Clinical and radiographic outcomes at 2 years and the effect of tocilizumab discontinuation following sustained remission in the second and third year of the ACT-RAY study

OBJECTIVE To assess the efficacy and safety of tocilizumab (TCZ) plus methotrexate/placebo (MTX/PBO) over 2 years and the course of disease activity in patients who discontinued TCZ due to sustained remission. METHODS ACT-RAY was a double-blind 3-year trial. Patients with active rheumatoid arthritis despite MTX were randomised to add TCZ to ongoing MTX (add-on strategy) or switch to TCZ plus PBO (switch strategy). Using a treat-to-target approach, open-label conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), other than MTX, were added from week 24 if Disease Activity Score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) >3.2. Between weeks 52 and 104, patients in sustained clinical remission (DAS28-ESR <2.6 at two consecutive visits 12 weeks apart) discontinued TCZ and were assessed every 4 weeks for 1 year. If sustained remission was maintained, added csDMARDs, then MTX/PBO, were discontinued. RESULTS Of the 556 randomised patients, 76% completed year 2. Of patients entering year 2, 50.4% discontinued TCZ after achieving sustained remission and 5.9% achieved drug-free remission. Most patients who discontinued TCZ (84.0%) had a subsequent flare, but responded well to TCZ reintroduction. Despite many patients temporarily stopping TCZ, radiographic progression was minimal, with differences favouring add-on treatment. Rates of serious adverse events and serious infections per 100 patient-years were 12.2 and 4.4 in add-on and 15.0 and 3.7 in switch patients. In patients with normal baseline values, alanine aminotransferase elevations >3×upper limit of normal were more frequent in add-on (14.3%) versus switch patients (5.4%). CONCLUSIONS Treat-to-target strategies could be successfully implemented with TCZ to achieve sustained remission, after which TCZ was stopped. Biologic-free remission was maintained for about 3 months, but most patients eventually flared. TCZ restart led to rapid improvement. TRIAL REGISTRATION NUMBER NCT00810199.

Topographic sleep EEG changes in the acute and chronic stage of hemispheric stroke.

After stroke, the injured brain undergoes extensive reorganization and reconnection. Sleep may play a role in synaptic plasticity underlying stroke recovery. To test this hypothesis, we investigated topographic sleep electroencephalographic characteristics, as a measure of brain reorganization, in the acute and chronic stages after hemispheric stroke. We studied eight patients with unilateral stroke in the supply territory of the middle cerebral artery and eight matched controls. All subjects underwent a detailed clinical examination including assessment of stroke severity, sleep habits and disturbances, anxiety and depression, and high-density electroencephalogram examination with 128 electrodes during sleep. The recordings were performed within 10 days after stroke in all patients, and in six patients also 3 months later. During sleep, we found higher slow-wave and theta activity over the affected hemisphere in the infarct area in the acute and chronic stage of stroke. Slow-wave, theta activity and spindle frequency range power over the affected hemisphere were lower in comparison to the non-affected side in a peri-infarct area in the patients' group, which persisted over time. Conversely, in wakefulness, only an increase of delta, theta activity and a slowing of alpha activity over the infarct area were found. Sleep slow-wave activity correlated with stroke severity and outcome. Stroke might have differential effects on the generation of delta activity in wakefulness and sleep slow waves (1-8 Hz). Sleep electroencephalogram changes over both the affected and non-affected hemispheres reflect the acute dysfunction caused by stroke and the plastic changes underlying its recovery. Moreover, these changes correlate with stroke severity and outcome.

Age matters in the prevalence and clinical significance of ultra-high-risk for psychosis symptoms and criteria in the general population: Findings from the BEAR and BEARS-kid studies

Early detection of psychosis is an important topic in psychiatry. Yet, there is limited information on the prevalence and clinical significance of high-risk symptoms in children and adolescents as compared to adults. We examined ultra-high-risk (UHR) symptoms and criteria in a sample of individuals aged 8-40 years from the general population of Canton Bern, Switzerland, enrolled from June 2011 to May 2014. The current presence of attenuated psychotic symptoms (APS) and brief intermittent psychotic symptoms (BLIPS) and the fulfillment of onset/worsening and frequency requirements for these symptoms in UHR criteria were assessed using the Structured Interview for Psychosis Risk Syndromes. Additionally, perceptive and non-perceptive APS were differentiated. Psychosocial functioning and current non-psychotic DSM-IV axis I disorders were also surveyed. Well-trained psychologists performed assessments. Altogether, 9.9% of subjects reported APS and none BLIPS, and 1.3% met all the UHR requirements for APS. APS were related to more current axis I disorders and impaired psychosocial functioning, indicating some clinical significance. A strong age effect was detected around age 16: compared to older individuals, 8-15-year olds reported more perceptive APS, that is, unusual perceptual experiences and attenuated hallucinations. Perceptive APS were generally less related to functional impairment, regardless of age. Conversely, non-perceptive APS were related to low functioning, although this relationship was weaker in those below age 16. Future studies should address the differential effects of perceptive and non-perceptive APS, and their interaction with age, also in terms of conversion to psychosis.

Soft gluon resummation in the signal-background interference process of gg(→ h ∗) → ZZ

We present a precise theoretical prediction for the signal-background interference process of gg(→ h ∗) → ZZ, which is useful to constrain the Higgs boson decay width and to measure Higgs couplings to the SM particles. The approximate NNLO K-factor is in the range of 2.05 − 2.45 (1.85 − 2.25), depending on M ZZ , at the 8 (13) TeV LHC. And the soft gluon resummation can increase the approximate NNLO result by about 10% at both the 8 TeV and 13 TeV LHC. The theoretical uncertainties including the scale, uncalculated multi-loop amplitudes of the background and PDF+αs are roughly O(10%) at NNLL′. We also confirm that the approximate K-factors in the interference and the pure signal processes are the same.

