Stratification of biological therapies by pathobiology in biologic-naive patients with rheumatoid arthritis (STRAP and STRAP-EU): two parallel, open-label, biopsy-driven, randomised trials.

BACKGROUND: Despite highly effective targeted therapies for rheumatoid arthritis, about 40% of patients respond poorly, and predictive biomarkers for treatment choices are lacking. We did a biopsy-driven trial to compare the response to rituximab, etanercept, and tocilizumab in biologic-naive patients with rheumatoid arthritis stratified for synovial B cell status. METHODS: STRAP and STRAP-EU were two parallel, open-label, biopsy-driven, stratified, randomised, phase 3 trials done across 26 university centres in the UK and Europe. Biologic-naive patients aged 18 years or older with rheumatoid arthritis based on American College of Rheumatology (ACR)-European League Against Rheumatism classification criteria and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) were included. Following ultrasound-guided synovial biopsy, patients were classified as B cell poor or B cell rich according to synovial B cell signatures and randomly assigned (1:1:1) to intravenous rituximab (1000 mg at week 0 and week 2), subcutaneous tocilizumab (162 mg per week), or subcutaneous etanercept (50 mg per week). The primary outcome was the 16-week ACR20 response in the B cell-poor, intention-to-treat population (defined as all randomly assigned patients), with data pooled from the two trials, comparing etanercept and tocilizumab (grouped) versus rituximab. Safety was assessed in all patients who received at least one dose of study drug. These trials are registered with the EU Clinical Trials Register, 2014-003529-16 (STRAP) and 2017-004079-30 (STRAP-EU). FINDINGS: Between June 8, 2015, and July 4, 2019, 226 patients were randomly assigned to etanercept (n=73), tocilizumab (n=74), and rituximab (n=79). Three patients (one in each group) were excluded after randomisation because they received parenteral steroids in the 4 weeks before recruitment. 168 (75%) of 223 patients in the intention-to-treat population were women and 170 (76%) were White. In the B cell-poor population, ACR20 response at 16 weeks (primary endpoint) showed no significant differences between etanercept and tocilizumab grouped together and rituximab (46 [60%] of 77 patients vs 26 [59%] of 44; odds ratio 1·02 [95% CI 0·47-2·17], p=0·97). No differences were observed for adverse events, including serious adverse events, which occurred in six (6%) of 102 patients in the rituximab group, nine (6%) of 108 patients in the etanercept group, and three (4%) of 73 patients in the tocilizumab group (p=0·53). INTERPRETATION: In this biologic-naive population of patients with rheumatoid arthrtitis, the dichotomic classification into synovial B cell poor versus rich did not predict treatment response to B cell depletion with rituximab compared with alternative treatment strategies. However, the lack of response to rituximab in patients with a pauci-immune pathotype and the higher risk of structural damage progression in B cell-rich patients treated with rituximab warrant further investigations into the ability of synovial tissue analyses to inform disease pathogenesis and treatment response. FUNDING: UK Medical Research Council and Versus Arthritis.

Serological and Molecular Evidence of the Circulation of the Venezuelan Equine Encephalitis Virus Subtype IIIA in Humans, Wild Vertebrates and Mosquitos in the Brazilian Amazon.

Understanding the interaction between viruses and ecosystems in areas with or without anthropic interference can contribute to the organization of public health services, as well as prevention and disease control. An arbovirus survey was conducted at Caxiuanã National Forest, Pará, Brazil, where 632 local residents, 338 vertebrates and 15,774 pools of hematophagous arthropods were investigated. Neutralization antibodies of the Venezuelan Equine Encephalitis virus, subtype IIIA, Mucambo virus (MUCV) were detected in 57.3% and 61.5% of humans and wild vertebrates, respectively; in addition, genomic fragments of MUCV were detected in pool of Uranotaenia (Ura.) geometrica. The obtained data suggest an enzootic circulation of MUCV in the area. Understanding the circulation of endemic and neglected arboviruses, such as MUCV, represents an important health problem for the local residents and for the people living in the nearby urban centers.

