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Objectives To re-evaluate cut-offs for disease activity states according to the Axial Spondyloarthritis Disease Activity Score (ASDAS), and study the impact of sex, age, calendar time, disease and symptom duration on ASDAS and ASDAS cut-offs in a large contemporary cohort.Methods Data from 2939 patients with axial spondyloarthritis (axSpA) starting their first tumour necrosis factor inhibitor in nine European registries were pooled and analysed. Receiver operating characteristic analyses were performed to identify cut-offs against external criteria. Six-month data including patient and physician global assessments, both ≤1 (0–10 integer scale), and Assessment of SpondyloArthritis International Society partial remission were used for separation of inactive disease (ID) from low disease activity (LDA), while patient and physician global ≤3 were applied as external criteria to separate LDA from high disease activity (HDA). Patient and physician global ≥6 were applied to separate HDA from very high disease activity in baseline data.Results The three ASDAS cut-offs identified to separate the four disease activity states in the overall patient population were 3.5. Cut-offs for ID and LDA in women were higher (

Lyciasalamandra species, like most amphibians, secrete a wide array of compounds from their granular and mucous skin glands, including the internally synthesized samandarine alkaloids, making their skin a complex organ performing a variety of functions. Lyciasalamandra helverseni and L. luschani basoglui are insular endemics of the Dodecanese islands of SE Greece, bearing distinct isolated populations, with well-documented phylogenetic profiles. Here, we employ a metabolomics approach, utilizing UPLC-ESI-HRMS/MS data of the skin secretions sampled from a number of specimens found in the islands of Karpathos, Kasos and Kastellorizo, in an effort to reveal aspects of their chemistry and diversity across populations. The results indicated statistically significant variation between all taxa examined, based on various secreted compounds. The underlying factors of variation highlighted by the multivariate analysis were differences in samandarine and other alkaloid content as well as in animal size. Metabolite annotation, based on dereplication tools and most importantly HRMS and HRMS/MS spectra, yielded a number of known samandarine alkaloids, reported for the first time in the currently studied Lyciasalamandra species. We also present documentation for novel members of the samandarine alkaloid family, as well as preliminary evidence for a possible dietary alkaloid sequestration. This work can set the basis for further research of this often-neglected endemic species of the Salamandridae, as well as the structural investigation of the samandarine alkaloid group.

An individual's likelihood of developing non-communicable diseases is often influenced by the types, intensities and duration of exposures at work. Job exposure matrices provide exposure estimates associated with different occupations. However, due to their time-consuming expert curation process, job exposure matrices currently cover only a subset of possible workplace exposures and may not be regularly updated. Scientific literature articles describing exposure studies provide important supporting evidence for developing and updating job exposure matrices, since they report on exposures in a variety of occupational scenarios. However, the constant growth of scientific literature is increasing the challenges of efficiently identifying relevant articles and important content within them. Natural language processing methods emulate the human process of reading and understanding texts, but in a fraction of the time. Such methods can increase the efficiency of both finding relevant documents and pinpointing specific information within them, which could streamline the process of developing and updating job exposure matrices. Named entity recognition is a fundamental natural language processing method for language understanding, which automatically identifies mentions of domain-specific concepts (named entities) in documents, e.g., exposures, occupations and job tasks. State-of-the-art machine learning models typically use evidence from an annotated corpus, i.e., a set of documents in which named entities are manually marked up (annotated) by experts, to learn how to detect named entities automatically in new documents. We have developed a novel annotated corpus of scientific articles to support machine learning based named entity recognition relevant to occupational substance exposures. Through incremental refinements to the annotation process, we demonstrate that expert annotators can attain high levels of agreement, and that the corpus can be used to train high-performance named entity recognition models. The corpus thus constitutes an important foundation for the wider development of natural language processing tools to support the study of occupational exposures.

Disentangling human brain connectivity requires an accurate description of nerve fiber trajectories, unveiled via detailed mapping of axonal orientations. However, this is challenging because axons can cross one another on a micrometer scale. Diffusion magnetic resonance imaging (dMRI) can be used to infer axonal connectivity because it is sensitive to axonal alignment, but it has limited spatial resolution and specificity. Scattered light imaging (SLI) and small-angle X-ray scattering (SAXS) reveal axonal orientations with microscopic resolution and high specificity, respectively. Here, we apply both scattering techniques on the same samples and cross-validate them, laying the groundwork for ground-truth axonal orientation imaging and validating dMRI. We evaluate brain regions that include unidirectional and crossing fibers in human and vervet monkey brain sections. SLI and SAXS quantitatively agree regarding in-plane fiber orientations including crossings, while dMRI agrees in the majority of voxels with small discrepancies. We further use SAXS and dMRI to confirm theoretical predictions regarding SLI determination of through-plane fiber orientations. Scattered light and X-ray imaging can provide quantitative micrometer 3D fiber orientations with high resolution and specificity, facilitating detailed investigations of complex fiber architecture in the animal and human brain.

