The modern understanding of sleep is based on the classification of sleep into stages defined by their electroencephalography (EEG) signatures, but the underlying brain dynamics remain unclear. Here ...we aimed to move significantly beyond the current state-of-the-art description of sleep, and in particular to characterise the spatiotemporal complexity of whole-brain networks and state transitions during sleep. In order to obtain the most unbiased estimate of how whole-brain network states evolve through the human sleep cycle, we used a Markovian data-driven analysis of continuous neuroimaging data from 57 healthy participants falling asleep during simultaneous functional magnetic resonance imaging (fMRI) and EEG. This Hidden Markov Model (HMM) facilitated discovery of the dynamic choreography between different whole-brain networks across the wake-non-REM sleep cycle. Notably, our results reveal key trajectories to switch within and between EEG-based sleep stages, while highlighting the heterogeneities of stage N1 sleep and wakefulness before and after sleep.
8000 years ago, prior to Neolithic agriculture, Europe was mostly a wooded continent. Since then, its forest cover has been progressively fragmented, so that today it covers less than half of ...Europe's land area, in many cases having been cleared to make way for fields and pasture-land. Establishing the origin of Europe's current, more open land-cover mosaic requires a long-term perspective, for which pollen analysis offers a key tool. In this study we utilise and compare three numerical approaches to transforming pollen data into past forest cover, drawing on >1000
C-dated site records. All reconstructions highlight the different histories of the mixed temperate and the northern boreal forests, with the former declining progressively since ~6000 years ago, linked to forest clearance for agriculture in later prehistory (especially in northwest Europe) and early historic times (e.g. in north central Europe). In contrast, extensive human impact on the needle-leaf forests of northern Europe only becomes detectable in the last two millennia and has left a larger area of forest in place. Forest loss has been a dominant feature of Europe's landscape ecology in the second half of the current interglacial, with consequences for carbon cycling, ecosystem functioning and biodiversity.
Key points
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It is often assumed that automatic movements such as walking require little conscious attention and it has therefore been argued that these movements require little cortical control.
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In humans, however, the gait function is often heavily impaired or completely lost following cortical lesions such as stroke.
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In this study we investigated synchrony between cortical signals recorded with electroencephalography (EEG) and electromyographic signals (EMG activity) recorded from the tibialis anterior muscle (TA) during walking.
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We found evidence of synchrony in the frequency domain (coherence) between the primary motor cortex and the TA muscle indicating a cortical involvement in human gait function.
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This finding underpins the importance of restoration of the activity and connectivity between the motor cortex and the spinal cord in the recovery of gait function in patients with damage of the central nervous system.
Indirect evidence that the motor cortex and the corticospinal tract contribute to the control of walking in human subjects has been provided in previous studies. In the present study we used coherence analysis of the coupling between EEG and EMG from active leg muscles during human walking to address if activity arising in the motor cortex contributes to the muscle activity during gait. Nine healthy human subjects walked on a treadmill at a speed of 3.5–4 km h−1. Seven of the subjects in addition walked at a speed of 1 km h−1. Significant coupling between EEG recordings over the leg motor area and EMG from the anterior tibial muscle was found in the frequency band 24–40 Hz prior to heel strike during the swing phase of walking. This signifies that rhythmic cortical activity in the 24–40 Hz frequency band is transmitted via the corticospinal tract to the active muscles during walking. These findings demonstrate that the motor cortex and corticospinal tract contribute directly to the muscle activity observed in steady‐state treadmill walking.
NeoRes I is a randomized phase II trial comparing neoadjuvant chemoradiotherapy with neoadjuvant chemotherapy in the treatment of resectable cancer of the esophagus or gastroesophageal junction. ...Patients with biopsy-proven adenocarcinoma or squamous cell carcinoma, T1N1 or T2-3N0-1 and M0-M1a (AJCC 6th ed.), were randomized to receive three 3-weekly cycles of cisplatin 100 mg/m2 day 1 and fluorouracil 750 mg/m2/24 hours, days 1-5 with or without the addition of concurrent radiotherapy 40 Gy, 2 Gy/fraction, 5 days a week, followed by esophageal resection with two-field lymphadenectomy. Primary endpoint was complete histopathological response rate in the primary tumor. Survival and recurrence patterns were evaluated as secondary endpoints. Between 2006 and 2013, 181 patients were enrolled in Sweden and Norway. All three chemotherapy cycles were delivered to 73% of the patients allocated to chemoradiotherapy and to 86% of the patients allocated to chemotherapy. 87% of those allocated to chemoradiotherapy received full dose radiotherapy. 