Impact of Treatment Delay on Outcome in the International Subarachnoid Aneurysm Trial

Background and Purpose - ISAT (International Subarachnoid Aneurysm Trial) demonstrated that 1 year after aneurysmal subarachnoid hemorrhage, coiling resulted in a significantly better clinical outcome than clipping. After 5 years, this difference did not reach statistical significance, but mortality was still higher in the clipping group. Here, we present additional analyses, reporting outcome after excluding pretreatment deaths. Methods - Outcome measures were death with or without dependency at 1 and 5 years after treatment, after exclusion of all pretreatment deaths. Treatment differences were assessed using relative risks (RRs). With sensitivity and exploratory analyses, the relation between treatment delay and outcome was analyzed. Results - After exclusion of pretreatment deaths, at 1-year follow-up coiling was favorable over clipping for death or dependency (RR, 0.77 [95% CI, 0.67-0.89]) but not for death alone (RR, 0.88 [95% CI, 0.66-1.19]). After 5 years, no significant differences were observed, neither for death or dependency (RR, 0.88 [95% CI, 0.77-1.02]) nor for death alone (RR, 0.82 [95% CI, 0.64-1.05]). Sensitivity analyses showed a similar picture. In good-grade patients, coiling remained favorable over clipping in the long-term. Time between randomization and treatment was significantly longer in the clipping arm (mean 1.7 versus 1.1 days; P<0.0001), during which 17 patients died because of rebleeding versus 6 pretreatment deaths in the endovascular arm (RR, 2.81 [95% CI, 1.11-7.11]). Conclusions - These additional analyses support the conclusion of ISAT that at 1-year follow-up after aneurysmal subarachnoid hemorrhage coiling has a better outcome than clipping. After 5 years, with pretreatment mortality excluded, the difference between coiling and clipping is not significant. The high number of pretreatment deaths in the clipping group highlights the importance of urgent aneurysm treatment to prevent early rebleeding

Prediction of 60 day case-fatality after aneurysmal subarachnoid haemorrhage: results from the International Subarachnoid Aneurysm Trial (ISAT)

Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating event with substantial case-fatality. Our purpose was to examine which clinical and neuro-imaging characteristics, available on admission, predict 60 day case-fatality in aSAH and to evaluate performance of our prediction model. We performed a secondary analysis of patients enrolled in the International Subarachnoid Aneurysm Trial (ISAT), a randomised multicentre trial to compare coiling with clipping in aSAH patients. Multivariable logistic regression analysis was used to develop a prognostic model to estimate the risk of dying within 60 days from aSAH based on clinical and neuro-imaging characteristics. The model was internally validated with bootstrapping techniques. The study population comprised of 2,128 patients who had been randomised to either endovascular coiling or neurosurgical clipping. In this population 153 patients (7.2%) died within 60 days. World Federation of Neurosurgical Societies (WFNS) grade was the most important predictor of case-fatality, followed by age, lumen size of the aneurysm and Fisher grade. The model discriminated reasonably between those who died within 60 days and those who survived (c statistic = 0.73), with minor optimism according to bootstrap re-sampling (optimism corrected c statistic = 0.70). Several strong predictors are available to predict 60 day case-fatality in aSAH patients who survived the early stage up till a treatment decision; after external validation these predictors could eventually be used in clinical decision making

Mutant calreticulin knockin mice develop thrombocytosis and myelofibrosis without a stem cell self-renewal advantage.

Somatic mutations in the endoplasmic reticulum chaperone calreticulin (CALR) are detected in approximately 40% of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF). Multiple different mutations have been reported, but all result in a +1-bp frameshift and generate a novel protein C terminus. In this study, we generated a conditional mouse knockin model of the most common CALR mutation, a 52-bp deletion. The mutant novel human C-terminal sequence is integrated into the otherwise intact mouse CALR gene and results in mutant CALR expression under the control of the endogenous mouse locus. CALRdel/+ mice develop a transplantable ET-like disease with marked thrombocytosis, which is associated with increased and morphologically abnormal megakaryocytes and increased numbers of phenotypically defined hematopoietic stem cells (HSCs). Homozygous CALRdel/del mice developed extreme thrombocytosis accompanied by features of MF, including leukocytosis, reduced hematocrit, splenomegaly, and increased bone marrow reticulin. CALRdel/+ HSCs were more proliferative in vitro, but neither CALRdel/+ nor CALRdel/del displayed a competitive transplantation advantage in primary or secondary recipient mice. These results demonstrate the consequences of heterozygous and homozygous CALR mutations and provide a powerful model for dissecting the pathogenesis of CALR-mutant ET and PMF

