Single closed-loop acoustic stimulation targeting memory consolidation suppressed hippocampal ripple and thalamo-cortical spindle activity in mice.

Brain rhythms of sleep reflect neuronal activity underlying sleep-associated memory consolidation. The modulation of brain rhythms, such as the sleep slow oscillation (SO), is used both to investigate neurophysiological mechanisms as well as to measure the impact of sleep on presumed functional correlates. Previously, closed-loop acoustic stimulation in humans targeted to the SO Up-state successfully enhanced the slow oscillation rhythm and phase-dependent spindle activity, although effects on memory retention have varied. Here, we aim to disclose relations between stimulation-induced hippocampo-thalamo-cortical activity and retention performance on a hippocampus-dependent object-place recognition task in mice by applying acoustic stimulation at four estimated SO phases compared to sham condition. Across the 3-h retention interval at the beginning of the light phase closed-loop stimulation failed to improve retention significantly over sham. However, retention during SO Up-state stimulation was significantly higher than for another SO phase. At all SO phases, acoustic stimulation was accompanied by a sharp increase in ripple activity followed by about a second-long suppression of hippocampal sharp wave ripple and longer maintained suppression of thalamo-cortical spindle activity. Importantly, dynamics of SO-coupled hippocampal ripple activity distinguished SOUp-state stimulation. Non-rapid eye movement (NREM) sleep was not impacted by stimulation, yet preREM sleep duration was effected. Results reveal the complex effect of stimulation on the brain dynamics and support the use of closed-loop acoustic stimulation in mice to investigate the inter-regional mechanisms underlying memory consolidation.

EBV+ tumors exploit tumor cell-intrinsic and -extrinsic mechanisms to produce regulatory T cell-recruiting chemokines CCL17 and CCL22.

The Epstein-Barr Virus (EBV) is involved in the etiology of multiple hematologic and epithelial human cancers. EBV+ tumors employ multiple immune escape mechanisms, including the recruitment of immunosuppressive regulatory T cells (Treg). Here, we show some EBV+ tumor cells express high levels of the chemokines CCL17 and CCL22 both in vitro and in vivo and that this expression mirrors the expression levels of expression of the EBV LMP1 gene in vitro. Patient samples from lymphoblastic (Hodgkin lymphoma) and epithelial (nasopharyngeal carcinoma; NPC) EBV+ tumors revealed CCL17 and CCL22 expression of both tumor cell-intrinsic and -extrinsic origin, depending on tumor type. NPCs grown as mouse xenografts likewise showed both mechanisms of chemokine production. Single cell RNA-sequencing revealed in vivo tumor cell-intrinsic CCL17 and CCL22 expression combined with expression from infiltrating classical resident and migratory dendritic cells in a CT26 colon cancer mouse tumor engineered to express LMP1. These data suggest that EBV-driven tumors employ dual mechanisms for CCL17 and CCL22 production. Importantly, both in vitro and in vivo Treg migration was effectively blocked by a novel, small molecule antagonist of CCR4, CCR4-351. Antagonism of the CCR4 receptor may thus be an effective means of activating the immune response against a wide spectrum of EBV+ tumors.

Chromogenic Assay Is More Efficient in Identifying α-Amylase Inhibitory Properties of Anthocyanin-Rich Samples When Compared to the 3,5-Dinitrosalicylic Acid (DNS) Assay.

The inhibition of carbohydrate digestion by plant bioactive compounds is a potential dietary strategy to counteract type 2 diabetes. Indeed, inhibition of α-amylase, a key enzyme that carries out the bulk of starch digestion, has been demonstrated for a range of bioactive compounds including anthocyanins; however, sample pigmentation often interferes with measurements, affecting colorimetric assay outcomes. Therefore, the present study compared the performance of a direct chromogenic assay, using 2-chloro-4 nitrophenyl α-D-maltotrioside (CNPG3) as a substrate, with the commonly used 3,5-dinitrosalicylic acid (DNS) assay. The direct chromogenic assay demonstrated a 5-10-fold higher sensitivity to determine α-amylase inhibition in various samples, including acarbose as a reference, pure anthocyanins, and anthocyanin-rich samples. The IC50 values of acarbose presented as 37.6 µg/mL and 3.72 µg/mL for the DNS assay and the direct chromogenic assay, respectively, whereas purified anthocyanins from blackcurrant showed IC50 values of 227.4 µg/mL and 35.0 µg/mL. The direct chromogenic assay is easy to perform, fast, reproducible, and suitable for high-throughput screening of pigmented α-amylase inhibitors.

