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Sarilumab is a human monoclonal antibody against interleukin (IL)-6Rα that has been approved for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) and an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). Mild liver function test abnormalities have been observed in patients treated with sarilumab. We describe a genome-wide association study of bilirubin elevations in RA patients treated with sarilumab. Array genotyping and exome sequencing were performed on DNA samples from 1075 patients. Variants in the UGT1A1 gene were strongly associated with maximum bilirubin elevations in sarilumab-treated patients (rs4148325; p = 2.88 × 10−41) but were not associated with aminotransferase elevations. No other independent loci showed evidence of association with bilirubin elevations after sarilumab treatment. These findings suggest that most bilirubin increases during sarilumab treatment are related to genetic variation in UGT1A1 rather than underlying liver injury.

The UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world1. Here we describe the release of exome-sequence data for the first 49,960 study participants, revealing approximately 4 million coding variants (of which around 98.6% have a frequency of less than 1%). The data include 198,269 autosomal predicted loss-of-function (LOF) variants, a more than 14-fold increase compared to the imputed sequence. Nearly all genes (more than 97%) had at least one carrier with a LOF variant, and most genes (more than 69%) had at least ten carriers with a LOF variant. We illustrate the power of characterizing LOF variants in this population through association analyses across 1,730 phenotypes. In addition to replicating established associations, we found novel LOF variants with large effects on disease traits, including PIEZO1 on varicose veins, COL6A1 on corneal resistance, MEPE on bone density, and IQGAP2 and GMPR on blood cell traits. We further demonstrate the value of exome sequencing by surveying the prevalence of pathogenic variants of clinical importance, and show that 2% of this population has a medically actionable variant. Furthermore, we characterize the penetrance of cancer in carriers of pathogenic BRCA1 and BRCA2 variants. Exome sequences from the first 49,960 participants highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community., Exome sequences from the first 49,960 participants in the UK Biobank highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community.

Patients with unresponsive wakefulness syndrome (UWS) or in minimally conscious state (MCS) after brain injury show significant fluctuations in their behavioural abilities over time. As the importance of event-related potentials (ERPs) in the detection of traces of consciousness increases, we investigated the retest reliability of ERPs with repeated tests at four different time points. Twelve healthy controls and 12 inpatients (8 UWS, 4 MCS; 6 traumatic, 6 non-traumatic) were tested twice a day (morning, afternoon) for 2 days with an auditory oddball task. ERPs were recorded with a 256-channel-EEG system, and correlated with behavioural test scores in the Coma Recovery Scale-revised (CRS-R). The number of identifiable P300 responses varied between zero and four in both groups. Reliabilities varied between Krippendorff's α = 0.43 for within-day comparison, and α = 0.25 for between-day comparison in the patient group. Retest reliability was strong for the CRS-R scores for all comparisons (α = 0.83-0.95). The stability of auditory information processing in patients with disorders of consciousness is the basis for other, even more demanding tasks and cognitive potentials. The relatively low ERP-retest reliability suggests that it is necessary to perform repeated tests, especially when probing for consciousness with ERPs. A single negative ERP test result may be mistaken for proof that a UWS patient truly is unresponsive.

Pacejka’s tire model is widely used and well-known by the automotive engineering community. The magic formula describes the brake force, side force and self-aligning torque in terms of the longitudinal slip and slip angle, plus several corrections. This paper uses approximation theory to obtain different types of approximations to the magic formula: rational functions (RA) resulting from the Remez algorithm, expansions in a series of Chebyshev polynomials (ACh), a series of Chebyshev rational polynomials (ARChPs), a series of rational orthogonal functions (ORF) and a series of ARChPs that result from grade-1 ORFs. The last expansion shows the fastest convergence and most effective computation. Jacobi rational polynomials can also be obtained to complement this expansion and facilitate fine-tuning in specific areas of the error curve. This work is complemented by obtaining the original rational approximations to the inverse tangent function, which take advantage of the curve symmetry to reduce the computation load and provide models that include the influence of the vertical load. The convergence properties of the development in series and the error values resulting from numeric examples for the three types of stress are shown. The proposed final ARChP expressions show very low error (1%) compared to the original magic formula. They can be computed 20 times faster; they can be evaluated, derived and integrated analytically easily; and their coefficients can be obtained from tests using common least-squares algorithms.