87% in the chemoradiotherapy group and 86% in the chemotherapy group underwent tumor resection. Initial results showed that patients allocated to chemoradiotherapy more often responded with complete histopathological response in the primary tumor (28% vs. 9%). Treatment-related complications were similar between the groups although postoperative complications were more severe in the chemoradiotherapy group. This article reports the long-term results. Five-year progression-free survival was 38.9% (95% CI 28.9%-48.8%) in the chemoradiotherapy group versus 33.0% (95% CI 23.6%-42.7%) in the chemotherapy group, P = 0.82. Five-year overall survival was 42.2% (95% CI 31.9%-52.1%) versus 39.6% (95% CI 29.5%-49.4%), P = 0.60. There were no differences in recurrence patterns between the treatment groups. This is to our knowledge that the largest completed randomized trial comparing neoadjuvant chemotherapy with neoadjuvant chemoradiotherapy followed by esophageal resection in patients with cancer in the esophagus or gastroesophageal junction. Despite a higher tumor tissue response in those who received neoadjuvant chemoradiotherapy, no survival advantages were seen. Consequently, the results do not support unselected addition of radiotherapy to neoadjuvant chemotherapy as a standard of care in patients with resectable esophageal cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Wheel–rail impact loads and noise at railway crossings are calculated by applying a hybrid prediction model. It combines the simulation of non-linear vertical dynamic vehicle‒track interaction in the ...time domain and the prediction of sound pressure level using a linear frequency-domain model. The two models are coupled based on the concept of an equivalent roughness spectrum. The time-domain model uses moving Green's functions for the linear vehicle and track models, accounting for wheel structural flexibility and a discretely supported rail with spatially-varying beam properties, and a non-Hertzian wheel–rail contact model. Three-dimensional surface geometry of the wheel and crossing is accounted for in the solution of the wheel–rail contact. The hybrid model is compared against field measurements and is demonstrated by investigating the influence of vehicle speed and crossing geometry on the radiated impact noise. Based on simulation results, it is concluded that the impact loads and noise can be mitigated by reducing the effective dip angle at the crossing, which is determined by the vertical trajectory of the wheel when making the transition between wing rail and crossing nose.
1-2-(2,4-Dimethylphenyl-sulfanyl)-phenyl-piperazine (Lu AA21004) is a human (h) serotonin (5-HT)(3A) receptor antagonist (K(i) = 3.7 nM), h5-HT(7) receptor antagonist (K(i) = 19 nM), h5-HT(1B) ...receptor partial agonist (K(i) = 33 nM), h5-HT(1A) receptor agonist (K(i) = 15 nM), and a human 5-HT transporter (SERT) inhibitor (K(i) = 1.6 nM) (J Med Chem 54:3206-3221, 2011). Here, we confirm that Lu AA21004 is a partial h5-HT(1B) receptor agonist EC(50) = 460 nM, intrinsic activity = 22% using a whole-cell cAMP-based assay and demonstrate that Lu AA21004 is a rat (r) 5-HT(7) receptor antagonist (K(i) = 200 nM and IC(50) = 2080 nM). In vivo, Lu AA21004 occupies the r5-HT(1B) receptor and rSERT (ED(50) = 3.2 and 0.4 mg/kg, respectively) after subcutaneous administration and is a 5-HT(3) receptor antagonist in the Bezold-Jarisch reflex assay (ED(50) = 0.11 mg/kg s.c.). In rat microdialysis experiments, Lu AA21004 (2.5-10.0 mg/kg s.c.) increased extracellular 5-HT, dopamine, and noradrenaline in the medial prefrontal cortex and ventral hippocampus. Lu AA21004 (5 mg/kg per day for 3 days; minipump subcutaneously), corresponding to 41% rSERT occupancy, significantly increased extracellular 5-HT in the ventral hippocampus. Furthermore, the 5-HT(3) receptor antagonist, ondansetron, potentiated the increase in extracellular levels of 5-HT induced by citalopram. Lu AA21004 has antidepressant- and anxiolytic-like effects in the rat forced swim (Flinders Sensitive Line) and social interaction and conditioned fear tests (minimal effective doses: 7.8, 2.0, and 3.9 mg/kg). In conclusion, Lu AA21004 mediates its pharmacological effects via two pharmacological modalities: SERT inhibition and 5-HT receptor modulation. In vivo, this results in enhanced release of several neurotransmitters and antidepressant- and anxiolytic-like profiles at doses for which targets in addition to the SERT are occupied. The multimodal activity profile of Lu AA21004 is distinct from that of current antidepressants.
Summary
Background
There is no consensus on core outcome domains for hidradenitis suppurativa (HS). Heterogeneous outcome measure instruments in clinical trials likely leads to outcome‐reporting bias ...and limits the ability to synthesize evidence.
Objectives
To achieve global multistakeholder consensus on a core outcome set (COS) of domains regarding what to measure in clinical trials for HS.
Methods
Six stakeholder groups participated in a Delphi process that included five anonymous e‐Delphi rounds and four face‐to‐face consensus meetings to reach consensus on the final COS. The aim was for a 1 : 1 ratio of patients to healthcare professionals (HCPs).
Results
A total of 41 patients and 52 HCPs from 19 countries in four continents participated in the consensus process, which yielded a final COS that included five domains: pain, physical signs, HS‐specific quality of life, global assessment and progression of course. A sixth domain, symptoms, was highly supported by patients and not by HCPs but is recommended for the core domain set.
Conclusions
Routine adoption of the COS in future HS trials should ensure that core outcomes of importance to both patients and HCPs are collected.