Closed-loop acoustic stimulation during an afternoon nap to modulate subsequent encoding.

Sleep is able to contribute not only to memory consolidation, but also to post-sleep learning. The notion exists that either synaptic downscaling or another process during sleep increase post-sleep learning capacity. A correlation between augmentation of the sleep slow oscillation and hippocampal activation at encoding support the contribution of sleep to encoding of declarative memories. In the present study, the effect of closed-loop acoustic stimulation during an afternoon nap on post-sleep encoding of two verbal (word pairs, verbal learning and memory test) and non-verbal (figural pairs) tasks and on electroencephalogram during sleep and learning were investigated in young healthy adults (N = 16). Closed-loop acoustic stimulation enhanced slow oscillatory and spindle activity, but did not affect encoding at the group level. Subgroup analyses and comparisons with similar studies lead us to the tentative conclusion that further parameters such as time of day and subjects' cognitive ability influenced responses to closed-loop acoustic stimulation.

Stimulation Augments Spike Sequence Replay and Memory Consolidation during Slow-Wave Sleep.

Newly acquired memory traces are spontaneously reactivated during slow-wave sleep (SWS), leading to the consolidation of recent memories. Empirical studies found that sensory stimulation during SWS can selectively enhance memory consolidation with the effect depending on the phase of stimulation. In this new study, we aimed to understand the mechanisms behind the role of sensory stimulation on memory consolidation using computational models implementing effects of neuromodulators to simulate transitions between awake and SWS sleep, and synaptic plasticity to allow the change of synaptic connections due to the training in awake or replay during sleep. We found that when closed-loop stimulation was applied during the Down states of sleep slow oscillation, particularly right before the transition from Down to Up state, it significantly affected the spatiotemporal pattern of the slow waves and maximized memory replay. In contrast, when the stimulation was presented during the Up states, it did not have a significant impact on the slow waves or memory performance after sleep. For multiple memories trained in awake, presenting stimulation cues associated with specific memory trace could selectively augment replay and enhance consolidation of that memory and interfere with consolidation of the others (particularly weak) memories. Our study proposes a synaptic-level mechanism of how memory consolidation is affected by sensory stimulation during sleep.SIGNIFICANCE STATEMENT Stimulation, such as training-associated cues or auditory stimulation, during sleep can augment consolidation of the newly encoded memories. In this study, we used a computational model of the thalamocortical system to describe the mechanisms behind the role of stimulation in memory consolidation during slow-wave sleep. Our study suggests that stimulation preferentially strengthens memory traces when delivered at a specific phase of the slow oscillation, just before the Down to Up state transition when it makes the largest impact on the spatiotemporal pattern of sleep slow waves. In the presence of multiple memories, presenting sensory cues during sleep could selectively strengthen selected memories. Our study proposes a synaptic-level mechanism of how memory consolidation is affected by sensory stimulation during sleep.

Brain Rhythms During Sleep and Memory Consolidation: Neurobiological Insights.

Sleep can benefit memory consolidation. The characterization of brain regions underlying memory consolidation during sleep, as well as their temporal interplay, reflected by specific patterns of brain electric activity, is surfacing. Here, we provide an overview of recent concepts and results on the mechanisms of sleep-related memory consolidation. The latest studies strongly impacting future directions of research in this field are highlighted.

Changes in sleep EEG with aging in humans and rodents.

Sleep is one of the most ubiquitous but also complex animal behaviors. It is regulated at the global, systems level scale by circadian and homeostatic processes. Across the 24-h day, distribution of sleep/wake activity differs between species, with global sleep states characterized by defined patterns of brain electric activity and electromyography. Sleep patterns have been most intensely investigated in mammalian species. The present review begins with a brief overview on current understandings on the regulation of sleep, and its interaction with aging. An overview on age-related variations in the sleep states and associated electrophysiology and oscillatory events in humans as well as in the most common laboratory rodents follows. We present findings observed in different studies and meta-analyses, indicating links to putative physiological changes in the aged brain. Concepts requiring a more integrative view on the role of circadian and homeostatic sleep regulatory mechanisms to explain aging in sleep are emerging.