Prediction of two month modified Rankin Scale with an ordinal prediction model in patients with aneurysmal subarachnoid haemorrhage

Background. Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating event with a frequently disabling outcome. Our aim was to develop a prognostic model to predict an ordinal clinical outcome at two months in patients with aSAH. Methods. We studied patients enrolled in the International Subarachnoid Aneurysm Trial (ISAT), a randomized multicentre trial to compare coiling and clipping in aSAH patients. Several models were explored to estimate a patient's outcome according to the modified Rankin Scale (mRS) at two months after aSAH. Our final model was validated internally with bootstrapping techniques. Results. The study population comprised of 2,128 patients of whom 159 patients died within 2 months (8%). Multivariable proportional odds analysis identified World Federation of Neurosurgical Societies (WFNS) grade as the most important predictor, followed by age, sex, lumen size of the aneurysm, Fisher grade, vasospasm on angiography, and treatment modality. The model discriminated moderately between those with poor and good mRS scores (c statistic = 0.65), with minor optimism according to bootstrap re-sampling (optimism corrected c statistic = 0.64). Conclusion. We presented a calibrated and internally validated ordinal prognostic model to predict two month mRS in aSAH patients who survived the early stage up till a treatment decision.

Genomic reconstruction of the SARS-CoV-2 epidemic in England.

The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus leads to new variants that warrant timely epidemiological characterization. Here we use the dense genomic surveillance data generated by the COVID-19 Genomics UK Consortium to reconstruct the dynamics of 71 different lineages in each of 315 English local authorities between September 2020 and June 2021. This analysis reveals a series of subepidemics that peaked in early autumn 2020, followed by a jump in transmissibility of the B.1.1.7/Alpha lineage. The Alpha variant grew when other lineages declined during the second national lockdown and regionally tiered restrictions between November and December 2020. A third more stringent national lockdown suppressed the Alpha variant and eliminated nearly all other lineages in early 2021. Yet a series of variants (most of which contained the spike E484K mutation) defied these trends and persisted at moderately increasing proportions. However, by accounting for sustained introductions, we found that the transmissibility of these variants is unlikely to have exceeded the transmissibility of the Alpha variant. Finally, B.1.617.2/Delta was repeatedly introduced in England and grew rapidly in early summer 2021, constituting approximately 98% of sampled SARS-CoV-2 genomes on 26 June 2021

Effects of circle of willis anatomic variations on angiographic and clinical outcomes of coiled anterior communicating artery aneurysms.

BACKGROUND AND PURPOSE: Anterior communicating artery aneurysms account for one-fourth of all intracranial aneurysms and frequently occur in the context of A1 vessel asymmetry. The purpose of this study was to correlate circle of Willis anatomic variation association to angiographic and clinical outcomes of anterior communicating aneurysm coiling. MATERIALS AND METHODS: The Cerecyte Coil Trial provides a subgroup of 124 cases with anterior communicating artery aneurysms after endovascular coiling. One hundred seventeen of 124 anterior communicating artery aneurysms had complete imaging and follow-up for clinical outcome analysis, stability of aneurysm coil packing, and follow-up imaging between 5 and 7 months after treatment. Clinical outcomes were assessed by the mRS at 6 months. RESULTS: Anterior cerebral artery trunk-dominance was seen in 91 of 124 (73%) anterior communicating artery aneurysms and codominance in 33 of 124 (27%) anterior communicating artery aneurysms. There was no significant difference (P > .5) in treatment success at 5-7 months for anterior communicating artery aneurysms between the anterior cerebral artery trunk-dominant (49 of 86, 57%) and anterior cerebral artery trunk-codominant (19 of 31) groups. Angiographic follow-up demonstrates a statistically significant increase in neck remnants and progressive aneurysm sac filling with the A1 dominant configuration (n = 21, 24% at follow-up versus n = 11, 12% at immediate posttreatment, P = .035). There was no statistically significant difference in clinical outcomes between types of anterior cerebral artery trunk configuration (P > .5). CONCLUSIONS: Anterior communicating artery aneurysms with anterior cerebral artery trunk-dominant circle of Willis configurations show less angiographic stability at follow-up than those with anterior cerebral artery trunk-codominance similar to other "termination" type aneurysms. This supports the hypothesis that anterior cerebral artery trunk-dominant flow contributes to aneurysm formation, growth, and instability after coiling treatment

Effects of circle of willis anatomic variations on angiographic and clinical outcomes of coiled anterior communicating artery aneurysms.

