Assessment of monoclonal antibody glycosylation: a comparative study using HRMS, NMR, and HILIC-FLD.

Monoclonal antibodies (mAbs) represent the largest class of therapeutic protein drug products. mAb glycosylation produces a heterogeneous, analytically challenging distribution of glycoforms that typically should be adequately characterized because glycosylation-based product quality attributes (PQAs) can impact product quality, immunogenicity, and efficacy. In this study, two products were compared using a panel of analytical methods. Two high-resolution mass spectrometry (HRMS) workflows were used to analyze N-glycans, while nuclear magnetic resonance (NMR) was used to generate monosaccharide fingerprints. These state-of-the-art techniques were compared to conventional analysis using hydrophilic interaction chromatography (HILIC) coupled with fluorescence detection (FLD). The advantages and disadvantages of each method are discussed along with a comparison of the identified glycan distributions. The results demonstrated agreement across all methods for major glycoforms, demonstrating how confidence in glycan characterization is increased by combining orthogonal analytical methodologies. The full panel of methods used represents a diverse toolbox that can be selected from based on the needs for a specific product or analysis.

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.

CLIPPERS: A case report with radiology, three serial biopsies and a literature review.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a rare central nervous system inflammatory disorder primarily affecting the brainstem and cerebellum. We report a case of CLIPPERS in a 45-year-old man presenting with left facial numbness and dizziness. Imaging studies were conducted repeatedly over an 8-year follow-up period. Given diagnostic uncertainty in the early stages of the disease, three serial biopsies were obtained, which together with the clinical and radiological findings, led to the diagnosis. This case highlights the diagnostic challenges regarding the rare entity of CLIPPERS and discusses the main differential diagnoses that are necessary to consider. Additionally, some of the atypical features of this case, including the presenting finding of a large, solidly enhancing lesion on radiological imaging and prominent plasma cells on pathology, contribute to expanding the spectrum of appearances for CLIPPERS.

Computation of the inverse additive relationship matrix for autopolyploid and multiple-ploidy populations.

KEY MESSAGE: Rules to generate the inverse additive relationship matrix (A -1 ) are defined to enable the adoption restricted maximum likelihood (REML) and best linear unbiased prediction (BLUP) in autopolyploid populations with multiple ploidy levels. Many important agronomic, horticultural, ornamental, forestry, and aquaculture species are autopolyploids. However, the adoption of restricted maximum likelihood (REML), for estimating co/variance components, and best linear unbiased prediction (BLUP), for predicting breeding values, has been hampered in autopolyploid breeding by the absence of an appropriate means of generating the inverse additive relationship matrix (A -1 ). This paper defines rules to generate the A -1 of autopolyploid populations comprised of individuals of the same or different ploidy-levels, including populations exhibiting (1) odd-numbered ploidy levels (e.g. triploids), (2) sex-based differences in the probability that gametic genes are identical by descent and (3) somatic chromosome doubling. Inbreeding, due to double reduction, in autopolyploid founders in the absence of mating among relatives is also accounted for. A previously defined approach is modified, whereby rules are initially defined to build an inverse matrix of kinship coefficients (K -1 ), which is then used to generate A -1 . An R package (polyAinv; https://github.com/mghamilton/polyAinv ) to implement these rules has been developed and examples of analyses provided. The adoption of REML and BLUP methods made possible by these new rules has the potential to provide further insights into the quantitative genetic architecture of autopolyploid and multiple-ploidy populations, improve estimates of breeding values, and increase genetic gains made through recurrent selection.

Complex Formed between Intramembrane Metalloprotease SpoIVFB and Its Substrate, Pro-σK.