Abstract Transdiagnostic psychotherapeutic approaches are increasingly used in neurorehabilitation to address psychological distress. Animal-assistance is thought to increase efficacy. The present study evaluates a psychotherapeutic mindfulness- and self-compassion-based group intervention (MSCBI) with and without animal-assistance for patients with acquired brain injury. Patients (N = 31) were randomly assigned to the 6-week intervention with (n = 14) or without animal-assistance (n = 17). Primary outcome was psychological distress at post- and follow-up treatment, secondary outcomes were changes within-session of patients’ emotional states, adherence to treatment and attrition. Psychological distress significantly decreased in both groups from pre- to follow-up treatment with no difference between groups. Patients in the animal-assisted MSCBI group reported significantly higher increases in feeling secure, accepted, comforted, grateful, motivated and at ease during the sessions compared to patients in the MSCBI group without animal-assistance. Adherence to sessions was significantly higher in the animal-assisted MSCBI group. Attrition did not significantly differ between groups. Our results show that both MSCBIs with and without animal-assistance are feasible and effective in reducing psychological distress in patients with acquired brain injury. The significant changes within-sessions mainly in relationship-based emotional states and the higher treatment adherence suggest additional effects of animal-assistance. Animal-assistance might increase acceptability and patients’ commitment to psychotherapy.

Abstract Current understanding of human genital-brain interactions relates primarily to neuroendocrine and autonomic control, whereas interactions during sexual stimulation remain largely unexplored. Here we present a systematic approach towards identifying how the human brain encodes sensory genital information. Using a validated affective touch paradigm and functional magnetic resonance imaging, we found that hedonic responses to discriminatory versus affective tactile stimulation were distinctly different for both penile shaft and forearm. This suggests that, as with other body sites, genital skin contains small diameter mechanoreceptive nerve fibres that signal pleasant touch. In the brain, secondary somatosensory cortex (S2) distinguished between affective and discriminative touch for the penile shaft, but not for the forearm. Frenulum stimulation induced the greatest reports of subjective pleasure and led to the greatest deactivation of the default-mode network. This study represents a first pass at investigating, in humans, the relationship between innervation of genital surfaces, hedonic feelings, and brain mechanisms, in a systematic way.

Abstract Orthopedic and neurological impairments (e.g., muscle contractures, spasticity) are often treated in children and young adults with cerebral palsy (CP). Due to challenges arising from combinatorics, research funding priorities, and medical practicalities, and despite extensive study, the evidence base is weak. Our goal was to estimate the short-term effectiveness of 13 common orthopedic and neurological treatments at four different levels of outcome in children and young adults diagnosed with CP. The outcome levels considered were body structures, specific gait kinematic deviations, overall gait kinematic deviations, and functional mobility. We used three well-establish causal inference approaches (direct matching, virtual twins, and Bayesian causal forests) and a large clinical gait analysis database to estimate the average treatment effect on the treated (ATT). We then examined the effectiveness across treatments, methods, and outcome levels. The dataset consisted of 2851 limbs from 933 individuals (some individuals underwent multiple treatment episodes). Current treatments have medium effects on body structures, but modest to minimal effects on gait and functional mobility. The median ATT of 13 common treatments in children and young adults with CP, measured as Cohen’s D, bordered on medium at the body structures level (median [IQR] = 0.42 [0.05, 0.60]) and became smaller as we moved along the causal chain through specific kinematic deviations (0.21 [0.01, 0.33]), overall kinematic deviations (0.09 [0.03, 0.19]), and functional mobility (-0.01 [-0.06, 0.13]). Further work is needed to understand the source of heterogeneous treatment effects, which are large in this patient population. Replication or refutation of these findings by other centers will be valuable to establish the generalizability of these results and for benchmarking of best practices.