BACKGROUND AND PURPOSE: Anterior communicating artery aneurysms account for one-fourth of all intracranial aneurysms and frequently occur in the context of A1 vessel asymmetry. The purpose of this study was to correlate circle of Willis anatomic variation association to angiographic and clinical outcomes of anterior communicating aneurysm coiling. MATERIALS AND METHODS: The Cerecyte Coil Trial provides a subgroup of 124 cases with anterior communicating artery aneurysms after endovascular coiling. One hundred seventeen of 124 anterior communicating artery aneurysms had complete imaging and follow-up for clinical outcome analysis, stability of aneurysm coil packing, and follow-up imaging between 5 and 7 months after treatment. Clinical outcomes were assessed by the mRS at 6 months. RESULTS: Anterior cerebral artery trunk-dominance was seen in 91 of 124 (73%) anterior communicating artery aneurysms and codominance in 33 of 124 (27%) anterior communicating artery aneurysms. There was no significant difference (P &gt; .5) in treatment success at 5-7 months for anterior communicating artery aneurysms between the anterior cerebral artery trunk-dominant (49 of 86, 57%) and anterior cerebral artery trunk-codominant (19 of 31) groups. Angiographic follow-up demonstrates a statistically significant increase in neck remnants and progressive aneurysm sac filling with the A1 dominant configuration (n = 21, 24% at follow-up versus n = 11, 12% at immediate posttreatment, P = .035). There was no statistically significant difference in clinical outcomes between types of anterior cerebral artery trunk configuration (P &gt; .5). CONCLUSIONS: Anterior communicating artery aneurysms with anterior cerebral artery trunk-dominant circle of Willis configurations show less angiographic stability at follow-up than those with anterior cerebral artery trunk-codominance similar to other "termination" type aneurysms. This supports the hypothesis that anterior cerebral artery trunk-dominant flow contributes to aneurysm formation, growth, and instability after coiling treatment

International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion.

BACKGROUND: Two types of treatment are being used for patients with ruptured intracranial aneurysms: endovascular detachable-coil treatment or craniotomy and clipping. We undertook a randomised, multicentre trial to compare these treatments in patients who were suitable for either treatment because the relative safety and efficacy of these approaches had not been established. Here we present clinical outcomes 1 year after treatment. METHODS: 2143 patients with ruptured intracranial aneurysms, who were admitted to 42 neurosurgical centres, mainly in the UK and Europe, took part in the trial. They were randomly assigned to neurosurgical clipping (n=1070) or endovascular coiling (n=1073). The primary outcome was death or dependence at 1 year (defined by a modified Rankin scale of 3-6). Secondary outcomes included rebleeding from the treated aneurysm and risk of seizures. Long-term follow up continues. Analysis was in accordance with the randomised treatment. FINDINGS: We report the 1-year outcomes for 1063 of 1073 patients allocated to endovascular treatment, and 1055 of 1070 patients allocated to neurosurgical treatment. 250 (23.5%) of 1063 patients allocated to endovascular treatment were dead or dependent at 1 year, compared with 326 (30.9%) of 1055 patients allocated to neurosurgery, an absolute risk reduction of 7.4% (95% CI 3.6-11.2, p=0.0001). The early survival advantage was maintained for up to 7 years and was significant (log rank p=0.03). The risk of epilepsy was substantially lower in patients allocated to endovascular treatment, but the risk of late rebleeding was higher. INTERPRETATION: In patients with ruptured intracranial aneurysms suitable for both treatments, endovascular coiling is more likely to result in independent survival at 1 year than neurosurgical clipping; the survival benefit continues for at least 7 years. The risk of late rebleeding is low, but is more common after endovascular coiling than after neurosurgical clipping