Intramembrane metalloproteases (IMMPs) are conserved from bacteria to humans and control many important signaling pathways, but little is known about how IMMPs interact with their substrates. SpoIVFB is an IMMP that cleaves Pro-σ(K) during Bacillus subtilis endospore formation. When catalytically inactive SpoIVFB was coexpressed with C-terminally truncated Pro-σ(K)(1-126) (which can be cleaved by active SpoIVFB) in Escherichia coli, the substrate dramatically improved solubilization of the enzyme from membranes with mild detergents. Both the Pro(1-20) and σ(K)(21-126) parts contributed to improving SpoIVFB solubilization from membranes, but only the σ(K) part was needed to form a stable complex with SpoIVFB in a pulldown assay. The last 10 residues of SpoIVFB were required for improved solubilization from membranes by Pro-σ(K)(1-126) and for normal interaction with the substrate. The inactive SpoIVFB·Pro-σ(K)(1-126)-His6 complex was stable during affinity purification and gel filtration chromatography. Disulfide cross-linking of the purified complex indicated that it resembled the complex formed in vivo Ion mobility-mass spectrometry analysis resulted in an observed mass consistent with a 4:2 SpoIVFB·Pro-σ(K)(1-126)-His6 complex. Stepwise photobleaching of SpoIVFB fused to a fluorescent protein supported the notion that the enzyme is tetrameric during B. subtilis sporulation. The results provide the first evidence that an IMMP acts as a tetramer, give new insights into how SpoIVFB interacts with its substrate, and lay the foundation for further biochemical analysis of the enzyme·substrate complex and future structural studies.

Structural and Mechanistic Insights into Development of Chemical Tools to Control Individual and Inter-Related Pathological Features in Alzheimer's Disease.

To elucidate the involvement of individual and inter-related pathological factors [i.e., amyloid-ß (Aß), metals, and oxidative stress] in the pathogenesis of Alzheimer's disease (AD), chemical tools have been developed. Characteristics required for such tool construction, however, have not been clearly identified; thus, the optimization of available tools or new design has been limited. Here, key structural properties and mechanisms that can determine tools' regulatory reactivities with multiple pathogenic features found in AD are reported. A series of small molecules was built up through rational structural selection and variations onto the framework of a tool useful for in vitro and in vivo metal-Aß investigation. Variations include: (i) location and number of an Aß interacting moiety; (ii) metal binding site; and (iii) denticity and structural flexibility. Detailed biochemical, biophysical, and computational studies were able to provide a foundation of how to originate molecular formulas to devise chemical tools capable of controlling the reactivities of various pathological components through distinct mechanisms. Overall, this multidisciplinary investigation illustrates a structure-mechanism-based strategy of tool invention for such a complicated brain disease.

The durability of endovascular coiling versus neurosurgical clipping of ruptured cerebral aneurysms: 18 year follow-up of the UK cohort of the International Subarachnoid Aneurysm Trial (ISAT).

BACKGROUND: Previous analyses of the International Subarachnoid Aneurysm Trial (ISAT) cohort have reported on the risks of recurrent subarachnoid haemorrhage and death or dependency for a minimum of 5 years and up to a maximum of 14 years after treatment of a ruptured intracranial aneurysm with either neurosurgical clipping or endovascular coiling. At 1 year there was a 7% absolute and a 24% relative risk reduction of death and dependency in the coiling group compared with the clipping group, but the medium-term results showed the increased need for re-treatment of the target aneurysm in the patients given coiling. We report the long-term follow-up of patients in this UK cohort. METHODS: In ISAT, patients were randomly allocated to either neurosurgical clipping or endovascular coiling after a subarachnoid haemorrhage, assuming treatment equipoise, between Sept 12, 1994, and May 1, 2002. We followed up 1644 patients in 22 UK neurosurgical centres for death and clinical outcomes for 10·0-18·5 years. We assessed dependency as self-reported modified Rankin scale score obtained through yearly questionnaires. Data for recurrent aneurysms and rebleeding events were collected from questionnaires and from hospital and general practitioner records. The Office for National Statistics supplied data on deaths. This study is registered, number ISRCTN49866681. FINDINGS: At 10 years, 674 (83%) of 809 patients allocated endovascular coiling and 657 (79%) of 835 patients allocated neurosurgical clipping were alive (odds ratio [OR] 1·35, 95% CI 1·06-1·73). Of 1003 individuals who returned a questionnaire at 10 years, 435 (82%) patients treated with endovascular coiling and 370 (78%) patients treated with neurosurgical clipping were independent (modified Rankin scale score 0-2; OR 1·25; 95% CI 0·92-1·71). Patients in the endovascular treatment group were more likely to be alive and independent at 10 years than were patients in the neurosurgery group (OR 1·34, 95% CI 1·07-1·67). 33 patients had a recurrent subarachnoid haemorrhage more than 1 year after their initial haemorrhage (17 from the target aneurysm). INTERPRETATION: Although rates of increased dependency alone did not differ between groups, the probability of death or dependency was significantly greater in the neurosurgical group than in the endovascular group. Rebleeding was more likely after endovascular coiling than after neurosurgical clipping, but the risk was small and the probability of disability-free survival was significantly greater in the endovascular group than in the neurosurgical group at 10 years. FUNDING: UK Medical Research Council.

