstruction was also discussed, generating a number of consensus statements by following a modified Delphi process. Key points include that the ALC consists of the superficial and deep aspects of the iliotibial tract with its Kaplan fibre attachments on the distal femur, along with the ALL, a capsular structure within the anterolateral capsule. A number of structures attach to the area of the Segond fracture including the capsule-osseous layer of the iliotibial band, the ALL and the anterior arm of the short head of biceps, and hence it is not clear which is responsible for this lesion. The ALC functions to provide anterolateral rotatory stability as a secondary stabiliser to the ACL. Whilst biomechanical studies have shown that these structures play an important role in controlling stability at the time of ACL reconstruction, the optimal surgical procedure has not yet been defined clinically. Concern remains that these procedures may cause constraint of motion, yet no clinical studies have demonstrated an increased risk of osteoarthritis development. Furthermore, clinical evidence is currently lacking to support clear indications for lateral extra-articular procedures as an augmentation to ACL reconstruction. The resulting statements and scientific rationale aim to inform readers on the most current thinking and identify areas of needed basic science and clinical research to help improve patient outcomes following ACL injury and subsequent reconstruction. Level of evidence V.

Transient enhancements in the dynamic pressure, so-called magnetosheath jets or simply jets, are abundantly found in the magnetosheath. They travel from the bow shock through the magnetosheath towards the magnetopause. On their way through the magnetosheath, jets disturb the ambient plasma. Multiple studies already investigated their scale size perpendicular to their propagation direction, and almost exclusively in a statistical manner. In this paper, we use multi-point measurements from the Time History of Events and Macroscale Interactions during Substorms (THEMIS) mission to study the passage of a single jet. The method described here allows us to estimate the spatial distribution of the dynamic pressure within the jet. Furthermore, the size perpendicular to the propagation direction can be estimated for different cross sections. In the jet event investigated here, both the dynamic pressure and the perpendicular size increase along the propagation axis from the front part towards the center of the jet and decrease again towards the rear part, but neither monotonically nor symmetrically. We obtain a maximum diameter in the perpendicular direction of about 1 RE and a dynamic pressure of about 6 nPa at the jet center.

Purpose To evaluate the likelihood-based methods for handling data below the quantification limit (BQL) using new features in NONMEM VI. Methods A two-compartment pharmacokinetic model with first-order absorption was chosen for investigation. Methods evaluated were: discarding BQL observations (M1), discarding BQL observations but adjusting the likelihood for the remaining data (M2), maximizing the likelihood for the data above the limit of quantification (LOQ) and treating BQL data as censored (M3), and like M3 but conditioning on the observation being greater than zero (M4). These four methods were compared using data simulated with a proportional error model. M2, M3, and M4 were also compared using data simulated from a positively truncated normal distribution. Successful terminations and bias and precision of parameter estimates were assessed. Results For the data simulated with a proportional error model, the overall performance was best for M3 followed by M2 and M1. M3 and M4 resulted in similar estimates in analyses without log transformation. For data simulated with the truncated normal distribution, M4 performed better than M3. Conclusions Analyses that maximized the likelihood of the data above the LOQ and treated BQL data as censored provided the most accurate and precise parameter estimates.

Background Disease activity differs in young patients with multiple sclerosis (MS) compared with the overall adult MS population. Objective The objective of this paper is to evaluate the effect of fingolimod 0.5 mg on disease activity in young adults with MS from three randomized, double-blind Phase 3 trials. Methods Annualized relapse rate (ARR), number of new/newly enlarging T2 lesions (neT2), and no evidence of disease activity (NEDA-3) were estimated in the intent-to-treat population at age 20 (youngest) and 30 (young) and compared to the overall population. Models used included a negative binomial regression (ARR/neT2) and a logistic regression (NEDA), with age at baseline as a continuous covariate. Results ARRs were higher in younger patients (all p < 0.05), and significantly reduced with fingolimod versus placebo or interferon beta-1a (IFN β-1a), with the percentage reduction inversely proportional to age. Fingolimod was significantly associated with a lower number of neT2 lesions versus placebo/IFN in all age groups except versus IFN in the youngest patients. Regardless of age, fingolimod-treated patients were more likely to achieve NEDA-3 versus placebo/IFN β-1a, with strongest benefits in the youngest patients (all p < 0.05). Conclusions Young adults show higher levels of MS disease activity, and may particularly benefit from fingolimod treatment compared with the overall study population.