Monosynaptic Hippocampal-Prefrontal Projections Contribute to Spatial Memory Consolidation in Mice.

Time locking between neocortical sleep slow oscillations, thalamo-cortical spindles, and hippocampal sharp-wave ripples has convincingly been shown to be a key element of systems consolidation. Here we investigate the role of monosynaptic projections from ventral/intermediate hippocampus to medial prefrontal cortex (mPFC) in sleep-dependent memory consolidation in male mice. Following acquisition learning in the Barnes maze, we optogenetically silenced the axonal terminals of hippocampal projections within mPFC during slow-wave sleep. This silencing during SWS selectively impaired recent but not remote memory in the absence of effects on error rate and escape latencies. Furthermore, it prevented the development of the most efficient search strategy and sleep spindle time-locking to slow oscillation. An increase in post-learning sleep sharp-wave ripple (SPWR) density and reduced time locking of learning-associated SPWR activity to sleep spindles may be a less specific response. Our results demonstrate that monosynaptic projections from hippocampus to mPFC contribute to sleep-dependent memory consolidation, potentially by affecting the temporal coupling of sleep-associated electrophysiological events.SIGNIFICANCE STATEMENT Convincing evidence supports the role of slow-wave sleep (SWS), and the relevance of close temporal coupling of neuronal activity between brain regions for systems consolidation. Less attention has been paid so far to the specific neuronal pathways underlying these processes. Here, we optogenetically silenced the direct monosynaptic projection from ventral/intermediate hippocampus (HC) to medial prefrontal cortex (mPFC) during SWS in male mice following repeated learning trials in a weakly aversive spatial task. Our results confirm the concept that the monosynaptic projection between HC and mPFC contributes to memory consolidation and support an important functional role of this pathway in shaping the temporal precision among sleep-associated electrophysiological events.

Impact of flare on radiographic progression after etanercept continuation, tapering or withdrawal in patients with rheumatoid arthritis.

OBJECTIVES: The structural consequences of flare after dose reduction/discontinuation of biologic DMARDs in patients with RA who achieve remission are unclear. We compared the incidence of radiographic progression in patients with RA who did and did not experience flare after etanercept (ETN) reduction/withdrawal. METHODS: Eligible adults with moderately active RA despite MTX received ETN 50 mg plus MTX weekly in a 36-week, open-label induction period; patients achieving sustained low disease activity by week 36 were randomized to ETN 50 mg plus MTX, ETN 25 mg plus MTX, or placebo plus MTX in a 52-week, double-blind maintenance period. In post hoc analyses, radiographic progression (Δ modified total Sharp score ⩾0.5 units/year) was compared in patients with and without flare [based on DAS28 relapse (main analysis), and clinical disease activity index and simplified disease activity index relapse (sensitivity analyses)]. Findings from patients receiving full- and reduced-dose combination therapy were pooled for comparison with those from patients receiving MTX only. RESULTS: Significantly more patients receiving MTX monotherapy experienced flare, defined as DAS28 relapse (62% vs 21%; P < 0.0001) and radiographic progression (17% vs 9%; P < 0.001), than patients receiving full-/reduced-dose combination therapy in the double-blind period. Patients with flare defined as clinical disease activity index and simplified disease activity index relapse had higher rates of radiographic progression than those without flare in the full-/reduced-dose combination therapy group (P < 0.01). CONCLUSION: Radiographic progression may be a consequence of flare after biologic DMARD dose reduction/withdrawal in patients with RA. If these approaches are taken, careful monitoring for signs/symptoms of relapse is needed. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT00565409.

Relationship between disease activity status or clinical response and patient-reported outcomes in patients with non-radiographic axial spondyloarthritis: 104-week results from the randomized controlled EMBARK study.