Abstract The chemical composition of exhaled breath was examined for volatile organic compound (VOC) indicators of sexual arousal in human beings. Participants (12-male, 12-female) were shown a randomized series of three emotion-inducing 10-min film clips interspersed with 3-min neutral film clips. The films caused different arousals: sports film (positive-nonsexual); horror film (negative-nonsexual); and erotic (sexual) that were monitored with physiological measurements including genital response and temperature. Simultaneously the breath was monitored for VOC and CO2. While some breath compounds (methanol and acetone) changed uniformly irrespective of the film order, several compounds did show significant arousal associated changes. For both genders CO2 and isoprene decreased in the sex clip. Some male individuals showed particularly strong increases of indole, phenol and cresol coincident with sexual arousal that decreased rapidly afterwards. These VOCs are degradation products of tyrosine and tryptophan, precursors for dopamine, noradrenalin, and serotonin, and therefore represent potential breath markers of sexual arousal.

Abstract Background In pediatric hereditary cystic kidney diseases, epithelial cell defects mostly result from rare, autosomal recessively inherited pathogenic variants in genes encoding proteins of the cilia-centrosome complex. Consequences of individual gene variants on epithelial function are often difficult to predict and can furthermore depend on the patient’s genetic background. Here, we studied urine-derived renal tubular epithelial cells (URECs) from genetically determined, pediatric cohorts of different hereditary cystic kidney diseases, comprising autosomal recessive polycystic kidney disease, nephronophthisis (NPH) and the Bardet Biedl syndrome (BBS). UREC characteristics and behavior in epithelial function-related 3D cell culture were compared in order to identify gene and variant-specific properties and to determine aspects of epithelial (cell) dysfunction. Results UREC preparations from patients (19) and healthy controls (39) were studied in a qualitative and quantitative manner using primary cells cultured for up-to 21 days. In patients with biallelic pathogenic variants in PKHD1 or NPHP genes, we were able to receive satisfactory amounts of URECs of reproducible quality. In BBS patients, UREC yield was lower and more dependent on the individual genotype. In contrast, in UREC preparations derived from healthy controls, no predictable and satisfactory outcome could be established. Considering cell proliferation, tubular origin and epithelial properties in 2D/3D culture conditions, we observed distinct and reproducible epithelial properties of URECs. In particular, the cells from patients carrying PKHD1 variants were characterized by a high incidence of defective morphogenesis of monolayered spheroids—a property proposed to be suitable for corrective intervention. Furthermore, we explored different ways to generate reference cell lines for both—patients and healthy controls—in order to eliminate restrictions in cell number and availability of primary URECs. Conclusions Ex vivo 3D cell culture of primary URECs represents a valuable, non-invasive source to evaluate epithelial cell function in kidney diseases and as such helps to elucidate the functional consequences of rare genetic disorders. In combination with genetically defined control cell lines to be generated in the future, the cultivation of primary URECs could become a relevant tool for testing personalized treatment of epithelial dysfunction in patients with hereditary cystic kidney disease.

[This corrects the article DOI: 10.1371/journal.pone.0015730.].

Objective To identify predictors of flare in a 2-year follow-up study of patients with rheumatoid arthritis (RA) in sustained clinical remission tapering towards withdrawal of biological disease-modifying anti-rheumatic drugs (bDMARDs).Methods Sustained clinical remission was defined as Disease Activity Score for 28 joints (DAS28)-C reactive protein (CRP) ≤2.6 without radiographic progression for >1 year. bDMARDs were tapered according to a mandatory clinical guideline to two-thirds of standard dose at baseline, half of dose at week 16 and discontinuation at week 32. Prospective assessments for 2 years included clinical evaluation, conventional radiography, ultrasound and MRI for signs of inflammation and bone changes. Flare was defined as DAS28-CRP ≥2.6 with ∆DAS28-CRP ≥1.2 from baseline. Baseline predictors of flare were assessed by logistic regression analyses.Results Of 142 included patients, 121 (85%) flared during follow-up of which 86% regained remission within 24 weeks after flare. Patients that flared were more often rheumatoid factor positive, had tried more bDMARDs and had higher baseline ultrasound synovitis sum scores than those not flaring. For patients on standard dose, predictors of flare within 16 weeks after reduction to two-thirds of standard dose were baseline MRI-osteitis (OR 1.16; 95% CI 1.03 to 1.33; p=0.014), gender (female) (OR 6.71; 95% CI 1.68 to 46.12; p=0.005) and disease duration (OR 1.06; 95% CI 1.01 to 1.11; p=0.020). Baseline predictors for flare within 2 years were ultrasound grey scale synovitis sum score (OR 1.19; 95% CI 1.02 to 1.44; p=0.020) and number of previous bDMARDs (OR 4.07; 95% CI 1.35 to 24.72; p=0.007).Conclusion The majority of real-world patients with RA tapering bDMARDs flared during tapering, with the majority regaining remission after stepwise dose increase. Demographic and imaging parameters (MR-osteitis/ultrasound greyscale synovitis) were independent predictors of immediate flare and flare overall and may be of importance for clinical decision-making in patients eligible for tapering.