Importance of the Dimethylamino Functionality on a Multifunctional Framework for Regulating Metals, Amyloid-ß, and Oxidative Stress in Alzheimer's Disease.

The complex and multifaceted pathology of Alzheimer's disease (AD) continues to present a formidable challenge to the establishment of long-term treatment strategies. Multifunctional compounds able to modulate the reactivities of various pathological features, such as amyloid-ß (Aß) aggregation, metal ion dyshomeostasis, and oxidative stress, have emerged as a useful tactic. Recently, an incorporation approach to the rational design of multipurpose small molecules has been validated through the production of a multifunctional ligand (ML) as a potential chemical tool for AD. In order to further the development of more diverse and improved multifunctional reagents, essential pharmacophores must be identified. Herein, we report a series of aminoquinoline derivatives (AQ1-4, AQP1-4, and AQDA1-3) based on ML's framework, prepared to gain a structure-reactivity understanding of ML's multifunctionality in addition to tuning its metal binding affinity. Our structure-reactivity investigations have implicated the dimethylamino group as a key component for supplying the antiamyloidogenic characteristics of ML in both the absence and presence of metal ions. Two-dimensional NMR studies indicate that structural variations of ML could tune its interaction sites along the Aß sequence. In addition, mass spectrometric analyses suggest that the ability of our aminoquinoline derivatives to regulate metal-induced Aß aggregation may be influenced by their metal binding properties. Moreover, structural modifications to ML were also observed to noticeably change its metal binding affinities and metal-to-ligand stoichiometries that were shown to be linked to their antiamyloidogenic and antioxidant activities. Overall, our studies provide new insights into rational design strategies for multifunctional ligands directed at regulating metal ions, Aß, and oxidative stress in AD and could advance the development of improved next-generation multifunctional reagents.

A Redox-Active, Compact Molecule for Cross-Linking Amyloidogenic Peptides into Nontoxic, Off-Pathway Aggregates: In Vitro and In Vivo Efficacy and Molecular Mechanisms.

Chemical reagents targeting and controlling amyloidogenic peptides have received much attention for helping identify their roles in the pathogenesis of protein-misfolding disorders. Herein, we report a novel strategy for redirecting amyloidogenic peptides into nontoxic, off-pathway aggregates, which utilizes redox properties of a small molecule (DMPD, N,N-dimethyl-p-phenylenediamine) to trigger covalent adduct formation with the peptide. In addition, for the first time, biochemical, biophysical, and molecular dynamics simulation studies have been performed to demonstrate a mechanistic understanding for such an interaction between a small molecule (DMPD) and amyloid-ß (Aß) and its subsequent anti-amyloidogenic activity, which, upon its transformation, generates ligand-peptide adducts via primary amine-dependent intramolecular cross-linking correlated with structural compaction. Furthermore, in vivo efficacy of DMPD toward amyloid pathology and cognitive impairment was evaluated employing 5xFAD mice of Alzheimer's disease (AD). Such a small molecule (DMPD) is indicated to noticeably reduce the overall cerebral amyloid load of soluble Aß forms and amyloid deposits as well as significantly improve cognitive defects in the AD mouse model. Overall, our in vitro and in vivo studies of DMPD toward Aß with the first molecular-level mechanistic investigations present the feasibility of developing new, innovative approaches that employ redox-active compounds without the structural complexity as next-generation chemical tools for amyloid management.

Aneurysm treatment <24 versus 24-72 h after subarachnoid hemorrhage.

