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Aim: Stent-retriever (SR) thrombectomy has demonstrated superior outcomes in patients with acute ischemic stroke compared with medical management alone, but differences among SRs remain unexplored. We conducted a Systematic Review/Meta-Analysis to compare outcomes between three SRs: EmboTrap ® , Solitaire™, and Trevo ® . Methods: We conducted a PRISMA-compliant Systematic Review among English-language studies published after 2014 in PubMed/MEDLINE that reported SRs in ≥25 patients. Functional and safety outcomes included 90-day modified Rankin scale (mRS 0-2), mortality, symptomatic intracranial hemorrhage (sICH), and embolization to new territory (ENT). Recanalization outcomes included modified thrombolysis in cerebral infarction (mTICI) and first-pass recanalization (FPR). We used a random effects Meta-Analysis to compare outcomes; subgroup and outlier-influencer analysis were performed to explore heterogeneity. Results: Fifty-one articles comprising 9,804 patients were included. EmboTrap had statistically significantly higher rates of mRS 0-2 (57.4%) compared with Trevo (50.0%, p = 0.013) and Solitaire (45.3%, p < 0.001). Compared with Solitaire (20.4%), EmboTrap (11.2%, p < 0.001) and Trevo (14.5%, p = 0.018) had statistically significantly lower mortality. Compared with Solitaire (7.7%), EmboTrap (3.9%, p = 0.028) and Trevo (4.6%, p = 0.049) had statistically significantly lower rates of sICH. There were no significant differences in ENT rates across all three devices (6.0% for EmboTrap, 5.3% for Trevo, and 7.7% for Solitaire, p = 0.518). EmboTrap had numerically higher rates of recanalization; however, no statistically significant differences were found. Conclusion: The results of our Systematic Review/Meta-Analysis suggest that EmboTrap may be associated with significantly improved functional outcomes compared with Solitaire and Trevo. EmboTrap and Trevo may be associated with significantly lower rates of sICH and mortality compared with Solitaire. No significant differences in recanalization and ENT rates were found. These conclusions are tempered by limitations of the analysis including variations in thrombectomy techniques in the field, highlighting the need for multi-arm RCT studies comparing different SR devices to confirm our findings.

Blinatumomab is an efficacious immunotherapeutic agent in B cell acute lymphoblastic leukemia (B-ALL). However, the pharmacogenomic basis of leukemia response to blinatumomab is unclear. Using genome-wide CRISPR, we comprehensively identified leukemia intrinsic factors of blinatumomab sensitivity, i.e., the loss of CD58 as a top driver for resistance, in addition to CD19 . Screening 1639 transcription factor genes, we then identified PAX5 as the key activator of CD58. ALL with the PAX5 P80R mutation also expressed the lowest level of CD58 among 20 ALL molecular subtypes in 1988 patients. Genome editing confirmed the effects of this mutation on CD58 expression and blinatumomab sensitivity in B-ALL, with validation in patient leukemic blasts. We described a PAX5-driven enhancer at the CD58 locus, which was disrupted by PAX5 P80R, and the loss of CD58 abolished blinatumomab-induced T cell activation with global changes in transcriptomic/epigenomic program. In conclusion, we identified previously unidentified genetic mechanisms of blinatumomab resistance in B-ALL, suggesting strategies for genomics-guided treatment individualization.

Background and Purpose— The American Heart Association and the American Stroke Association guidelines for early management of patients with ischemic stroke offer guidance to physicians involved in acute stroke care and clarify endovascular treatment indications. The purpose of this study was to assess concordance of physicians’ endovascular treatment decision-making with current American Heart Association and the American Stroke Association stroke treatment guidelines using a survey-approach and to explore how decision-making in the absence of guideline recommendations is approached. Methods— In an international cross-sectional survey (UNMASK-EVT), physicians were randomly assigned 10 of 22 case scenarios (8 constructed with level 1A and 11 with level 2B evidence for endovascular treatment and 3 scenarios without guideline coverage) and asked to declare their treatment approach (1) under their current local resources and (2) assuming there were no external constraints. The proportion of physicians offering endovascular therapy (EVT) was calculated. Subgroup analysis was performed for different specialties, geographic regions, with regard to physicians’ age, endovascular, and general stroke treatment experience. Results— When facing level 1A evidence, participants decided in favor of EVT in 86.8% under current local resources and in 90.6% under assumed ideal conditions, that is, 9.4% decided against EVT even under assumed ideal conditions. In case scenarios with level 2B evidence, 66.3% decided to proceed with EVT under current local resources and 69.7% under assumed ideal conditions. Conclusions— There is potential for improving thinking around the decision to offer endovascular treatment, since physicians did not offer EVT even under assumed ideal conditions in 9.4% despite facing level 1A evidence. A majority of physicians would offer EVT even for level 2B evidence cases.