Traumatic vascular injury of the brachial artery by closed posterolateral complete elbow dislocation, without fracture is an unusual injury. Based on clinical and radiological evidence, emergency treatment is necessary.We present a case of complete brachial artery rupture, with a clot resulting from a closed posterolateral elbow dislocation, without fracture. We report the early assessment and operative treatment.A brachial artery injury due to a closed elbow dislocation, without fracture is uncommon. The diagnosis poses a dilemma and the operation is a challenge. It is addressed by Orthopaedic and Vascular team.

Abstract Processing of N-terminally elongated antigenic peptide precursors by Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) is a key step in antigen presentation and the adaptive immune response. Although ERAP1 can efficiently process long peptides in solution, it has been proposed that it can also process peptides bound onto Major Histocompatibility Complex I molecules (MHCI). In a previous study, we suggested that the occasionally observed “ontο MHCI” trimming by ERAP1 is likely due to fast peptide dissociation followed by solution trimming, rather than direct action of ERAP1 onto the MHCI complex. However, other groups have proposed that ERAP1 can trim peptides covalently bound onto MHCI, which would preclude peptide dissociation. To explore this interaction, we constructed disulfide-linked MHCI-peptide complexes using HLA-B*08 and a 12mer kinetically labile peptide, or a 16mer carrying a phosphinic transition-state analogue N-terminus with high-affinity for ERAP1. Kinetic and biochemical analyses suggested that while both peptides could access the ERAP1 active site when free in solution, they were unable to do so when tethered in the MHCI binding groove. Our results suggest that MHCI binding protects, rather than promotes, antigenic peptide precursor trimming by ERAP1 and thus solution trimming is the more likely model of antigenic peptide processing.

We have designed a platform to aid people with motor disabilities to be part of digital environments, in order to create digitally and socially inclusive activities that promote their quality of life. To evaluate in depth the impact of the platform on social inclusion indicators across patients with various motor disabilities, we constructed a questionnaire in which the following indicators were assessed: (i) Well Being, (ii) Empowerment, (iii) Participation, (iv) Social Capital, (v) Education, and (vi) Employment. In total 30 participants (10 with Neuromuscular Disorders-NMD, 10 with Spinal Cord Injury-SCI, and 10 with Parkinson's Disease-PD) used the platform for ~1 month, and its impact on social inclusion indicators was measured before and after the usage. Moreover, monitoring mechanisms were used to track computer usage as well as an online social activity. Finally, testimonials and experimenter input were collected to enrich the study with qualitative understanding. All participants were favorable to use the suggested platform, while they would prefer it for longer periods of time in order to become “re-awakened” to possibilities of expanded connection and inclusion, while it became clear that the platform has to offer them further the option to use it in a reclining position. The present study has clearly shown that the challenge of social inclusion cannot be tackled solely with technology and it needs to integrate persuasive design elements that foster experimentation and discovery.

Blood clot formation initiates ischemic events, but coagulation roles during postischemic tissue repair are poorly understood. The endothelial protein C receptor (EPCR) regulates coagulation, as well as immune and vascular signaling, by protease activated receptors (PARs). Here, we show that endothelial EPCR-PAR1 signaling supports reperfusion and neovascularization in hindlimb ischemia in mice. Whereas deletion of PAR2 or PAR4 did not impair angiogenesis, EPCR and PAR1 deficiency or PAR1 resistance to cleavage by activated protein C caused markedly reduced postischemic reperfusion in vivo and angiogenesis in vitro. These findings were corroborated by biased PAR1 agonism in isolated primary endothelial cells. Loss of EPCR-PAR1 signaling upregulated hemoglobin expression and reduced endothelial nitric oxide (NO) bioavailability. Defective angiogenic sprouting was rescued by the NO donor DETA-NO, whereas NO scavenging increased hemoglobin and mesenchymal marker expression in human and mouse endothelial cells. Vascular specimens from patients with ischemic peripheral artery disease exhibited increased hemoglobin expression, and soluble EPCR and NO levels were reduced in plasma. Our data implicate endothelial EPCR-PAR1 signaling in the hypoxic response of endothelial cells and identify suppression of hemoglobin expression as an unexpected link between coagulation signaling, preservation of endothelial cell NO bioavailability, support of neovascularization, and prevention of fibrosis.

