Aneurysm treatment within 6 h versus 6-24 h after rupture in patients with subarachnoid hemorrhage

BACKGROUND The risk of rebleeding after aneurysmal subarachnoid hemorrhage (aSAH) is the highest during the initial hours after rupture. Emergency aneurysm treatment may decrease this risk, but is a logistic challenge and economic burden. We aimed to investigate whether aneurysm treatment <6 h after rupture is associated with a decreased risk of poor functional outcome compared to aneurysm treatment 6-24 h after rupture. METHODS We used data of patients included in the ULTRA trial (NCT02684812). All patients in ULTRA were admitted within 24 h after aneurysm rupture. For the current study, we excluded patients in whom the aneurysm was not treated <24 h after rupture. We calculated crude and adjusted risk ratios (aRR) with 95% confidence intervals using Poisson regression analyses for poor functional outcome (death or dependency, assessed by the modified Rankin Scale) after aneurysm treatment <6 h versus 6-24 h after rupture. Adjustments were made for age, sex, clinical condition on admission (WFNS scale), amount of extravasated blood (Fisher score), aneurysm location, tranexamic acid treatment, and aneurysm treatment modality. RESULTS We included 497 patients. Poor outcome occurred in 63/110 (57%) patients treated within 6 h compared to 145/387 (37%) patients treated 6-24 h after rupture (crude RR: 1.53, 95% CI: 1.24-1.88; adjusted RR: 1.36, 95% CI: 1.11-1.66). CONCLUSION Aneurysm treatment <6 h is not associated with better functional outcome than aneurysm treatment 6-24 h after rupture. Our results do not support a strategy aiming to treat every patient with a ruptured aneurysm <6 h after rupture

Growth rings show limited evidence for ungulates' potential to suppress shrubs across the Arctic

Global warming has pronounced effects on tundra vegetation, and rising mean temperatures increase plant growth potential across the Arctic biome. Herbivores may counteract the warming impacts by reducing plant growth, but the strength of this effect may depend on prevailing regional climatic conditions. To study how ungulates interact with temperature to influence growth of tundra shrubs across the Arctic tundra biome, we assembled dendroecological data from 20 sites, comprising 1153 individual shrubs and 223 63 annual growth rings. Evidence for ungulates suppressing shrub radial growth was only observed at intermediate summer temperatures (6.5 degrees C-9 degrees C), and even at these temperatures the effect was not strong. Multiple factors, including forage preferences and landscape use by the ungulates, and favourable climatic conditions enabling effective compensatory growth of shrubs, may weaken the effects of ungulates on shrubs, possibly explaining the weakness of observed ungulate effects. Earlier local studies have shown that ungulates may counteract the impacts of warming on tundra shrub growth, but we demonstrate that ungulates' potential to suppress shrub radial growth is not always evident, and may be limited to certain climatic conditions

Defining and simulating open-ended novelty: requirements, guidelines, and challenges

The open-endedness of a system is often defined as a continual production of novelty. Here we pin down this concept more fully by defining several types of novelty that a system may exhibit, classified as variation, innovation, and emergence. We then provide a meta-model for including levels of structure in a system’s model. From there, we define an architecture suitable for building simulations of open-ended novelty-generating systems and discuss how previously proposed systems fit into this framework. We discuss the design principles applicable to those systems and close with some challenges for the community

Detection and localization of early- and late-stage cancers using platelet RNA

Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I–IV cancer patients and in half of 352 stage I–III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening

The primary stability of a cementless PEEK femoral component is sensitive to BMI:A population-based FE study

The use of polyetheretherketone (PEEK) for cementless femoral total knee arthroplasty (TKA) components is of interest due to several potential advantages, e.g. the use in patients with metal hypersensitivity. Additionally, the stiffness of PEEK closer resembles the stiffness of bone, and therefore, peri-prosthetic stress-shielding may be avoided. When introducing a new implant material for cementless TKA designs, it is important to study its effect on the primary fixation, which is required for the long-term fixation. Finite element (FE) studies can be used to study the effect of PEEK as implant material on the primary fixation, which may be dependent on patient factors such as age, gender and body weight index (BMI). Therefore, the research objectives of this study were to investigate the effect of PEEK vs cobalt-chrome (CoCr) and patient characteristics on the primary fixation of a cementless femoral component. 280 FE models of 70 femora were created with varying implant material and gait and squat activity. Overall, the PEEK models generated larger peak micromotions than the CoCr models. Distinct differences were seen in the micromotion distributions between the PEEK and CoCr models for both the gait and squat models. The micromotions of all femoral models significantly increased with BMI. Neither gender nor age of the patients had a significant effect on the micromotions. This population study gives insights into the primary fixation of a cementless femoral component in a cohort of FE models with varying implant material and patient characteristics.</p