Background and purpose Differences in the treatment practice of female and male physicians have been shown in several medical subspecialties. It is currently not known whether this also applies to endovascular stroke treatment. The purpose of this study was to explore whether there are differences in endovascular treatment decisions made by female and male stroke physicians and neurointerventionalists. Methods In an international survey, stroke physicians and neurointerventionalists were randomly assigned 10 case scenarios and asked how they would treat the patient: (A) assuming there were no external constraints and (B) given their local working conditions. Descriptive statistics were used to describe baseline demographics, and the adjusted OR for physician gender as a predictor of endovascular treatment decision was calculated using logistic regression. Results 607 physicians (97 women, 508 men, 2 who did not wish to declare) participated in this survey. Physician gender was neither a significant predictor for endovascular treatment decision under assumed ideal conditions (endovascular therapy was favored by 77.0% of female and 79.3% of male physicians, adjusted OR 1.03, P=0.806) nor under current local resources (endovascular therapy was favored by 69.1% of female and 76.9% of male physicians, adjusted OR 1.03, P=0.814). Conclusion Endovascular therapy decision making between male and female physicians did not differ under assumed ideal conditions or under current local resources.

Background and Purpose— Little is known about the real-life factors that clinicians use in selection of patients that would receive endovascular treatment (EVT) in the real world. We sought to determine patient, practitioner, and health system factors associated with therapeutic decisions around endovascular treatment. Methods— We conducted a multinational cross-sectional web-based study comprising of 607 clinicians and interventionalists from 38 countries who are directly involved in acute stroke care. Participants were randomly allocated to 10 from a pool of 22 acute stroke case scenarios. Each case was classified as either Class I, Class II, or unknown evidence according to the current guidelines. We used logistic regression analysis applying weight of evidence approach. Main outcome measures were multilevel factors associated with EVT, adherence to current EVT guidelines, and practice gaps between current and ideal practice settings. Results— Of the 1330 invited participants, 607 (45.6%) participants completed the study (53.7% neurologists, 28.5% neurointerventional radiologists, 17.8% other clinicians). The weighed evidence approach revealed that National Institutes of Health Stroke Scale (34.9%), level of evidence (30.2%), ASPECTS (Alberta Stroke Program Early CT Score) or ischemic core volume (22.4%), patient’s age (21.6%), and clinicians’ experience in EVT use (19.3%) are the most important factors for EVT decision. Of 2208 responses that met Class I evidence for EVT, 1917 (86.8%) were in favor of EVT. In case scenarios with no available guidelines, 1070 of 1380 (77.5%) responses favored EVT. Comparison between current and ideal practice settings revealed a small practice gap (941 of 6070 responses, 15.5%). Conclusions— In this large multinational survey, stroke severity, guideline-based level of evidence, baseline brain imaging, patients’ age and physicians’ experience were the most relevant factors for EVT decision-making. The high agreement between responses and Class I guideline recommendations and high EVT use even when guidelines were not available reflect the real-world acceptance of EVT as standard of care in patients with disabling acute ischemic stroke.

We determined whether activation of G proteins can affect the force developed for a given intracellular Ca2+concentration ([Ca2+]; i.e., the Ca2+sensitivity) by mechanisms in addition to changes in regulatory myosin light chain (rMLC) phosphorylation. Responses in α-toxin-permeabilized canine tracheal smooth muscle were determined with Ca2+alone or in the presence of ACh, endothelin-1 (ET-1), or aluminum fluoride (AlF[Formula: see text]; acute or 1-h exposure). Acute exposure to each compound increased Ca2+sensitivity without changing the response to high [Ca2+] (maximal force). However, chronic exposure to AlF[Formula: see text], but not to chronic ACh or ET-1, increased maximal force by increasing the force produced for a given rMLC phosphorylation. Studies employing thiophosphorylation of rMLC showed that the increase in force produced by chronic AlF[Formula: see text] exposure required Ca2+during activation to be manifest. Unlike the acute response to receptor agonists, which is mediated solely by increases in rMLC phosphorylation, chronic direct activation of G proteins further increases Ca2+sensitivity in airways by additional mechanisms that are independent of rMLC phosphorylation.