Abstract Baffin Bay hosts the largest and most productive of the Arctic polynyas: the North Water (NOW). Despite its significance and active role in water mass formation, the history of the NOW beyond the observational era remains poorly known. We reconcile the previously unassessed relationship between long-term NOW dynamics and ocean conditions by applying a multiproxy approach to two marine sediment cores from the region that, together, span the Holocene. Declining influence of Atlantic Water in the NOW is coeval with regional records that indicate the inception of a strong and recurrent polynya from ~ 4400 yrs BP, in line with Neoglacial cooling. During warmer Holocene intervals such as the Roman Warm Period, a weaker NOW is evident, and its reduced capacity to influence bottom ocean conditions facilitated northward penetration of Atlantic Water. Future warming in the Arctic may have negative consequences for this vital biological oasis, with the potential knock-on effect of warm water penetration further north and intensified melt of the marine-terminating glaciers that flank the coast of northwest Greenland.

Walking is an important skill with positive impacts on health, function, and well-being. Many disorders impair walking and its positive impacts through a variety of complex and interrelated mechanisms. Any attempt to understand walking impairments, or the effects of interventions intended to treat these impairments, must respect this complexity. Therefore, our main objectives in conducting this study were to (1) propose a comprehensive model for quantifying the causes and consequences of walking impairments and (2) demonstrate the potential utility of the model for supporting clinical care and addressing basic scientific questions related to walking. To achieve these goals, we introduced a model, described by a directed acyclic graph, consisting of 10 nodes and 23 primary causal paths. We gave detailed descriptions of each node and path based on domain knowledge. We then demonstrated the model's utility using a large sample of gait data (N = 9504) acquired as part of routine care at a regional referral center. We analyzed five relevant examples that involved many of the model's nodes and paths. We computed causal effect magnitudes as Shapley values and displayed the overall importance of variables (mean absolute Shapley value), the variation of Shapley values with respect to underlying variables, and Shapley values for individual observations (case studies). We showed that the model was plausible, captured some well-known cause-effect relationships, provided new insights into others, and generated novel hypotheses requiring further testing through simulation or experiment. To aid in transparency, reproducibility, and future enhancements we have included an extensively commented Rmarkdown file and a deidentified data set.

Background There is a broad range of known effects of animal contact on human mental and physical health. Neurological correlates of human interaction with animals have been sparsely investigated. We investigated changes in frontal brain activity in the presence of and during contact with a dog. Methods Twenty-one healthy individuals each participated in six sessions. In three sessions, participants had contact with a dog, and in three control sessions they interacted with a plush animal. Each session had five two-minute phases with increasing intensity of contact to the dog or plush animal from the first to the fourth phase. We measured oxygenated, deoxygenated, and total hemoglobin and oxygen saturation of the blood in the frontal lobe/frontopolar area with functional near-infrared spectroscopy (SenSmart Model X-100) to assess brain activity. Findings In both conditions, the concentration of oxygenated hemoglobin increased significantly from the first to the fourth phase by 2.78 μmol/l (CI = 2.03–3.53, p < .001). Oxygenated hemoglobin concentration was 0.80 μmol/l higher in the dog condition compared to in the control condition (CI = 0.27–1.33, p = .004). Deoxygenated-hemoglobin concentration, total hemoglobin concentration, and oxygen saturation showed similar patterns. Conclusion Prefrontal brain activation in healthy subjects increased with the rise in interaction closeness with a dog or a plush animal. Moreover, interaction with a dog stimulated more brain activity compared to the control condition, suggesting that interactions with a dog can activate stronger attentional processes and elicit more emotional arousal than interacting with a nonliving stimulus.

Innate immunity and chronic inflammation are involved in atherosclerosis and atherothrombosis, leading to target organ damage in essential hypertension (EH). However, the role of neutrophils in EH is still elusive. We investigated the association between angiotensin II (Ang II) and neutrophil extracellular traps (NETs) in pathogenesis of EH. Plasma samples, kidney biopsies, and surgical specimens of abdominal aortic aneurysms (AAAs) from patients with EH were used. Cell-based assays, NETs/human aortic endothelial cell cocultures, and in situ studies were performed. Increased plasma levels of NETs and tissue factor (TF) activity were detected in untreated, newly diagnosed patients with EH. Stimulation of control neutrophils with plasma from patients with untreated EH generated TF-enriched NETs promoting endothelial collagen production. Ang II induced NETosis in vitro via an ROS/peptidylarginine deiminase type 4 and autophagy-dependent pathway. Circulating NETs and thrombin generation levels were reduced substantially in patients with EH starting treatment with Ang II receptor blockers, whereas their plasma was unable to trigger procoagulant NETs. Moreover, TF-bearing NETotic neutrophils/remnants accumulated in sites of interstitial renal fibrosis and in the subendothelial layer of AAAs. These data reveal the important pathogenic role of an Ang II/ROS/NET/TF axis in EH, linking thromboinflammation with endothelial dysfunction and fibrosis.