BACKGROUND: We assessed the external validity of composite indices Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and Assessment in SpondyloArthritis international Society (ASAS) 40 response (ASAS40) by evaluating the correlations between the changes in some patient reported outcomes (PROs) for patients with non-radiographic axial spondyloarthritis (nr-axSpA) and the changes in the scores of the composite indices. METHODS: This was a post-hoc analysis of data from the EMBARK study in patients with nr-axSpA treated with etanercept. PROs were grouped according to ASDAS status (inactive [< 1.3], low [≥ 1.3 to < 2.1], high [≥ 2.1 to ≤3.5], and very high [> 3.5]), patient achievement of > 50% improvement in BASDAI (BASDAI50 responders), and > 40% improvement in ASAS (ASAS40 responders) at 104 weeks. Analyses were conducted on observed cases available at Week 104. Changes in PROs from Baseline to Week 104 were assessed using analysis of covariance with adjustment for baseline with linear contrast. RESULTS: Higher ASDAS disease activity at 104 weeks was associated with lower long-term improvement from baseline in PROs (e.g., total back pain [visual analog scale, cm (95% confidence interval): - 4.58 (- 4.95, - 4.21), - 3.86 (- 4.28, - 3.43), - 2.15 (- 2.68, - 1.61), and 1.30 (- 0.51, 3.12) for inactive, low, high, and very high ASDAS disease activity, respectively; Multidimensional Fatigue Inventory (MFI) general fatigue: - 4.77 (- 5.70, - 3.84), - 2.96 (- 4.04, - 1.87), - 1.00 (- 2.32, 0.31), and 2.14 (- 2.10, 6.38); all p < 0.001)]. BASDAI50 non-responders had less improvement in PROs from Baseline to Week 104 vs. responders (e.g., total back pain: - 1.61 (- 2.05, - 1.18) vs. -4.43 (- 4.69, - 4.18); MFI general fatigue: - 0.01 (- 1.12, 1.09) vs. -4.30 (- 4.98, - 3.62); all p < 0.001). ASAS40 non-responders also had less improvement in PROs from Baseline to Week 104 vs. responders (e.g., total back pain: - 1.91 (- 2.30, - 1.52) vs. -4.75 (- 5.05, - 4.46); MFI general fatigue: - 0.63 (- 1.56, 0.30) vs. -4.64 (- 5.37, - 3.91); all p < 0.001). CONCLUSION: Composite indices are valid for monitoring treatment response and adequately reflect treatment-related changes experienced by patients with nr-axSpA. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01258738. Registered 9 December 2010.

Co-creation of the Safewards Model in a Forensic Mental Health Care Facility.

Violence and aggression are highly complex problems in mental health care facilities; thus, multi-faceted conflict-reduction strategies are required to mitigate and reduce violence. Safewards is an evidence-informed model aimed at preventing events that have the capacity to trigger aggression and violence. Effectiveness studies of the implementation of Safewards have shown mixed results, including that implementation strategies failed to engage staff and fidelity was low. The objective of this study was to examine the effectiveness of implementing the Safewards model with an approach that embedded co-creation principles in the staff training. Overall, results showed high staff engagement. The average rate of attendance at the classroom-based, staff champion training (n = 108) was 79% (SD = 23). Additionally, online training modules were available to all staff and were completed by 238 of 259 forensic program staff (92%). Overall, staff perceived co-creation to be a positive strategy; staff liked being asked to be involved in the planning, felt that their voices were heard, and believed that it contributed to the success of the Safewards implementation. This study showed that the inclusion of co-creation principles in the implementation strategy enhanced staff adherence to the Safewards model as demonstrated by the high fidelity scores, and effectively led to increased buy-in and engagement of staff.

Efficacy of slow oscillatory-transcranial direct current stimulation on EEG and memory - contribution of an inter-individual factor.