We tested the hypothesis that increases in force at a given cytosolic Ca2+concentration (i.e., Ca2+sensitization) produced by muscarinic stimulation of canine tracheal smooth muscle (CTSM) are produced in part by mechanisms independent of changes in regulatory myosin light chain (rMLC) phosphorylation. This was accomplished by comparing the relationship between rMLC phosphorylation and force in α-toxin-permeabilized CTSM in the absence and presence of acetylcholine (ACh). Forces were normalized to the contraction induced by 10 μM Ca2+in each strip, and rMLC phosphorylation is expressed as a percentage of total rMLC. ACh (100 μM) plus GTP (1 μM) significantly shifted the Ca2+-force relationship curve to the left (EC50: 0.39 ± 0.06 to 0.078 ± 0.006 μM Ca2+) and significantly increased the maximum force (104.4 ± 4.8 to 120.2 ± 2.8%; n = 6 observations). The Ca2+-rMLC phosphorylation relationship curve was also shifted to the left (EC50: 1.26 ± 0.57 to 0.13 ± 0.04 μM Ca2+) and upward (maximum rMLC phosphorylation: 70.9 ± 7.9 to 88.5 ± 5.1%; n = 6 observations). The relationships between rMLC phosphorylation and force constructed from mean values at corresponding Ca2+concentrations were not different in the presence and absence of ACh. We find no evidence that muscarinic stimulation increases Ca2+sensitivity in CTSM by mechanisms other than increases in rMLC phosphorylation.

ABSTRACTBackground and objectivePneumothorax is a co‐morbidity in patients with idiopathic pulmonary fibrosis (IPF). However, its incidence, risk factors and prognostic significance in IPF remain unclear. The aim of this study was to clarify the incidence and prognostic significance of pneumothorax in patients with IPF, and to further investigate the risk factors for its onset.MethodsEighty‐four consecutive patients with IPF based on the consensus guideline were included in this study. We retrospectively reviewed the medical records, pulmonary function tests and chest high‐resolution computed tomography images, and determined the incidence of pneumothorax. The prognostic significance of pneumothorax was evaluated using the Cox proportional hazards model analysis with time‐dependent covariates. We also assessed the cumulative incidence and the risk factors for pneumothorax.ResultsOf the 84 patients, 17 (20.2%) developed pneumothorax. The cumulative incidence of pneumothorax was 8.5%, 12.5% and 17.7% at 1, 2 and 3 years, respectively. Univariate analysis demonstrated that pneumothorax was significantly related to poor prognosis (hazards ratio, 2.99; P = 0.002). Multivariate analysis, adjusting for sex, age and forced vital capacity (% predicted), revealed that pneumothorax was an independent predictor of poor outcome in IPF (hazards ratio, 2.85; P = 0.006). Lower BMI and the presence of extensive reticular abnormalities were significantly associated with developing pneumothorax.ConclusionThese results confirm that patients with IPF often develop pneumothorax during their clinical course and that the onset of pneumothorax predicts a poor outcome.

ABSTRACT Several recent studies suggest that obesity may be a risk factor for fracture. The aim of this study was to investigate the association between body mass index (BMI) and future fracture risk at different skeletal sites. In prospective cohorts from more than 25 countries, baseline data on BMI were available in 398,610 women with an average age of 63 (range, 20–105) years and follow up of 2.2 million person-years during which 30,280 osteoporotic fractures (6457 hip fractures) occurred. Femoral neck BMD was measured in 108,267 of these women. Obesity (BMI ≥ 30 kg/m2) was present in 22%. A majority of osteoporotic fractures (81%) and hip fractures (87%) arose in non-obese women. Compared to a BMI of 25 kg/m2, the hazard ratio (HR) for osteoporotic fracture at a BMI of 35 kg/m2 was 0.87 (95% confidence interval [CI], 0.85–0.90). When adjusted for bone mineral density (BMD), however, the same comparison showed that the HR for osteoporotic fracture was increased (HR, 1.16; 95% CI, 1.09–1.23). Low BMI is a risk factor for hip and all osteoporotic fracture, but is a protective factor for lower leg fracture, whereas high BMI is a risk factor for upper arm (humerus and elbow) fracture. When adjusted for BMD, low BMI remained a risk factor for hip fracture but was protective for osteoporotic fracture, tibia and fibula fracture, distal forearm fracture, and upper arm fracture. When adjusted for BMD, high BMI remained a risk factor for upper arm fracture but was also a risk factor for all osteoporotic fractures. The association between BMI and fracture risk is complex, differs across skeletal sites, and is modified by the interaction between BMI and BMD. At a population level, high BMI remains a protective factor for most sites of fragility fracture. The contribution of increasing population rates of obesity to apparent decreases in fracture rates should be explored. © 2014 American Society for Bone and Mineral Research.