INTRODUCTION: In patients with aneurysmal subarachnoid hemorrhage (aSAH), it is unclear whether aneurysm treatment <24 h after ictus results in better outcomes than treatment 24-72 h after aSAH. We studied whether aneurysm occlusion <24 h is associated with better outcomes than occlusion 24-72 h after aSAH. METHODS: We used two cohorts of patients with aSAH: (1) the UMC Utrecht cohort with patients admitted between 2008 and 2012 and (2) the International Subarachnoid Aneurysm Trial cohort. Aneurysm treatment was categorized into <24 h and 24-72 h after ictus. We calculated adjusted risk ratios (aRRs) with 95% confidence intervals (CIs) using Poisson regression analyses for poor functional outcome (death or dependency) for both cohorts separately, and performed a pooled analysis based on individual patient data. We also performed a worst-case scenario analysis wherein all patients with rebleeding >3 h after admission were re-categorized into the group with aneurysm treatment 24-72 h after aSAH. RESULTS: We included 1,238 patients (UMC Utrecht cohort: n = 330; ISAT: n = 908). The aRR for poor outcome after treatment <24 h was in the UMC Utrecht cohort 1.84 (95% CI: 1.25-2.70), in ISAT 1.14 (95% CI 0.84-1.55), in the pooled analysis 1.37 (95% CI 1.11-1.68), and in the worst-case scenario pooled analysis 1.24 (95% CI 1.01-1.52). CONCLUSION: Our results suggest that aneurysm occlusion can be performed in day time within 72 h after ictus, instead of on an emergency basis. However, due to the retrospective, non-randomized design of our study, our results cannot be considered as definitive evidence.

Genetic control of interactions among individuals: contrasting outcomes of indirect genetic effects arising from neighbour disease infection and competition in a forest tree.

Indirect genetic effects (IGEs) are heritable effects of individuals on trait values of their conspecifics. IGEs may substantially affect response to selection, but empirical studies on IGEs are sparse and their magnitude and correlation with direct genetic effects are largely unknown in plants. Here we used linear mixed models to estimate genetic (co)variances attributable to direct and indirect effects for growth and foliar disease damage in a large pedigreed population of Eucalyptus globulus. We found significant IGEs for growth and disease damage, which increased with age for growth. The correlation between direct and indirect genetic effects was highly negative for growth, but highly positive for disease damage, consistent with neighbour competition and infection, respectively. IGEs increased heritable variation by 71% for disease damage, but reduced heritable variation by 85% for growth, leaving nonsignificant heritable variation for later age growth. Thus, IGEs are likely to prevent response to selection in growth, despite a considerable ordinary heritability. IGEs change our perspective on the genetic architecture and potential response to selection. Depending on the correlation between direct and indirect genetic effects, IGEs may enhance or diminish the response to natural or artificial selection compared with that predicted from ordinary heritability.

Timing of aneurysm treatment after subarachnoid hemorrhage: relationship with delayed cerebral ischemia and poor outcome.

BACKGROUND AND PURPOSE: The ideal timing of coiling or clipping after aneurysmal subarachnoid hemorrhage is unknown. Within the International Subarachnoid Aneurysm Trial we assessed differences in incidence of delayed cerebral ischemia and clinical outcome between different timings of treatment. METHODS: The treated 2106 patients randomized to coiling or clipping were divided into 4 categories: treatment <2 days, on days 3 to 4, on days 5 to 10, and >10 days after the hemorrhage. ORs with 95% CI were calculated with logistic regression analysis for delayed cerebral ischemia, poor outcome at 2 months, and 1 year for the different timing categories, with treatment <2 days as reference. Analyses were performed for all patients, and for coiled and clipped patients separately, and were adjusted for baseline characteristics. RESULTS: Adjusted ORs of delayed cerebral ischemia for treatment on days 5 to 10 were 1.18 (95% CI, 0.91-1.53) for all patients, 1.68 (95% CI, 1.17-2.43) after coiling, and 0.79 (95% CI, 0.54-1.16) after clipping. ORs for poor outcome at 2 months were 1.16 (95% CI, 0.89-1.50) for treatment (clipping and coiling combined) at 3 to 4 days, 1.39 (95% CI, 1.08-1.80) for treatment at 5 to 10 days, and 1.84 (95% CI, 1.36-2.51) for treatment >10 days. ORs for coiled and clipped patients separately were in the same range. Results for outcome at 1 year were similar. CONCLUSIONS: Our results support the current practice for early aneurysm treatment in subarachnoid hemorrhage patients. The risk for poor outcome was highest when treatment was performed after day 10; postponing treatment in patients who are eligible for treatment between days 5 to 10 after subarachnoid hemorrhage is not recommended.

Use of the numerator relationship matrix in genetic analysis of autopolyploid species.