Gas origin linked to paleo BSR.

The Central-South Chile margin is an excellent site to address the changes in the gas hydrate system since the last deglaciation associated with tectonic uplift and great earthquakes. However, the dynamic of the gas hydrate/free gas system along south central Chile is currently not well understood. From geophysical data and modeling analyses, we evaluate gas hydrate/free gas concentrations along a seismic line, derive geothermal gradients, and model past positions of the Bottom Simulating Reflector (BSR; until 13,000 years BP). The results reveal high hydrate/free gas concentrations and local geothermal gradient anomalies related to fluid migration through faults linked to seafloor mud volcanoes. The BSR-derived geothermal gradient, the base of free gas layers, BSR distribution and models of the paleo-BSR form a basis to evaluate the origin of the gas. If paleo-BSR coincides with the base of the free gas, the gas presence can be related to the gas hydrate dissociation due to climate change and geological evolution. Only if the base of free gas reflector is deeper than the paleo-BSR, a deeper gas supply can be invoked.

A cold seep triggered by a hot ridge subduction.

The Chile Triple Junction, where the hot active spreading centre of the Chile Rise system subducts beneath the South American plate, offers a unique opportunity to understand the influence of the anomalous thermal regime on an otherwise cold continental margin. Integrated analysis of various geophysical and geological datasets, such as bathymetry, heat flow measured directly by thermal probes and calculated from gas hydrate distribution limits, thermal conductivities, and piston cores, have improved the knowledge about the hydrogeological system. In addition, rock dredging has evidenced the volcanism associated with ridge subduction. Here, we argue that the localized high heat flow over the toe of the accretionary prism results from fluid advection promoted by pressure-driven discharge (i.e., dewatering/discharge caused by horizontal compression of accreted sediments) as reported previously. However, by computing the new heat flow values with legacy data in the study area, we raise the assumption that these anomalous heat flow values are also promoted by the eastern flank of the currently subducting Chile Rise. Part of the rift axis is located just below the toe of the wedge, where active deformation and vigorous fluid advection are most intense, enhanced by the proximity of the young volcanic chain. Our results provide valuable information to current and future studies related to hydrothermal circulation, seismicity, volcanism, gas hydrate stability, and fluid venting in this natural laboratory.

Efficacy of chestnut and quebracho wood extracts to control Salmonella in poultry.

AIMS: The study was aimed to evaluate the antibacterial activity and efficacy of chestnut and quebracho wood extracts against Salmonella by in vitro assays and in vivo trials. METHODS AND RESULTS: The extracts showed inhibitory activity against Salmonella determined by the minimum inhibitory concentration method as well as on the adhesion and invasion of S. Gallinarum (SG) and S. Enteritidis (SE) in Caco-2 cells. Also, transmission electron microscopy revealed that extract-treated Salmonella showed disruption of cell walls and membranes, damage of the cytoplasm and tannin-protein aggregations. In addition, efficacy of the extracts to control SG and SE was evaluated in experimental infection trials in laying hens and broilers respectively. SE excretion was significantly reduced on days 5 (P < 0·01) and 12 (P < 0·025) only in the quebracho group. In the fowl typhoid infection model, hens that received the chestnut extract showed a significantly reduced mortality (P < 0·05). CONCLUSIONS: Our results evidence that these alternative natural products may be a useful tool to control Salmonella in poultry. SIGNIFICANCE AND IMPACT OF THE STUDY: Salmonella is a zoonotic pathogen usually associated with poultry production. This study provides information about the mechanism of antibacterial effects of chestnut and quebracho wood extracts to control Salmonella in poultry.

Gas hydrate versus seabed morphology offshore Lebu (Chilean margin).