Abstract Background Many people who have common mental disorders, such as depression and anxiety, also have some psychotic experiences. These experiences are associated with higher clinical complexity, poor treatment response, and negative clinical outcomes. Psychological interventions have the potential to improve outcomes for people with psychotic experiences. The aims of this systematic review are to (1) synthesise the evidence on the effectiveness and cost-effectiveness of psychological interventions to reduce psychotic experiences and their associated distress and (2) identify key components of effective interventions. Methods Our search strategy will combine terms for (1) psychological interventions, (2) psychotic experiences, and (3) symptoms associated with psychotic experiences. We will search the following online databases: MEDLINE, Embase, PsycINFO, all Cochrane databases, British Nursing Index (BNI), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Health Management Information Consortium (HMIC), Education Resources Information Center (ERIC), and EconLit. Our primary outcome is the proportion of people who recovered or remitted from psychotic experiences after the intervention. Our secondary outcomes are changes in positive psychotic symptoms, negative psychotic symptoms, depression, anxiety, functioning (including social, occupational, and academic), quality of life, and cost-effectiveness. Two independent reviewers will judge each study against pre-specified inclusion and exclusion criteria and will extract study characteristics, outcome data, and intervention components. Risk of bias and methodological quality will be assessed using the Effective Public Health Practice Project Quality Assessment Tool for Quantitative Studies and the Drummond Checklist. Results will be synthesised using random-effects meta-analysis and narrative synthesis. Discussion The identification of effective psychological interventions and of specific components associated with intervention effectiveness will augment existing evidence that can inform the development of a new, tailored intervention to improve outcomes related to psychotic symptoms, anxiety and depression, distress, functioning, and quality of life. Systematic review registration PROSPERO CRD42016033869

Key Clinical Message With few cases of PUNLMPs in young adults being reported in the literature, we hope to raise clinical awareness of prompt and effective diagnosis, while maintaining a high index of suspicion among health professionals. Even in the absence of red blood cells in the urine and subsequent negative imaging workup, clinicians should not delay performance of diagnostic cystoscopy.

Introduction Pneumonia is one of the leading complications and causes of death after a spinal cord injury (SCI). After a cervical or thoracic lesion, impairment of the respiratory muscles decreases respiratory function, which increases the risk of respiratory complications. Pneumonia substantially reduces patient’s quality of life, may prolong inpatient rehabilitation time, increase healthcare costs or at worse, lead to early death. Respiratory function and coughing can be improved through various interventions after SCI, but the available evidence as to which aspect of respiratory care should be optimised is inconclusive. Furthermore, ability of respiratory function parameters to predict pneumonia risk is insufficiently established. This paper details the protocol for a large-scale, multicentre research project that aims to evaluate the ability of parameters of respiratory function to predict and understand variation in inpatient risk of pneumonia in SCI.Methods and analysis RESCOM, a prospective cohort study, began recruitment in October 2016 across 10 SCI rehabilitation centres from Australia, Austria, Germany, the Netherlands and Switzerland. Inpatients with acute SCI, with complete or incomplete cervical or thoracic lesions, 18 years or older and not/no more dependent on 24-hour mechanical ventilation within the first 3 months after injury are eligible for inclusion. The target sample size is 500 participants. The primary outcome is an occurrence of pneumonia; secondary outcomes include pneumonia-related mortality and quality of life. We will use the longitudinal data for prognostic models on inpatient pneumonia risk factors.Ethics and dissemination The study has been reviewed and approved by all local ethics committees of all participating centres. Study results will be disseminated to the scientific community through peer-reviewed journals and conference presentations, to the SCI community, other stakeholders and via social media, newsletters and engagement activities.Trial registration details ClinicalTrials.gov NCT02891096.