Mixed models incorporating the inverse of a numerator relationship matrix (NRM) are widely used to estimate genetic parameters and to predict breeding values in animal breeding. A simple and quick method to directly calculate the inverse of the NRM has been historically developed for diploid animal species. Mixed models are less used in plant breeding partly because the existing method for diploids is not applicable to autopolyploid species. This is because of the phenomenon of double reduction and the possibility that gametes carry alleles which are identical by descent. This paper generalises the NRM and its inverse for autopolyploid species, so it can be easily incorporated into their genetic analysis. The technique proposed is to first calculate the kinship coefficient matrix and its inverse as a precursor to calculating the NRM and its inverse. This allows the NRM to be calculated for populations containing individuals of mixed ploidy levels. This generalization can also accommodate uncertain parentage by generating the "average" relationship matrix. The possibility that non-inbred parents can produce inbred progeny (double reduction) is also discussed. Rules are outlined that are applicable for any level of ploidy. Examples of use of the matrix are provided using simulated pedigrees.

Dosing of adult pigeons with as little as one #9 lead pellet caused severe δ-ALAD depression, suggesting potential adverse effects in wild populations.

Avian wildlife species commonly ingest lead (Pb) spent shot or bullet fragments as grit or mistakenly as food. In previous studies in our laboratory and others, the toxicity varied based on the diet as well as type and quantity of Pb ingested. In the current study, domestic pigeons were gavaged with 1, 2, or 3 Pb pellets and then followed with weekly radiographs and blood physiologic endpoints for 28 days. Pellet retention decreased by roughly 50 % per week as pellets were either absorbed or excreted, except for week 4 where pellet number no longer was diminished. Size of retained pellets visually decreased over retention time. Birds dosed with a single #9 pellet showed mean blood Pb levels over 80 times higher than those of the controls, verifying Pb pellet absorption from the gut. A single Pb pellet also reduced plasma δ-aminolevulinic acid dehydratase (δ-ALAD) activity by over 80 % compared to controls, suggesting the potential for population injury in Pb pellet-exposed pigeons.

Current issues and future considerations for the wider implementation of robotic-assisted surgery: a qualitative study.

OBJECTIVES: The effective implementation of a fast-changing healthcare delivery innovation, such as robotic-assisted surgery (RAS), into a healthcare system, can be affected (both positively and negatively) by external contextual factors. As part of a wider project investigating ways to optimise the implementation of RAS, this qualitative study aimed to uncover current issues of RAS and predictions about the future of robotic surgery. We refer to 'current issues' as the topical and salient challenges and opportunities related to the introduction of RAS in the UK healthcare system, from the perspectives of key stakeholders involved in the delivery and implementation of RAS. DESIGN: Semi-structured interviews and focus groups were conducted. A thematic analysis was conducted to summarise salient issues that were articulated by the participants. SETTING AND PARTICIPANTS: The interview sample (n=35) comprised surgeons, wider theatre staff and other relevant personnel involved in the introduction and delivery of RAS services across the UK, including service managers and policymakers/commissioners. Two focus groups were also conducted with surgical trainees (n=7) and members of the public (n=8), respectively. RESULTS: The results revealed a largely positive attitude towards the introduction of RAS technology and an expectation of continued rapid expansion. Areas perceived to be particularly pertinent and requiring ongoing attention were also highlighted, including the need to achieve improved quality control, expertise quantification and training issues and the need to educate the public. Issues of centralisation, service organisation and equity of access were also emphasised. CONCLUSIONS: Our study has highlighted a range of issues perceived to be particularly pertinent to the current and future provision of RAS which should be addressed. The areas outlined can enable healthcare managers and surgeons to plan for the adoption and/or expansion of RAS services.

Oral lead bullet fragment exposure in northern bobwhite (Colinus virginianus).

Lead (Pb) is a worldwide environmental contaminant known to adversely affect multiple organ systems in both mammalian and avian species. In birds, a common route of exposure is via oral ingestion of lead particles. Data are currently lacking for the retention and clearance of Pb bullet fragments in gastrointestinal (GI) tract of birds while linking toxicity with blood Pb levels. In the present study, northern bobwhite quail fed a seed-based diet were orally gavaged with Pb bullet fragments (zero, one or five fragments/bird) and evaluated for rate of fragment clearance, and changes in peripheral blood, renal, immune, and gastrointestinal parameters. Based on radiographs, the majority of the birds cleared or absorbed the fragments by seven days, with the exception of one five-fragment bird which took between 7 and 14 days. Blood Pb levels were higher in males than females, which may be related to egg production in females. In males but not females, feed consumption, body weight gain, packed cell volume (PCV), plasma protein concentration, and δ-aminolevulinic acid dehydratase (δ-ALAD) activity were all adversely affected by five Pb fragments. Birds of both sexes that received a single Pb fragment displayed depressed δ-ALAD, suggesting altered hematologic function, while all birds dosed with five bullet fragments exhibited greater morbidity.

