Clinical Utility of Random Anti–Tumor Necrosis Factor Drug–Level Testing and Measurement of Antidrug Antibodies on the Long-Term Treatment Response in Rheumatoid Arthritis

Objective: To investigate whether antidrug antibodies and/or drug non-trough levels predict the long-term treatment response in a large cohort of patients with rheumatoid arthritis (RA) treated with adalimumab or etanercept and to identify factors influencing antidrug antibody and drug levels to optimize future treatment decisions.  Methods: A total of 331 patients from an observational prospective cohort were selected (160 patients treated with adalimumab and 171 treated with etanercept). Antidrug antibody levels were measured by radioimmunoassay, and drug levels were measured by enzyme-linked immunosorbent assay in 835 serial serum samples obtained 3, 6, and 12 months after initiation of therapy. The association between antidrug antibodies and drug non-trough levels and the treatment response (change in the Disease Activity Score in 28 joints) was evaluated.  Results: Among patients who completed 12 months of followup, antidrug antibodies were detected in 24.8% of those receiving adalimumab (31 of 125) and in none of those receiving etanercept. At 3 months, antidrug antibody formation and low adalimumab levels were significant predictors of no response according to the European League Against Rheumatism (EULAR) criteria at 12 months (area under the receiver operating characteristic curve 0.71 [95% confidence interval (95% CI) 0.57, 0.85]). Antidrug antibody–positive patients received lower median dosages of methotrexate compared with antidrug antibody–negative patients (15 mg/week versus 20 mg/week; P = 0.01) and had a longer disease duration (14.0 versus 7.7 years; P = 0.03). The adalimumab level was the best predictor of change in the DAS28 at 12 months, after adjustment for confounders (regression coefficient 0.060 [95% CI 0.015, 0.10], P = 0.009). Etanercept levels were associated with the EULAR response at 12 months (regression coefficient 0.088 [95% CI 0.019, 0.16], P = 0.012); however, this difference was not significant after adjustment. A body mass index of ≥30 kg/m2 and poor adherence were associated with lower drug levels.  Conclusion: Pharmacologic testing in anti–tumor necrosis factor–treated patients is clinically useful even in the absence of trough levels. At 3 months, antidrug antibodies and low adalimumab levels are significant predictors of no response according to the EULAR criteria at 12 months

Glutamine-to-glutamate ratio in the nucleus accumbens predicts effort-based motivated performance in humans

Substantial evidence implicates the nucleus accumbens in motivated performance, but very little is known about the neurochemical underpinnings of individual differences in motivation. Here, we applied 1H magnetic resonance spectroscopy (1H-MRS) at ultra-high-field in the nucleus accumbens and inquired whether levels of glutamate (Glu), glutamine (Gln), GABA or their ratios predict interindividual differences in effort-based motivated task performance. Given the incentive value of social competition, we also examined differences in performance under self-motivated or competition settings. Our results indicate that higher accumbal Gln-to-Glu ratio predicts better overall performance and reduced effort perception. As performance is the outcome of multiple cognitive, motor and physiological processes, we applied computational modeling to estimate best-fitting individual parameters related to specific processes modeled with utility, effort and performance functions. This model-based analysis revealed that accumbal Gln-to-Glu ratio specifically relates to stamina; i.e., the capacity to maintain performance over long periods. It also indicated that competition boosts performance from task onset, particularly for low Gln-to-Glu individuals. In conclusion, our findings provide novel insights implicating accumbal Gln and Glu balance on the prediction of specific computational components of motivated performance. This approach and findings can help developing therapeutic strategies based on targeting metabolism to ameliorate deficits in effort engagement

Orbital tuning of a coastal succession of Late Eocene-Early Oligocene age: Clays, cycles and sea-level change in the Solent Group, Isle of Wight, UK.