Despite many reports on beneficial effects of anodal slow oscillatory-transcranial direct current stimulation (so-tDCS) during non-rapid eye movement (NREM) sleep on memory consolidation, frequent negative outcomes have also been observed. Our working hypothesis is that so-tDCS efficacy is strongly dependent upon the susceptibility of the underlying network. One component determining susceptibility of the network is hypothesized to be reflected in learning or 'task-induced' plastic changes. Another component is hypothesized to represent inter-individual confounds. Twenty-five (15 female) healthy students participated in two learning conditions with and without so-tDCS during early nocturnal NREM sleep and in one control condition without learning tasks. So-tDCS was applied in five 5-min blocks. EEG was assessed during two time windows: an acute period with five 1-min epochs after each stimulation block and a 150-min post-stimulation time period. Inter-individual differences were assessed by a memory quotient (MQ) and subjects classified into high- vs. low-scoring groups. Although so-tDCS was efficient in enhancing fast spindle parameters in the 150-min time period in all subjects, so-tDCS failed to modulate memory consolidation. In contrast, in subjects with a high MQ, memory retention on a figural paired-associate task was significantly increased after so-tDCS. Task-induced slow spindle density was modulated in the opposite direction in subjects with high vs. low MQ being increased in the high-MQ group only. Effects of so-tDCS on EEG were limited to fast spindle modulations in both time windows. These results reveal that inter-individual confound can impact so-tDCS efficacy, suggesting potential use of such factors as biomarkers.

Modification of structural lesions on MRI of the sacroiliac joints by etanercept in the EMBARK trial: a 12-week randomised placebo-controlled trial in patients with non-radiographic axial spondyloarthritis.

OBJECTIVE: To evaluate the impact on structural lesions observed on MRI in the sacroiliac joints (SIJ) at 12 weeks in patients with non-radiographic axial spondyloarthritis (nr-axSpA) receiving etanercept or placebo in EMBARK (Effect of Etanercept on Symptoms and Objective Inflammation in nr-axSpA, a 104 week study). METHODS: Patients were randomised to double-blind etanercept 50 mg/week or placebo for 12 weeks. Structural lesions at baseline and 12 weeks were scored by two independent readers using the Spondyloarthritis Research Consortium of Canada (SPARCC) SIJ structural score (SSS) on T1-weighted MRI. Change in SPARCC SSS and correlation with improvement in clinical outcomes was evaluated. RESULTS: MRI scans from 185 patients (etanercept, n=88; placebo, n=97) were reviewed. At baseline, there were no significant differences in mean SPARCC SSS between etanercept and placebo. From baseline to 12 weeks, change in mean SPARCC SSS was significantly greater for etanercept than placebo for erosion (-0.57 vs -0.08, respectively, adjusted p value=0.017) and backfill (0.36 vs 0.06, adjusted p value=0.022). A treatment difference was also present for the subgroup of patients with SIJ inflammation on MRI (SPARCC bone marrow oedema ≥2): erosion: -0.81 versus -0.13 for etanercept versus placebo, respectively, p=0.007; backfill: 0.48 versus 0.08, respectively, p=0.032. Decrease in erosion and increase in backfill correlated with improvement in more clinical outcomes for etanercept than placebo. CONCLUSION: Treatment with etanercept was associated with significantly greater reduction in erosions and increase in backfill at 12 weeks compared with placebo, consistent with a very early reparative response to antitumour necrosis factor therapy. The impact on disease progression in spondyloarthritis should be studied further. TRIAL REGISTRATION NUMBER: NCT01258738; Post-results.

Modulation of the orthostatic blood pressure response by acute nitrate consumption is dependent upon ethnic origin.

Orthostatic stress triggers a response to maintain cerebral perfusion and prevent syncope. Given the hypotensive effects of inorganic nitrate this response to orthostasis may be altered by acute supplementation with inorganic nitrate and modified by ethnic origin. Caucasian and SE Asian (n = 30 for both), were recruited and subjected to an 'active stand test' and brachial artery blood pressure (BP), digit blood flow and ECG were recorded. Following inorganic nitrate supplementation, (10 mg/kg body mass) the tests were repeated. For both Caucasian and SE Asians transition to standing increased diastolic pressure (DP) and heart rate (HR) (P < 0.001 for both) and by calculation increased rate-pressure product (P < 0.001) and decreased pulse pressure (P < 0.01 for both) indicative of decreased ventricular filling. Nitrate supplementation decreased both DP (P < 0.001) and HR (P < 0.001). Assessment of HR variability suggested sympathetic nerve activity, was higher throughout in Caucasians (P < 0.05) coupled with higher parasympathetic tone (P < 0.01). Nitrate had no effect on cardiac autonomic nerve activity, as estimated using HR variability, for supine or standing subjects. The tachycardia and hypertension associated with orthostatic stress were preserved in both Caucasian and SE Asian subjects, however, we highlight possible differences in autonomic nervous system activity between Caucasians and SE Asians. SE Asians are resistant to the hypotensive effects of inorganic nitrate supplementation suggesting the absence of a crucial mechanism for activation of the nitrate-nitrite-nitric oxide system.