Introduction Neurogenic lower urinary tract dysfunction (NLUTD), including neurogenic detrusor overactivity (NDO) and detrusor sphincter dyssynergia, is one of the most frequent and devastating sequelae of spinal cord injury (SCI), as it can lead to urinary incontinence and secondary damage such as renal failure. Transcutaneous tibial nerve stimulation (TTNS) is a promising, non-invasive neuromodulatory intervention that may prevent the emergence of the C-fibre evoked bladder reflexes that are thought to cause NDO. This paper presents the protocol for TTNS in acute SCI (TASCI), which will evaluate the efficacy of TTNS in preventing NDO. Furthermore, TASCI will provide insight into the mechanisms underlying TTNS, and the course of NLUTD development after SCI.Methods and analysis TASCI is a nationwide, randomised, sham-controlled, double-blind clinical trial, conducted at all four SCI centres in Switzerland. The longitudinal design includes a baseline assessment period 5–39 days after acute SCI and follow-up assessments occurring 3, 6 and 12 months after SCI. A planned 114 participants will be randomised into verum or sham TTNS groups (1:1 ratio), stratified on study centre and lower extremity motor score. TTNS is performed for 30 min/day, 5 days/week, for 6–9 weeks starting within 40 days after SCI. The primary outcome is the occurrence of NDO jeopardising the upper urinary tract at 1 year after SCI, assessed by urodynamic investigation. Secondary outcome measures assess bladder and bowel function and symptoms, sexual function, neurological structure and function, functional independence, quality of life, as well as changes in biomarkers in the urine, blood, stool and bladder tissue. Safety of TTNS is the tertiary outcome.Ethics and dissemination TASCI is approved by the Swiss Ethics Committee for Northwest/Central Switzerland, the Swiss Ethics Committee Vaud and the Swiss Ethics Committee Zürich (#2019-00074). Findings will be disseminated through peer-reviewed publications.Trial registration number NCT03965299.

BackgroundThe COVID-19 pandemic has already changed our globalised world and its long-term impact is not yet known. It is apparent that businesses and institutions are increasingly affected. COVID-19 discussions often focus on intensive care units in hospitals. However, COVID-19 also effects life-saving and -prolonging radiotherapy for patients suffering from cancer.MethodWe have conducted a structured online survey among medical physicists in Germany, Austria and Switzerland from March 23rd to 26th 2020. In total 154 responses (82 completed, 72 partially completed) were analysed in the context of the COVID-19 dissemination.Results72.4% of the respondent's state that their processes are affected due to COVID-19, while the top three answers are longer processing times (54.2%), patient no-shows (42.5%) and staff reduction (36.7%). 75.8% expect further unavailability of their personnel in the upcoming weeks. All participants have already taken several measures, especially providing information for patients at the entrance (89.6%) or over the phone (73.6%), restricting access for accompanying persons (77.4%) and providing disinfectant at the entrance (72.6%).DiscussionThe results presented in this article aim to support business continuity and risk management for radiotherapy centres to prepare for future challenges. The results show that most radiotherapy centres has implemented initial contingency measures, applying them pragmatically. The main problem however remains, that is the high risk of infection both for patients and medical personnel along with the associated risk of temporarily loss of personnel and ordered closure of business.

Abstract Metabolic phenotypes reflect both the genetic and environmental factors which contribute to the development of varicose veins (VV). This study utilises analytical techniques to provide a comprehensive metabolic picture of VV disease, with the aim of identifying putative cellular pathways of disease pathogenesis. VV (n = 80) and non-VV (n = 35) aqueous and lipid metabolite extracts were analysed using 600 MHz 1H Nuclear Magnetic Resonance spectroscopy and Ultra-Performance Liquid Chromatography Mass Spectrometry. A subset of tissue samples (8 subjects and 8 controls) were analysed for microRNA expression and the data analysed with mirBase (www.mirbase.org). Using Multivariate statistical analysis, Ingenuity pathway analysis software, DIANALAB database and published literature, the association of significant metabolites with relevant cellular pathways were understood. Higher concentrations of glutamate, taurine, myo-inositol, creatine and inosine were present in aqueous extracts and phosphatidylcholine, phosphatidylethanolamine and sphingomyelin in lipid extracts in the VV group compared with non-VV group. Out of 7 differentially expressed miRNAs, spearman correlation testing highlighted correlation of hsa-miR-642a-3p, hsa-miR-4459 and hsa-miR-135a-3p expression with inosine in the vein tissue, while miR-216a-5p, conversely, was correlated with phosphatidylcholine and phosphatidylethanolamine. Pathway analysis revealed an association of phosphatidylcholine and sphingomyelin with inflammation and myo-inositol with cellular proliferation.