The Solent Group in the Hampshire Basin UK comprises over 200m of clays, silts, limestones and infrequent sands of Late Eocene-Early Oligocene age deposited in continental (fluvatile and lacustrine facies with many palaeosols), estuarine and rarely shallow marine facies. The accumulation rate was rapid (40-60m/Ma), and the succession displays conspicuous sequence-scale sea-level cycles (10-30m) representing transitions from transgressive shallow marine/estuarine envrionments through brackish floodplain highstands to ephemeral freshwater carbonate lakes representing lowstands. Stratigraphy has traditionally been based on mammals and charophytes, although a number of levels provide sufficient nannofossils to identify NP Zones. We have used these important horizons, in conjunction with a new magnetostratigraphy, to correlate with the global chronostratigraphical scale. Although the succession is not conspicuously cyclic on the scale of bedding, high-resolution clay mineralogy and elemental geochemistry display striking cyclical changes on several frequencies. We have chosen one parameter, the percentage of illite and illite-smectite in the clay fraction of the sediment, to investigate orbital controls on the succession. Illite/illite smectite in this succession is neoformed in gley palaeosols, and was formed by repeated wetting and drying of the sediment in response to strongly contrasting seasons (ie high seasonality). There is a strong correlation between illite abundance and the occurrence of the pulmonate gastropod Lymnaea, which has a selective advantage in ephemeral ponds because it can breathe air. Because the orbital configuration which maximises seasonality has high eccentricity and obliquity values, we tuned high illite values to eccentricity maxima, and hypothesised that conspicuous groups of high illite peaks correspond with long eccentricity (400Ka) maxima. We anchored this age model to the global chronostratigraphical scale using magnetic chrons; C13n (base of chron) and C15n (top of chron) and the results compared closely with published timescales for this interval. Filters of the tuned dataset recovered convincing short eccentricity (100Ka) and obliquity (41 Ka) signals, but little evidence of precession. Spectral analysis using the Blackman-Tukey method demonstrated eccentricity, obliquity and precession peaks, and supports our assumption that major variations in clay mineralogy are linked to the long eccentricity cycles. An important conclusion of this study is that the sequence-scale changes, reflecting the major sea-level changes, are directly related to the 400Ka cycle, and presumably were responses to changes in volume of Antarctic ice cover. A major hypothesised ice-growth event in the Early Oligocene has been interpreted by various authors from a heavy oxygen isotope shift approximately coincident with the base of chron 13n. The corresponding level in the UK does not display any evidence of significant sea-level change in the coastal plain deposits of the Isle of Wight

Palaeomagnetic studies on rock formations in the High Atlas and Anti-Atlas regions of Morocco

PhD ThesisThe first part of this thesis (Chapters I to 8) describes the results of palaeomagnetic studies on samples collected from the High- Atlas and Anti-Atlas regions of Morocco. New palaeomagnetic pole positions are described from formations of Late Precambrian, Lower Cambrian, Devonian, Triassic, Jurassic and Cretaceous ages. The new Moroccan Late Precambrian and Lower Cambrian poles are shownto be more consistent with reliable Lower Palaeozoic poles of the same age from North America than ones from Southeast Africa, when the two continents are plotted on a Bullard-type reconstruction. It is concluded that a small part of Northwest Africa, including Morocco, may originally have been attached to North America, and that the rest of Africa was widely separated from North America at that time. Collision between Africa and Eastern North America probably occurred during the Carboniferous period, resulting in the formation of the Hercynian fold-belts along the present-day North Atlantic margins of the two continents and the welding of extreme Northwest Africa to the rest of the continent. Subsequent separation probably took place along a slightly different line, so that Morocco was left attached to Africa. Radiometric dating results from Moroccan igneous intrusions paralleling the local coastline yielded a mean age of 183 my, i. e. Lower Juraszic. other evidence suggests that the Mesozoic rifting between North America and Northwest Africa began at this time, and it is considered likely that the intrusion of the Moroccan Lower Jurassic igneous bodies was directly related to this event. Palaeomagnetic results from the Moroccan Cretaceous sediments indicate a gradual widening of the North Atlantic Ocean during the course of the Mesozoic. There are no significant differences between mean Triassic, Jurassic and Cretaceous poles from Morocco, and corresponding poles from South-east and Central Africa, and it is concluded that no significant post-Triassic relative tectonic movement has occurrcd between North-west and South-east Africa. The second part of the thesis (Chapters 9 and 10) describes an attempt at the AF demagnetisation of sediments by means of alternating fields of strangths up to 5000 Oe. Experiments were performed to investigate the effects of small asymmetries (up to 5%) in waveform of the applied alternating field, and it was shown that asymmetrics present in 'the natural AC mains supply at the Close House Laboratory at certain times, of the day are sufficiently high to produce appreciable AMM's in rock samples, if no sample rotation system is used during the demao-natisation processShell International Petroleum Co. NER