Wiskott–Aldrich syndrome (WAS) is caused by loss-of-function mutations in the WASp gene. Decreased cellular responses in WASp-deficient cells have been interpreted to mean that WASp directly regulates these responses in WASp-sufficient cells. Here, we identify an exception to this concept and show that WASp-deficient dendritic cells have increased activation of Rac2 that support cross-presentation to CD8 + T cells. Using two different skin pathology models, WASp-deficient mice show an accumulation of dendritic cells in the skin and increased expansion of IFNγ-producing CD8 + T cells in the draining lymph node and spleen. Specific deletion of WASp in dendritic cells leads to marked expansion of CD8 + T cells at the expense of CD4 + T cells. WASp-deficient dendritic cells induce increased cross-presentation to CD8 + T cells by activating Rac2 that maintains a near neutral pH of phagosomes. Our data reveals an intricate balance between activation of WASp and Rac2 signalling pathways in dendritic cells. Wiskott–Aldrich syndrome (WAS) is a severe X-linked primary immunodeficiency syndrome. Here, the authors show that loss of WAS gene in dendritic cells results in increased activity of Rac2, increase of phagosomal pH, and more efficient cross-presentation.

Previous genome-wide association (GWA) studies have identified SNPs associated with areal bone mineral density (aBMD). However, this measure is influenced by several different skeletal parameters, such as periosteal expansion, cortical bone mineral density (BMD(C)) cortical thickness, trabecular number, and trabecular thickness, which may be under distinct biological and genetic control. We have carried out a GWA and replication study of BMD(C), as measured by peripheral quantitative computed tomography (pQCT), a more homogenous and valid measure of actual volumetric bone density. After initial GWA meta-analysis of two cohorts (ALSPAC n = 999, aged ∼15 years and GOOD n = 935, aged ∼19 years), we attempted to replicate the BMD(C) associations that had p<1×10(-5) in an independent sample of ALSPAC children (n = 2803) and in a cohort of elderly men (MrOS Sweden, n = 1052). The rs1021188 SNP (near RANKL) was associated with BMD(C) in all cohorts (overall p = 2×10(-14), n = 5739). Each minor allele was associated with a decrease in BMD(C) of ∼0.14SD. There was also evidence for an interaction between this variant and sex (p = 0.01), with a stronger effect in males than females (at age 15, males -6.77mg/cm(3) per C allele, p = 2×10(-6); females -2.79 mg/cm(3) per C allele, p = 0.004). Furthermore, in a preliminary analysis, the rs1021188 minor C allele was associated with higher circulating levels of sRANKL (p<0.005). We show this variant to be independent from the previously aBMD associated SNP (rs9594738) and possibly from a third variant in the same RANKL region, which demonstrates important allelic heterogeneity at this locus. Associations with skeletal parameters reflecting bone dimensions were either not found or were much less pronounced. This finding implicates RANKL as a locus containing variation associated with volumetric bone density and provides further insight into the mechanism by which the RANK/RANKL/OPG pathway may be involved in skeletal development.

Most previous genetic epidemiology studies within the field of osteoporosis have focused on the genetics of the complex trait areal bone mineral density (aBMD), not being able to differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits. The objective of this study was to separately identify genetic determinants of these bone traits as analysed by peripheral quantitative computed tomography (pQCT). Separate GWA meta-analyses for cortical and trabecular vBMDs were performed. The cortical vBMD GWA meta-analysis (n = 5,878) followed by replication (n = 1,052) identified genetic variants in four separate loci reaching genome-wide significance (RANKL, rs1021188, p = 3.6×10⁻¹⁴; LOC285735, rs271170, p = 2.7×10⁻¹²; OPG, rs7839059, p = 1.2×10⁻¹⁰; and ESR1/C6orf97, rs6909279, p = 1.1×10⁻⁹). The trabecular vBMD GWA meta-analysis (n = 2,500) followed by replication (n = 1,022) identified one locus reaching genome-wide significance (FMN2/GREM2, rs9287237, p = 1.9×10⁻⁹). High-resolution pQCT analyses, giving information about bone microstructure, were available in a subset of the GOOD cohort (n = 729). rs1021188 was significantly associated with cortical porosity while rs9287237 was significantly associated with trabecular bone fraction. The genetic variant in the FMN2/GREM2 locus was associated with fracture risk in the MrOS Sweden cohort (HR per extra T allele 0.75, 95% confidence interval 0.60-0.93) and GREM2 expression in human osteoblasts. In conclusion, five genetic loci associated with trabecular or cortical vBMD were identified. Two of these (FMN2/GREM2 and LOC285735) are novel bone-related loci, while the other three have previously been reported to be associated with aBMD. The genetic variants associated with cortical and trabecular bone parameters differed, underscoring the complexity of the genetics of bone parameters. We propose that a genetic variant in the RANKL locus influences cortical vBMD, at least partly, via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences GREM2 expression in osteoblasts and thereby trabecular number and thickness as well as fracture risk.