Gas-hydrate occurrences along the Chilean margin have been widely documented, but the processes associated with fluid escapes caused by the dissociation of gas hydrates are still unknown. We report a seabed morphology growth related to fluid migration offshore Lebu associated with mud cones by analysing oxygen and deuterium stable water isotopes in pore water, bathymetric, biological and sedimentological data. A relief was observed at - 127 m water depth with five peaks. Enrichment values of δ18O (0.0-1.8‰) and δD (0.0-5.6‰) evidenced past hydrate melting. The orientation of the relief could be associated with faults and fractures, which constitute pathways for fluid migration. The benthic foraminifera observed can be associated with cold seep areas. We model that the mud cones correspond to mud growing processes related to past gas-hydrate dissociation. The integration of (i) the seismic data analysis performed in the surrounding area, (ii) the orientation of our studied relief, (iii) the infaunal foraminifera observed, (iv) the grain size and (v) the total organic matter and isotope values revealed that this area was formerly characterised by the presence of gas hydrates. Hence, this part of the Chilean margin represents a suitable area for investigating fluid-migration processes.

Acute offline transcranial direct current stimulation does not change pain or anxiety produced by the cold pressor test.

Transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) has an antalgic effect on acute experimental pain in healthy volunteers. Many published studies have used online stimulation (i.e., tDCS performed during painful stimulation). On the other hand, daily tDCS sessions have been proposed as a therapy for chronic pain (offline tDCS). In such cases, the therapeutic potential depends on the possible aftereffects of each tDCS session. We set out to investigate whether a single tDCS session before application of a classical experimental pain paradigm (the Cold Pressor Test, CPT) would be capable of modulating physiological measures of anxiety as well as pain perception. tDCS was applied to 30 healthy volunteers, 18-28 years old (mean 18.5), with the anode positioned over either the left M1 or the left dorsolateral prefrontal cortex (l-DLPFC), which has been linked to the affective aspects of experienced pain, including anxiety. All volunteers underwent the CPT procedure before and after a tDCS session. Real 2 mA tDCS sessions for 20 min were compared to sham stimulations. No significant difference was found for any variable after real tDCS sessions when compared to the sham stimulations. This result suggests that effective offline tDCS for chronic pain might have different mechanisms of action. Cumulative effects, functional targeting and the unintended simultaneous stimulation of both M1 and the l-DLPFC are likely responsible for the therapeutic effects of tDCS sessions in the clinical setting.

SAFIIRA: A heavy-ion multi-purpose irradiation facility in Brazil.

This work describes the new facility for applied nuclear physics at the University of Sao Paulo, mainly for irradiation of electronic devices. It is a setup composed of a quadrupole doublet for beam focusing/defocusing plus multiple scattering through gold foils to produce low intensity, large-area, and high-uniformity heavy-ion beams from 1H to 107Ag. Beam intensities can be easily adjusted from 102 particles cm2/s to hundreds of nA for an area as large as 2.0 cm2 and uniformity better than 90%. Its irradiation chamber has a high-precision motorized stage, and the system is controlled by a LabViewTM environment, allowing measurement automation. Design considerations and examples of use are presented.

CuInSe2 quantum dots grown by molecular beam epitaxy on amorphous SiO2 surfaces.

The currently most efficient polycrystalline solar cells are based on the Cu(In,Ga)Se2 compound as a light absorption layer. However, in view of new concepts of nanostructured solar cells, CuInSe2 nanostructures are of high interest. In this work, we report CuInSe2 nanodots grown through a vacuum-compatible co-evaporation growth process on an amorphous surface. The density, mean size, and peak optical emission energy of the nanodots can be controlled by changing the growth temperature. Scanning transmission electron microscopy measurements confirmed the crystallinity of the nanodots as well as chemical composition and structure compatible with tetragonal CuInSe2. Photoluminescence measurements of CdS-passivated nanodots showed that the nanodots are optoelectronically active with a broad emission extending to energies above the CuInSe2 bulk bandgap and in agreement with the distribution of sizes. A blue-shift of the luminescence is observed as the average size of the nanodots gets smaller, evidencing quantum confinement in all samples. By using simple quantum confinement calculations, we correlate the photoluminescence peak emission energy with the average size of the nanodots.