Survival, Dependency, and Health-Related Quality of Life in Patients With Ruptured Intracranial Aneurysm: 10-Year Follow-up of the United Kingdom Cohort of the International Subarachnoid Aneurysm Trial.

BACKGROUND: Previous analyses of the International Subarachnoid Aneurysm Trial (ISAT) cohort have reported on clinical outcomes after treatment of a ruptured intracranial aneurysm with either neurosurgical clipping or endovascular coiling. OBJECTIVE: To evaluate the long-term quality-adjusted life years (QALYs) gained of endovascular coiling compare to neurosurgical clipping in the UK cohort of ISAT. METHODS: Between September 12, 1994 and May 1, 2002, patients with ruptured intracranial aneurysms who were assumed treatment equipoise were randomly allocated to either neurosurgical clipping or endovascular coiling. We followed-up 1644 patients in 22 UK neurosurgical centers for a minimum of 10 yr. Health-related quality of life (HRQoL) was collected through yearly questionnaires, measured by utilities calculated from the EQ-5D-3L. We compared HRQoL between the 2 treatment groups over a period of 10 yr. In all, 1-yr, 5-yr, and 10-yr QALYs were estimated by combining utility and survival information. RESULTS: Higher average utility values were found in the endovascular group throughout the follow-up period, with mean differences between groups statistically significant in most years. The 10-yr QALYs were estimated to be 6.68 (95% CI: 6.45-6.90) in the coiling group and 6.32 (95% CI: 6.10-6.55) in the clipping group, respectively, a significant mean difference of 0.36 (95% CI: 0.04-0.66). A third of this mean QALYs gain was estimated to derive solely from HRQoL differences. CONCLUSION: HRQoL after treatment of a ruptured intracranial aneurysm was better after endovascular coiling compared to neurosurgical clipping, which contributed significantly to the QALYs gained over a 10-yr period.

Improved cognitive outcomes with endovascular coiling of ruptured intracranial aneurysms: neuropsychological outcomes from the International Subarachnoid Aneurysm Trial (ISAT).

BACKGROUND AND PURPOSE: The International Subarachnoid Aneurysm Trial (ISAT) reported lower rates of death and disability with endovascular versus neurosurgical treatment of ruptured intracranial aneurysms. However, assessment of functional outcome was limited to the modified Rankin Scale, which is known to be insensitive to cognitive function. A neuropsychological substudy (N-ISAT) was therefore done in all recruits from 8 ISAT centers in the United Kingdom. METHODS: Detailed neuropsychological assessment was performed at a 12-month follow-up visit. Impairment was defined as performance below the 5th percentile of the study population on at least 2 tests in >or=2 major cognitive domains. Analysis was restricted to patients who were not known to be otherwise disabled according to the modified Rankin Scale (ie, modified Rankin Scale 0 to 2). RESULTS: Of 836 patients randomized in ISAT in the 8 UK centers (411 allocated endovascular treatment versus 425 neurosurgery), 224 were dead or disabled before 12-month follow-up (78 allocated endovascular treatment versus 135 neurosurgery). Of the remaining 612 patients eligible for neuropsychological assessment, 137 (65 allocated endovascular treatment versus 72 neurosurgery) did not attend. Of the 474 nondisabled patients who were assessed, 152 (32.1%) had cognitive impairment. Patients with cognitive impairment had reduced self-reported health-related quality of life (P<0.001) in both treatment groups, but cognitive impairment was less common in those allocated endovascular treatment (70 of 262 versus 82 of 212 allocated neurosurgery, OR=0.58, 95% CI 0.38 to 0.87, P=0.0055). The incidence of epilepsy was also lower in the N-ISAT endovascular group (7 versus 18, OR=0.30, 0.11 to 0.77, P=0.005) but was independent of the effect on cognitive function. CONCLUSIONS: Cognitive impairment occurred in approximately one third of patients who were not otherwise disabled according to the modified Rankin Scale in N-ISAT and was more frequent in the neurosurgery group. These results have implications for management of ruptured intracranial aneurysms and more generally for interpretation of the outcomes of clinical trials that use the modified Rankin Scale.