Long-term man–environment interactions in the Bolivian Amazon: 8000 years of vegetation dynamics

Only few studies documenting the vegetation history of the Llanos de Moxos, one of the largest seasonally flooded wetland areas in South America, are available and little is known about the environmental impact of pre-Columbian settlements. We use radiocarbon-dated terrestrial plant macrofossils to establish a sound chronology and palynological analyses to reconstruct the vegetation and fire history of the Lago Rogaguado area. The sedimentary pollen and spore record suggests that wetland and wooded savannah (Cerrado) environments occurred around the lake between 8100 and 5800 cal BP. Fire activity was high during this period and was probably connected to the dry Cerrado environments. The pollen evidence suggests early plant cultivation (Zea mays, Annonaceae and Cucurbitaceae) from 6500 cal BP onwards, which is significantly earlier than hitherto assumed for Amazonia. Gallery forests expanded after 5800 cal BP, when fire activity strongly declined. Forest expansion intensified around 2800 cal BP and continued until 2000 cal BP, when forest cover reached its maximum and fire activity its minimum. The late-Holocene forest expansion to the south and the decrease of fire activity may have resulted from a climatic shift to moister conditions (possibly a shorter dry season). New crops (e.g. Avena-type) or adventive plants (e.g. Rumex acetosella-type) document the impact of European economies after ca. 500 cal BP. Land use intensity remained rather stable over the most recent centuries, arguing against a collapse of settlements in response to the arrival of Europeans, as reconstructed from other Amazonian pollen records.

Vegetation Changes and Timberline Fluctuations in the Central Alps as Indicators of Holocene Climatic Oscillations

Pollen and plant-macrofossil data are presented for two lakes near the timberline in the Italian (Lago Basso, 2250 m) and Swiss Central Alps (Gouille Rion, 2343 m). The reforestation at both sites started at 9700-9500 BP with Pinus cembra, Larbc decidua, and Betula. The timberline reached its highest elevation between 8700 and 5000 BP and retreated after 5000 BP, due to a mid-Holocene climatic change and increasing human impact since about 3500 BP (Bronze Age). The expansion of Picea abies at Lago Basso between ca. 7500 and 6200 BP was probably favored by cold phases accompanied by increased oceanicity, whereas in the area of Gouille Rion, where spruce expanded rather late (between 4500 and 3500 BP), human influence equally might have been important. The mass expansion of Alnus viridis between ca. 5000 and 3500 BP probably can be related to both climatic change and human activity at timberline. During the early and middle Holocene a series of timberline fluctuations is recorded as declines in pollen and macrofossil concentrations of the major tree species, and as increases in nonarboreal pollen in the pollen percentage diagram of Gouille Rion. Most of ·the periods of low timberline can be correlated by radiocarbon dating with climatic changes in the Alps as indicated by glacier ad­ vances in combination with palynological records, solifluction, and dendrocli­ matical data. Lago Basso and Gouille Rion are the only sites in the Alps showing complete palaeobotanical records of cold phases between 10,000 and 2000 BP with very good time control. The altitudinal range of the Holocene treeline fluc­ tuations caused by climate most likely was not more than 100 to 150 m. A possible correlation of a cold period at ca. 7500-6500 BP (Misox oscil­ lation) in the Alps is made with paleoecological data from North America and Scandinavia and a climatic signal in the GRIP ice core from central Greenland 8200 yr ago (ca. 7400 yr uncal. BP).

Characterization of fetal antigen 1/delta-like 1 homologue expressing cells in the rat nigrostriatal system: effects of a unilateral 6-hydroxydopamine lesion.

Fetal antigen 1/delta-like 1 homologue (FA1/dlk1) belongs to the epidermal growth factor superfamily and is considered to be a non-canonical ligand for the Notch receptor. Interactions between Notch and its ligands are crucial for the development of various tissues. Moreover, FA1/dlk1 has been suggested as a potential supplementary marker of dopaminergic neurons. The present study aimed at investigating the distribution of FA1/dlk1-immunoreactive (-ir) cells in the early postnatal and adult midbrain as well as in the nigrostriatal system of 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian adult rats. FA1/dlk1-ir cells were predominantly distributed in the substantia nigra (SN) pars compacta (SNc) and in the ventral tegmental area. Interestingly, the expression of FA1/dlk1 significantly increased in tyrosine hydroxylase (TH)-ir cells during early postnatal development. Co-localization and tracing studies demonstrated that FA1/dlk1-ir cells in the SNc were nigrostriatal dopaminergic neurons, and unilateral 6-OHDA lesions resulted in loss of both FA1/dlk1-ir and TH-ir cells in the SNc. Surprisingly, increased numbers of FA1/dlk1-ir cells (by 70%) were detected in dopamine-depleted striata as compared to unlesioned controls. The higher number of FA1/dlk1-ir cells was likely not due to neurogenesis as colocalization studies for proliferation markers were negative. This suggests that FA1/dlk1 was up-regulated in intrinsic cells in response to the 6-OHDA-mediated loss of FA1/dlk1-expressing SNc dopaminergic neurons and/or due to the stab wound. Our findings hint to a significant role of FA1/dlk1 in the SNc during early postnatal development. The differential expression of FA1/dlk1 in the SNc and the striatum of dopamine-depleted rats could indicate a potential involvement of FA1/dlk1 in the cellular response to the degenerative processes.