Safety of transcranial direct current stimulation in a patient with deep brain stimulation electrodes.

BACKGROUND: Transcranial direct current stimulation (tDCS) has been investigated in movement disorders, making it a therapeutic alternative in clinical settings. However, there is still no consensus on the most appropriate treatment protocols in most cases, and the presence of deep brain stimulation (DBS) electrodes has been regarded as a contraindication to the procedure. We recently studied the effects of cerebellar tDCS on a female patient already undergoing subthalamic nucleus deep brain stimulation (STN-DBS) for generalized dystonia. She also presented with chronic pain and depression. With STN-DBS, there was improvement of dystonia, and botulinum toxin significantly reduced pain. However, depressive symptoms were worse after STN-DBS surgery. METHODS: Neuromodulation with 2 mA anodal cerebellar tDCS was initiated, targeting both hemispheres in each daily 30 minute session: 15 minutes of left cerebellar stimulation followed by 15 minutes of right cerebellar stimulation. The DBS electrodes were in place and functional, but the current was turned off during tDCS. RESULTS: Although our goal was to improve dystonic movements, after 10 tDCS sessions there was also improvement in mood with normalization of Beck Depression Inventory scores. There were no complications in spite of the implanted STN-DBS leads. CONCLUSION: Our results indicate that tDCS is safe in patients with DBS electrodes and may be an effective add-on neuromodulatory tool in the treatment of potential DBS partial efficacy in patients with movement disorders.

Safety of transcranial direct current stimulation in a patient with deep brain stimulation electrodes / Segurança da estimulação transcraniana por corrente contínua em uma paciente com implante de eletrodos de estimulação cerebral profunda

ABSTRACT Background: Transcranial direct current stimulation (tDCS) has been investigated in movement disorders, making it a therapeutic alternative in clinical settings. However, there is still no consensus on the most appropriate treatment protocols in most cases, and the presence of deep brain stimulation (DBS) electrodes has been regarded as a contraindication to the procedure. We recently studied the effects of cerebellar tDCS on a female patient already undergoing subthalamic nucleus deep brain stimulation (STN-DBS) for generalized dystonia. She also presented with chronic pain and depression. With STN-DBS, there was improvement of dystonia, and botulinum toxin significantly reduced pain. However, depressive symptoms were worse after STN-DBS surgery. Methods: Neuromodulation with 2 mA anodal cerebellar tDCS was initiated, targeting both hemispheres in each daily 30 minute session: 15 minutes of left cerebellar stimulation followed by 15 minutes of right cerebellar stimulation. The DBS electrodes were in place and functional, but the current was turned off during tDCS. Results: Although our goal was to improve dystonic movements, after 10 tDCS sessions there was also improvement in mood with normalization of Beck Depression Inventory scores. There were no complications in spite of the implanted STN-DBS leads. Conclusion: Our results indicate that tDCS is safe in patients with DBS electrodes and may be an effective add-on neuromodulatory tool in the treatment of potential DBS partial efficacy in patients with movement disorders.

RESUMO Descrição: A estimulação transcraniana por corrente contínua (ETCC) tem sido investigada nos distúrbios de movimento, tornando-a uma alternativa terapêutica no contexto clínico. Contudo, não há consenso quanto aos protocolos mais apropriados na maioria dos casos e a presença de eletrodos de estimulação cerebral profunda (ECP) é geralmente considerada uma contraindicação. Recentemente, estudamos os efeitos da ETCC cerebelar em uma paciente do sexo feminino com implante de eletrodos de estimulação cerebral profunda (ECP) para distonia generalizada. Ela também apresentava dor crônica e depressão. A ETCC foi realizada dois anos após o implante de eletrodos de ECP. Com a ECP houve melhora da distonia e a toxina botulínica reduziu a dor. Contudo, os sintomas depressivos pioraram após a cirurgia de ECP. Métodos: Foi proposta ETCC cerebelar anódica de 2mA, sobre os dois hemisférios em cada sessão de 30min: 15 min de ETCC cerebelar esquerda seguida de 15min de ETCC cerebelar direita. Resultados: Embora o nosso objetivo tenha sido melhorar os movimentos distônicos, após 10 sessões de ETCC houve melhora também do humor da paciente. Não houve nenhuma complicação, apesar da presença de eletrodos de ECP. Conclusão: Nossos resultados apontam para a segurança da tDCS e sua aplicação potencial e efetiva como ferramenta neuromodulatória adicional no tratamento de possíveis sintomas persistentes após a ECP em pacientes com distúrbios de movimento.