What's already known about this topic?
Outcome measure instruments used for hidradenitis suppurativa (HS) are markedly heterogeneous with 30 instruments recently found in 12 randomized trials.
Lack of consensus regarding outcome measure instruments limits evidence synthesis and increases the risk of outcome reporting bias.
A core domain set is an agreed minimum set of what to measure that should be reported in all clinical trials of a specific condition.
What does this study add?
Our study provides global multistakeholder consensus on core outcome domains for HS.
The final core domain set includes five domains: pain, physical signs, HS‐specific quality of life, global assessment and progression of course.
A sixth domain, symptoms, was highly supported by patients and not by healthcare professionals; it is recommended by the steering committee as an additional core domain, in the context of being a patient‐reported domain.
What are the clinical implications of this work?
The routine adoption of this core outcome set in future HS trials should ensure that outcome domains of importance to both patients and HCPs are included and reported.
Linked Editorial: Kottner & Schmitt. Br J Dermatol 2018; 179:549–550.
Plain language summary available online
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We derive a Bayesian criterion for assessing whether signals observed in two separate data sets originate from a common source. The Bayes factor for a common versus unrelated origin of signals ...includes an overlap integral of the posterior distributions over the common-source parameters. Focusing on multimessenger gravitational-wave astronomy, we apply the method to the spatial and temporal association of independent gravitational-wave and electromagnetic (or neutrino) observations. As an example, we consider the coincidence between the recently discovered gravitational-wave signal GW170817 from a binary neutron star merger and the gamma-ray burst GRB 170817A: we find that the common-source model is enormously favored over a model describing them as unrelated signals.
Summary
Background
Monitoring disease activity over time is a prerequisite for clinical practice and research. Valid and reliable outcome measurement instruments (OMIs) and staging systems provide ...researchers and clinicians with benchmark tools to assess the primary and secondary outcomes of interventional trials and to guide treatment selection properly.
Objectives
To investigate inter‐rater reliability and agreement in instruments currently used in hidradenitis suppurativa (HS), with dermatologists experienced in HS as the rater population of interest.
Methods
In a prospective completely balanced design, 24 patients with HS underwent a physical examination by 12 raters (288 assessments) using nine instruments. The results were analysed using generalized linear mixed models.
Results
For the staging systems, the study found good inter‐rater reliability for Hurley staging in the axillae and gluteal region, moderate inter‐rater reliability for Hurley staging in the groin and for Physician's Global Assessment, and fair inter‐rater reliability for refined Hurley staging and the International HS Severity Scoring System. For all the tested OMIs, the observed intervals for limits of agreement were very wide relative to the ranges of the scales.
Conclusions
The very wide intervals for limits of agreement imply that substantial changes are needed in clinical research in order to rule out measurement error. The results illustrate a difficulty, even for experienced HS experts, to agree on the type and number of lesions when evaluating disease severity. The apparent caveats call for global efforts, such as the HIdradenitis SuppuraTiva cORe outcomes set International Collaboration (HISTORIC) to reach consensus on how best to measure physical signs of HS reliably in randomized trials.
What's already known about this topic?
Without valid and reliable instruments to measure outcomes, researchers and clinicians lack the necessary benchmarks to assess primary and secondary end points of interventional trials properly.
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease.
Several outcome measure instruments exist for HS, but their validation is generally incomplete or of relatively low methodological quality.
What does this study add?
Using a prospective completely balanced design this study examined inter‐rater reliability with HS‐experienced dermatologists as the rater population of interest.
The study did not find very good reliability for any included instrument or lesion counts.
This study illustrates the difficulty in finding agreement on the type and number of HS lesions, even among experts.
The results question whether physical signs are best measured by a traditional physician lesion count instrument.
What are the clinical implications of this work?
For staging, Hurley staging and physician global visual analogue scale proved to be acceptable instruments in terms of inter‐rater reliability.
For the instruments designed to measure changes in health status, our study illustrates how difficult it is, even for experts, to measure the physical signs of HS using a simple rater counting.
Consequently, other assessment methods of physicals signs, such as ultrasound evaluation, require consideration.
Linked Comment: Oosterhaven. Br J Dermatol 2019; 181:438–439.
Plain language summary available online
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The near-term progression of ocean acidification (OA) is projected to bring about sharp changes in the chemistry of coastal upwelling ecosystems. The distribution of OA exposure across these ...early-impact systems, however, is highly uncertain and limits our understanding of whether and how spatial management actions can be deployed to ameliorate future impacts. Through a novel coastal OA observing network, we have uncovered a remarkably persistent spatial mosaic in the penetration of acidified waters into ecologically-important nearshore habitats across 1,000 km of the California Current Large Marine Ecosystem. In the most severe exposure hotspots, suboptimal conditions for calcifying organisms encompassed up to 56% of the summer season, and were accompanied by some of the lowest and most variable pH environments known for the surface ocean. Persistent refuge areas were also found, highlighting new opportunities for local adaptation to address the global challenge of OA in productive coastal systems.
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