We investigated a CAG trinucleotide repeat expansion in the ATXN2 gene in amyotrophic lateral sclerosis (ALS). Two new case-control studies, a British dataset of 1474 ALS cases and 567 controls, and a Dutch dataset of 1328 ALS cases and 691 controls were analyzed. In addition, to increase power, we systematically searched PubMed for case-control studies published after 1 August 2010 that investigated the association between ATXN2 intermediate repeats and ALS. We conducted a meta-analysis of the new and existing studies for the relative risks of ATXN2 intermediate repeat alleles of between 24 and 34 CAG trinucleotide repeats and ALS. There was an overall increased risk of ALS for those carrying intermediate sized trinucleotide repeat alleles (odds ratio 3.06 [95% confidence interval 2.37-3.94]; p = 6 × 10^-18), with an exponential relationship between repeat length and ALS risk for alleles of 29-32 repeats (R² = 0.91, p = 0.0002). No relationship was seen for repeat length and age of onset or survival. In contrast to trinucleotide repeat diseases, intermediate ATXN2 trinucleotide repeat expansion in ALS does not predict age of onset but does predict disease risk.

Background and Purpose: Outcome prediction after aneurysmal subarachnoid hemorrhage (aSAH) is challenging. CRP (C-reactive protein) has been reported to be associated with outcome, but it is unclear if this is independent of other predictors and applies to aSAH of all grades. Therefore, the role of CRP in aSAH outcome prediction models is unknown. The purpose of this study is to assess if CRP is an independent predictor of outcome after aSAH, develop new prognostic models incorporating CRP, and test whether these can be improved by application of machine learning. Methods: This was an individual patient-level analysis of data from patients within 72 hours of aSAH from 2 prior studies. A panel of statistical learning methods including logistic regression, random forest, and support vector machines were used to assess the relationship between CRP and modified Rankin Scale. Models were compared with the full Subarachnoid Hemmorhage International Trialists’ (SAHIT) prediction tool of outcome after aSAH and internally validated using cross-validation. Results: One thousand and seventeen patients were included for analysis. CRP on the first day after ictus was an independent predictor of outcome. The full SAHIT model achieved an area under the receiver operator characteristics curve (AUC) of 0.831. Addition of CRP to the predictors of the full SAHIT model improved model performance (AUC, 0.846, P =0.01). This improvement was not enhanced when learning was performed using a random forest (AUC, 0.807), but was with a support vector machine (AUC of 0.960, P <0.001). Conclusions: CRP is an independent predictor of outcome after aSAH. Its inclusion in prognostic models improves performance, although the magnitude of improvement is probably insufficient to be relevant clinically on an individual patient level, and of more relevance in research. Greater improvements in model performance are seen with support vector machines but these models have the highest classification error rate on internal validation and require external validation and calibration.

The aim of this study was to provide the evidence base to guide interconversion of the modified Rankin Scale (mRS) and Glasgow Outcome Scale (GOS) in neurological research. A retrospective analysis of paired mRS and GOS recordings was conducted using datasets with the following selection criteria: (1) patients had haemorrhagic stroke, (2) simultaneous mRS and GOS measurements were available, and (3) data sharing was possible. The relationship between mRS and GOS was assessed using correlation analysis. The optimum dichotomisation thresholds for agreement between the mRS and GOS were identified using Cohen's kappa coefficient. Two-way conversion tables between mRS and GOS were developed based on the highest agreement between scores. Finally, to identify which direction of conversion (mRS to GOS or vice versa) was better, the Kolmogorov-Smirnov D statistic was calculated. Using 3474 paired recordings the mRS and GOS were shown to be highly correlated (ρ = 0.90, p < 0.0001). The greatest agreement between the two scoring systems occurred when mRS=0-2 and GOS=4-5 was used to define good outcome (κ=0.83, 95% confidence interval: 0.81-0.85). Converting from mRS to GOS was better than the reverse direction as evidenced by a lower Kolmogorov-Smirnov statistic (D=0.054 compared to D=0.157). This study demonstrates that the mRS and GOS are highly correlated, establishes the optimum dichotomisation threshold for agreement, provides a method for interconversion and shows that mRS to GOS conversion is superior to the reverse direction if a choice is available.

Introduction The UK population is ageing with increasing number of elderly patients suffering traumatic brain injury (TBI). The purpose of this study was to identify national TBI admission demographics, analyse the temporal evolution of TBI mortality in a single centre and conduct a systematic review of the literature to identify whether there is an age bias amongst researchers studying TBI. Methods National demographics for TBI were obtained from Health Episode Statistics. TBI patients admitted from 2000 to 2011 to Cambridge University Hospitals Neurocritical Care Unit (NCCU) were divided into age groups (<60, 60–74, ≥75 years). Temporal evolution of mortality was analysed using a logistic regression method. A systematic literature review was conducted to identify primary TBI research studies. Patient’s ages were extracted and an average mean age was calculated and compared over time. Results From 1998, national TBI admissions have increased with the greatest rise in >60-year age group (p < 0.0001). In a tertiary referral critical care unit (n = 1145), the 60–74 year age group (compared to <60) had a significantly lower improvement in mortality over time (OR: 1.15, 95% CI: 1.02–1.31). A literature review revealed a mean age of 32.73 years (SD ± 12.85) for patients recruited to primary TBI studies. Conclusion Despite increased admissions of elderly patients following TBI and static mortality (single centre, 60–74 year age group) there is little or no evidence of a corresponding increase in the age of patients recruited for TBI studies. In addition to the difficulties this presents in forming evidence-based decisions for the patient with TBI, it may also represent a wider problem for ICU research in an ever-ageing critical care population. More research needs to be conducted to establish the treatment end points for an ageing population.

Haptoglobin (Hp) is a plasma protein involved in clearing extracellular haemoglobin and regulating inflammation; it exists as two genetic variants (Hp1 and Hp2). In a meta‐analysis of six published studies, we confirm that Hp genotype affects short‐term outcome (cerebral vasospasm and/or delayed cerebral ischemia) after subarachnoid haemorrhage (SAH) but not long‐term outcome (Glasgow Outcome Score and modified Rankin Scale between one and three months). A closer examination of the heterozygous group revealed that the short‐term outcome of Hp2‐1 individuals clustered with that of Hp1‐1 and not Hp2‐2, suggesting that the presence of one Hp1 allele was sufficient to confer protection. Since the presence of the Hp dimer is the only common feature between Hp1‐1 and Hp2‐1 individuals, the absence of this Hp moiety is most likely to underlie vasospasm in Hp2‐2 individuals. These results have implications for prognosis after SAH and will inform further research into Hp‐based mechanism of action and treatment.