Effects of Prefrontal Transcranial Direct Current Stimulation and Motivation to Quit in Tobacco Smokers: A Randomized, Sham Controlled, Double-Blind Trial.

Transcranial direct current stimulation (tDCS) applied over the dorsolateral prefrontal cortex (DLPFC) has been shown to reduce cravings in tobacco addiction; however, results have been somewhat mixed. In this study, we hypothesized that motivation to quit smoking is a critical factor of tDCS effects in smokers. Therefore, we conducted a double-blind, randomized clinical trial to evaluate the effects of both tDCS and motivation to quit on cigarette consumption and the relationship between these two factors. DLPFC tDCS was applied once a day for 5 days. Our primary outcome was the amount of cigarettes smoked per day. We collected this information at baseline (d1), at the end of the treatment period (d5), 2 days later (d7) and at the 4-week follow-up (d35). Visual Analog Scale (VAS) for motivation to quit was collected at the same time-points. 36 subjects (45 ± 11 years old; 24.2 ± 11.5 cigarettes daily smoked, 21 women) were randomized to receive either active or sham tDCS. In our multivariate analysis, as to take into account the mediation and moderation effects of motivation to quit, we found a significant main effect of tDCS, showing that tDCS was associated with a significant reduction of cigarettes smoked per day. We also showed a significant interaction effect of motivation to quit and treatment, supporting our hypothesis that tDCS effects were moderated by motivation to quit, indicating that higher levels of motivation were associated with a larger tDCS response. We found that the participants' motivation to quit alone, both at baseline and at follow-up, does not explain the decrease in the average cigarette consumption. Repetitive prefrontal tDCS coupled with high motivation significantly reduced cigarette consumption up to 4-weeks post-intervention. CLINICAL TRIAL REGISTRATION: http://ClinicalTrials.gov, NCT02146014.

Substrate and Mg doping effects in GaAs nanowires.

Mg doping of GaAs nanowires has been established as a viable alternative to Be doping in order to achieve p-type electrical conductivity. Although reports on the optical properties are available, few reports exist about the physical properties of intermediate-to-high Mg doping in GaAs nanowires grown by molecular beam epitaxy (MBE) on GaAs(111)B and Si(111) substrates. In this work, we address this topic and present further understanding on the fundamental aspects. As the Mg doping was increased, structural and optical investigations revealed: i) a lower influence of the polytypic nature of the GaAs nanowires on their electronic structure; ii) a considerable reduction of the density of vertical nanowires, which is almost null for growth on Si(111); iii) the occurrence of a higher WZ phase fraction, in particular for growth on Si(111); iv) an increase of the activation energy to release the less bound carrier in the radiative state from nanowires grown on GaAs(111)B; and v) a higher influence of defects on the activation of nonradiative de-excitation channels in the case of nanowires only grown on Si(111). Back-gate field effect transistors were fabricated with individual nanowires and the p-type electrical conductivity was measured with free hole concentration ranging from 2.7 × 1016 cm-3 to 1.4 × 1017 cm-3. The estimated electrical mobility was in the range ≈0.3-39 cm2/Vs and the dominant scattering mechanism is ascribed to the WZ/ZB interfaces. Electrical and optical measurements showed a lower influence of the polytypic structure of the nanowires on their electronic structure. The involvement of Mg in one of the radiative transitions observed for growth on the Si(111) substrate is suggested.