Incidence of Antidrug Antibodies in Rheumatoid Arthritis Patients From Argentina Treated With Adalimumab, Etanercept, or Infliximab in a Real-World Setting.

BACKGROUND: Biologic agents may induce immune responses that could impact drug action. OBJECTIVES: The aims of this study were to assess antidrug antibodies (ADAs) in patients with rheumatoid arthritis (RA) from Argentina treated with etanercept, adalimumab, or infliximab at a single visit and correlate it with efficacy outcomes. METHODS: In this subset analysis of a noninterventional, multinational, cross-sectional study (NCT01981473), adult patients with RA treated continuously for 6 to 24 months with etanercept, adalimumab, or infliximab were evaluated for ADAs and trough drug concentrations of 2 days or less prior to the next scheduled dose. Efficacy measurements included Disease Activity Score based on a 28-joint count-erythrocyte sedimentation rate, low disease activity, and Health Assessment Questionnaire-Disability Index. Targeted medical history of injection site/infusion reactions, serum sickness, and thromboembolic events were reported. RESULTS: Baseline demographics, disease characteristics, and duration of treatment of the 119 patients (etanercept: n = 54, adalimumab: n = 52, infliximab: n = 13) were similar across all groups. No etanercept-treated patient tested positive for ADAs compared with 19 (36.5%) of 52 patients and 4 (30.8%) of 13 patients treated with adalimumab and infliximab, respectively. In adalimumab- and infliximab-treated patients, ADA presence correlated negatively with trough drug levels. A greater proportion of ADA-negative patients achieved Health Assessment Questionnaire-Disability Index of 0.5 or less and had better composite efficacy measures compared with ADA-positive patients. The rate of targeted medical events reported was low. CONCLUSIONS: In this subset analysis, RA patients from Argentina treated with adalimumab or infliximab, but not etanercept, tested positive for ADAs. Antidrug antibody-negative patients showed a tendency toward better clinical outcomes compared with ADA-positive patients.

A Thalamocortical Neural Mass Model of the EEG during NREM Sleep and Its Response to Auditory Stimulation.

Few models exist that accurately reproduce the complex rhythms of the thalamocortical system that are apparent in measured scalp EEG and at the same time, are suitable for large-scale simulations of brain activity. Here, we present a neural mass model of the thalamocortical system during natural non-REM sleep, which is able to generate fast sleep spindles (12-15 Hz), slow oscillations (<1 Hz) and K-complexes, as well as their distinct temporal relations, and response to auditory stimuli. We show that with the inclusion of detailed calcium currents, the thalamic neural mass model is able to generate different firing modes, and validate the model with EEG-data from a recent sleep study in humans, where closed-loop auditory stimulation was applied. The model output relates directly to the EEG, which makes it a useful basis to develop new stimulation protocols.

Switching Between Reference Biologics and Biosimilars for the Treatment of Rheumatology, Gastroenterology, and Dermatology Inflammatory Conditions: Considerations for the Clinician.

PURPOSE OF REVIEW: Biosimilars of the reference biologic therapeutics infliximab, etanercept, adalimumab, and rituximab are entering the market. Clinical and real-world data on the effects of reference â†’ biosimilar switching are limited. This review was carried out to assess the current body of switching data. RECENT FINDINGS: Fifty-three switching studies were identified. Infliximab publications covered CT-P13 (25 studies), SB2 (1), infliximab NK (1), and unspecified infliximab biosimilars (2). Etanercept publications covered SB4 (2) and GP2015 (2). Adalimumab publications covered ABP 501 (2) and SB5 (1). Rituximab publications covered CT-P10 (1). Efficacy and safety data generally showed no differences between patients who switched treatments versus those who did not. No differences were seen pre- and post-switch. Immunogenicity data were presented in 19/37 (51%) studies. Additional data from switching studies of these therapies are still required, as is continuing pharma-covigilance. Switching should remain a case-by-case clinical decision made by the physician and patient on an individual basis supported by scientific evidence.