Update of the ULtra-early TRranexamic Acid after subarachnoid hemorrhage (ULTRA) trial: statistical analysis plan

BACKGROUND: Recurrent bleeding from an intracranial aneurysm after subarachnoid hemorrhage (SAH) is associated with unfavorable outcome. Recurrent bleeding before aneurysm occlusion can be performed occurs in up to one in five patients and most often happens within the first 6 h after the primary hemorrhage. Reducing the rate of recurrent bleeding could be a major factor in improving clinical outcome after SAH. Tranexamic acid (TXA) reduces the risk of recurrent bleeding but has thus far not been shown to improve functional outcome, probably because of a higher risk of delayed cerebral ischemia (DCI). To reduce the risk of ultraearly recurrent bleeding, TXA should be administered as soon as possible after diagnosis and before transportation to a tertiary care center. If TXA is administered for a short duration (i.e., < 24 h), it may not increase the risk of DCI. The aim of this paper is to present in detail the statistical analysis plan (SAP) of the ULTRA trial (ULtra-early TRranexamic Acid after Subarachnoid Hemorrhage), which is currently enrolling patients and investigating whether ultraearly and short-term TXA treatment in patients with aneurysmal SAH improves clinical outcome at 6 months. METHODS/DESIGN: The ULTRA trial is a multicenter, prospective, randomized, open, blinded endpoint, parallel-group trial currently ongoing at 8 tertiary care centers and 16 of their referral centers in the Netherlands. Participants are randomized to standard care or to receive TXA at a loading dose of 1 g, immediately followed by 1 g every 8 h for a maximum of 24 h, in addition to standard care, as soon as SAH is diagnosed. In the TXA group, TXA administration is stopped immediately prior to treatment (coil or clip) of the causative aneurysm. Primary outcome is the modified Rankin Scale (mRS) score at 6 months after SAH, dichotomized into good (mRS 0-3) and poor (mRS 4-6) outcomes, assessed blind to treatment allocation. Secondary outcomes include case fatalities at 30 days and at 6 months and causes of poor clinical outcome. Safety outcomes are recurrent bleeding, DCI, hydrocephalus, per-procedural complications, and other complications such as infections occurring during hospitalization. Data analyses will be according to this prespecified SAP. TRIAL REGISTRATION: Netherlands Trial Register, NTR3272. Registered on 25 January 2012. ClinicalTrials.gov, NCT02684812. Registered on 17 February 2016

Ultra-early tranexamic acid after subarachnoid hemorrhage (ULTRA): study protocol for a randomized controlled trial

BACKGROUND A frequent complication in patients with subarachnoid hemorrhage (SAH) is recurrent bleeding from the aneurysm. The risk is highest within the first 6 hours after the initial hemorrhage. Securing the aneurysm within this timeframe is difficult owing to logistical delays. The rate of recurrent bleeding can also be reduced by ultra-early administration of antifibrinolytics, which probably improves functional outcome. The aim of this study is to investigate whether ultra-early and short-term administration of the antifibrinolytic agent tranexamic acid (TXA), as add-on to standard SAH management, leads to better functional outcome. METHODS/DESIGN This is a multicenter, prospective, randomized, open-label trial with blinded endpoint (PROBE) assessment. Adult patients with the diagnosis of non-traumatic SAH, as proven by computed tomography (CT) within 24 hours after the onset of headache, will be randomly assigned to the treatment group or the control group. Patients in the treatment group will receive standard treatment with the addition of a bolus of TXA (1 g intravenously) immediately after randomization, followed by continuous infusion of 1 g per 8 hours until the start of aneurysm treatment, or a maximum of 24 hours after the start of medication. Patients in the control group will receive standard treatment without TXA. The primary outcome measure is favorable functional outcome, defined as a score of 0 to 3 on the modified Rankin Scale (mRS), at 6 months after SAH. Primary outcome will be determined by a trial nurse blinded for treatment allocation. We aim to include 950 patients in 3 years. DISCUSSION The strengths of this study are: 1. the ultra-early and short-term administration of TXA, resulting in a lower dose as compared to previous studies, which should reduce the risk for delayed cerebral ischemia (DCI), an important risk factor in the long-term treatment with antifibrinolytics; 2. the power calculation is based on functional outcome and calculated with use of recent study results of our own population, supported by data from prominent studies; and 3. the participation of several specialized SAH centers, and their referring hospitals, in the Netherlands with comparative treatment protocols. TRIAL REGISTRATION Nederlands Trial Register (Dutch Trial Registry) number NTR3272