Motor Cortex Stimulation for Pain Relief: Do Corollary Discharges Play a Role?

Both invasive and non-invasive motor cortex stimulation techniques have been successfully employed in the treatment of chronic pain, but the precise mechanism of action of such treatments is not fully understood. It has been hypothesized that a mismatch of normal interaction between motor intention and sensory feedback may result in central pain. Sensory feedback may come from peripheral nerves, vision and also from corollary discharges originating from the motor cortex itself. Therefore, a possible mechanism of action of motor cortex stimulation might be corollary discharge reinforcement, which could counterbalance sensory feedback deficiency. In other instances, primary deficiency in the production of corollary discharges by the motor cortex might be the culprit and stimulation of cortical motor areas might then be beneficial by enhancing production of such discharges. Here we review evidence for a possible role of motor cortex corollary discharges upon both the pathophysiology and the response to motor cortex stimulation of different types of chronic pain. We further suggest that the right dorsolateral prefrontal cortex (DLPC), thought to constantly monitor incongruity between corollary discharges, vision and proprioception, might be an interesting target for non-invasive neuromodulation in cases of chronic neuropathic pain.

Following the trail: factors underlying the sudden expansion of the Egyptian mongoose (Herpestes ichneumon) in Portugal.

Species range-limits are influenced by a combination of several factors. In our study we aimed to unveil the drivers underlying the expansion of the Egyptian mongoose in Portugal, a carnivore that was confined to southern Portugal and largely increased its range during the last three decades. We evaluated the expansion of the species in three periods (1980-1990, 1990-2000 and 2000-2010), by projecting the presence/absence data of the species in each temporal range and proposed four hypotheses to explain this sudden expansion associated to changes in the barrier effects of human infrastructure and topographic features, and in the availability of suitable areas due to climate change or land use. An exploratory analysis was made using Spearman rank correlation, followed by a hierarchical partitioning analysis to select uncorrelated potential explanatory variables associated with the different hypotheses. We then ran Generalized Linear Models (GLM) for every period for each hypothesis and for every combination of hypotheses. Our main findings suggest that dynamic transitions of land-use coupled with temperature and rainfall variations over the decades are the main drivers promoting the mongoose expansion. The geographic barriers and the human infrastructures functioned as barriers for mongoose expansion and have shaped its distribution. The expansion of the Egyptian mongoose across the Portuguese territory was due to a variety of factors. Our results suggest a rapid shift in species range in response to land-use and climate changes, underlining the close link between species ranges and a changing environment.

Uterine artery Doppler in the management of early pregnancy loss: a prospective, longitudinal study.

BACKGROUND: The pharmacological management of early pregnancy loss reduced substantially the need for dilation and curettage. However, prognostic markers of successful outcome were not established. Thus the major purpose of this study was to determine the sensitivity and specificity of the uterine artery pulsatility (PI) and resistance (RI) indices to detect early pregnancy loss patients requiring dilation and curettage after unsuccessful management. METHODS: A cohort prospective observational study was undertaken to include women with early pregnancy loss, ≤ 12 weeks of gestation, managed with mifepristone (200 mg) and misoprostol (1600 µg) followed by PI and RI evaluation of both uterine arteries 2 weeks after. At this time, in 173/315 patients, incomplete miscarriage was diagnosed. Among them, 32 underwent uterine dilatation and curettage at 8 weeks of follow-up. RESULTS: The cut-off points for the uterine artery PI and RI, leading to the maximum values of sensitivity (69.5%, CI95%: 61.5%-76.5% and 75.0%, CI95%: 57.9%-86.8%, respectively) and specificity (75.0%, CI95%: 57.9%-86.8% and 65.6%, CI95%: 48.3%-79.6%, respectively), for the discrimination between the women who needed curettage from those who resolved spontaneously were 2.8 and 1, respectively. CONCLUSIONS: The potential usefulness of uterine artery Doppler evaluation to predict the need for uterine curettage in patients submitted to medical treatment for early pregnancy loss was demonstrated.