Down-titration of biologics for the treatment of rheumatoid arthritis: a systematic literature review.

Biologic therapies have improved the management of rheumatoid arthritis (RA) and the treat-to-target approach has resulted in many patients achieving remission. In the current treatment landscape, clinicians have begun considering dose reduction/tapering for their patients. Rheumatology guidelines in Asia, Europe, and the United States include down-titration of biologics but admit that the level of evidence is moderate. We conducted a systematic literature review to assess the published studies that evaluate down-titration of biologics in RA. The published literature was searched for studies that down-titrated the following biologics: abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab. Eligible studies included randomized controlled trials (RCTs), non-RCTs, observational, and pharmacoeconomic studies. The outcomes of interest were (1) efficacy and health-related quality of life, (2) disease flares, and (3) impact on cost. Eleven full-text publications were identified; only three were RCTs. Study results suggest that dosing down may be an option in many patients who have achieved remission or low disease activity. However, some patients are likely to experience a disease flare. Across the studies, the definition of disease flare and the down-titration criteria were inconsistent, making it difficult to conclude which patients may be appropriate and when to attempt down-titration. Studies have evaluated the practice of dosing down biologic therapy in patients with RA; however, a relatively small number of RCTs have been published. Although down-titration may be an option for some patients in LDA or remission, additional RCTs are needed to provide guidance on this practice.

Timing matters: open-loop stimulation does not improve overnight consolidation of word pairs in humans.

The application of auditory clicks during non-rapid eye movement (NREM) sleep phase-locked to the up state of the slow oscillation (closed-loop stimulation) has previously been shown to enhance the consolidation of declarative memories. We designed and applied sequences of three clicks during deep NREM sleep to achieve a quasi-phase-dependent open-loop stimulation. This stimulation was successful in eliciting slow oscillation power in the stimulation period. Although fast and slow spindle power were markedly decreased during the stimulation period, memory consolidation did not differ from control. During putative up states fast spindle power remained, however, at control levels. We conclude that concurrence of slow oscillations and fast spindles suffices to maintain memory consolidation at control levels despite an overall decreased spindle activity.

Clinical and MRI responses to etanercept in early non-radiographic axial spondyloarthritis: 48-week results from the EMBARK study.

OBJECTIVE: To evaluate the efficacy and safety of etanercept (ETN) after 48 weeks in patients with early active non-radiographic axial spondyloarthritis (nr-axSpA). METHODS: Patients meeting Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axSpA, but not modified New York radiographic criteria, received double-blind ETN 50 mg/week or placebo (PBO) for 12 weeks, then open-label ETN (ETN/ETN or PBO/ETN). Clinical, health, productivity, MRI and safety outcomes were assessed and the 48-week data are presented here. RESULTS: 208/225 patients (92%) entered the open-label phase at week 12 (ETN, n=102; PBO, n=106). The percentage of patients achieving ASAS40 increased from 33% to 52% between weeks 12 and 48 for ETN/ETN and from 15% to 53% for PBO/ETN (within-group p value <0.001 for both). For ETN/ETN and PBO/ETN, the EuroQol 5 Dimensions utility score improved by 0.14 and 0.08, respectively, between baseline and week 12 and by 0.23 and 0.22 between baseline and week 48. Between weeks 12 and 48, MRI Spondyloarthritis Research Consortium of Canada sacroiliac joint (SIJ) scores decreased by -1.1 for ETN/ETN and by -3.0 for PBO/ETN, p<0.001 for both. Decreases in MRI SIJ inflammation and C-reactive protein correlated with several clinical outcomes at weeks 12 and 48. CONCLUSIONS: Patients with early active nr-axSpA demonstrated improvement from week 12 in clinical, health, productivity and MRI outcomes that was sustained to 48 weeks. TRIAL REGISTRATION NUMBER: NCT01258738.