OBJECTIVE:To investigate if animal-assisted therapy (AAT) leads to higher consciousness in patients in a minimally conscious state during a therapy session, measured via behavioral reactions, heart rate and heart rate variability. METHODS:In a randomized two treatment multi-period crossover trial, 10 patients in a minimally conscious state participated in eight AAT sessions and eight paralleled conventional therapy sessions, leading to 78 AAT and 73 analyzed control sessions. Patients' responses during sessions were assessed via behavioral video coding and the Basler Vegetative State Assessment (BAVESTA), heart rate and heart rate variability (SDNN, RMSSD, HF and LF). Data were analyzed with generalized linear mixed models. RESULTS:Patients showed more eye movements (IRR = 1.31, 95% CI: 1.23 to 1.40, p < 0.001) and active movements per tactile input during AAT compared to control sessions (IRR = 1.13, 95% CI: 1.02 to 1.25, p = 0.018). No difference was found for positive emotions. With BAVESTA, patients' overall behavioral reactions were rated higher during AAT (b = 0.11, 95% CI: 0.01 to 0.22, p = 0.038). AAT led to significantly higher LF (b = 5.82, 95% CI: 0.55 to 11.08, p = 0.031) and lower HF (b = -5.80, 95% CI: -11.06 to -0.57, p = 0.030), while heart rate, SDNN, RMSSD did not differ. CONCLUSIONS:Patients in a minimally conscious state showed more behavioral reactions and increased physiological arousal during AAT compared to control sessions. This might indicate increased consciousness during therapeutic sessions in the presence of an animal. TRIAL REGISTRATION:ClinicalTrials.gov NCT02629302.

Needles are commonly used in the clinic for percutaneous procedures. The outcome of such procedures heavily depends on accurate placement of the needle. There are two main challenges to achieve high accuracy: First, aligning the needle with the targeted lesion, and second, compensating for the deflection of the needle in the tissue. In order to address these challenges, scientists have developed several robotic setups for needle steering. However, the subject is still under research and reliable implementations which can be used in clinical practice are not yet available. In this paper, we have taken some steps in order to bring needle steering closer to practice. A new hybrid control algorithm is developed, which enables us to control a flexible needle by combing base-manipulation and beveled-tip steering methods. A pre-operative path planner is developed which considers the clinical requirements. The proposed method is tested in the lung of a fresh-frozen human cadaver. The work-flow of the experiments are similar to the current clinical practice. Three experimental cases are used to evaluate the proposed steering algorithm. Experimental Case I shows that using the proposed steering algorithm controllability of the needle is increased. In Case II and Case III, the needle is steered in a gelatin phantom and a human cadaver, respectively. The targeting accuracy of 1.35±0.49mm in gelatin phantom and 1.97±0.89mm in cadave is achieved. A feasibility study is performed, in which a fine needle aspiration (FNA) needle is steered in the lungs of a human cadaver under computed tomography guidance. The targeting error for the feasibility study is 2.89±0.22mm. The results suggest that such a robotic system can be beneficial for clinical use and the patient receives less x-ray radiation.

Pathogenic protein accumulation and spread are fundamental principles of neurodegenerative diseases and ultimately account for the atrophy patterns that distinguish these diseases clinically. However, the biological mechanisms that link pathogenic proteins to specific neural network damage patterns have not been defined. We developed computational models for mechanisms of pathogenic protein accumulation, spread and toxic effects in an artificial neural network of cortical columns. By varying simulation parameters we assessed the effects of modelled mechanisms on network breakdown patterns. Our findings suggest that patterns of network breakdown and the convergence of patterns follow rules determined by particular protein parameters. These rules can account for empirical data on pathogenic protein spread in neural networks. This work provides a basis for understanding the effects of pathogenic proteins on neural circuits and predicting progression of neurodegeneration.

BACKGROUND:Consumption of meat prepared by barbecuing is associated with risk of cancer due to formation of carcinogenic compounds including benzo[a]pyrene (BaP). Assessment of a population's risk of disease and people's individual probability of disease given specific consumer attributes may direct food safety strategies to where impact on public health is largest. The aim of this study was to propose a model that estimates the risk of cancer caused by exposure to BaP from barbecued meat in Denmark, and to estimate the probability of developing cancer in subgroups of the population given different barbecuing frequencies. METHODS:We developed probabilistic models applying two dimensional Monte Carlo simulation to take into account the variation in exposure given age and sex and in the individuals' sensitivity to develop cancer after exposure to BaP, and the uncertainty in the dose response model. We used the Danish dietary consumption survey, monitoring data of chemical concentrations, data on consumer behavior of frequency of barbecuing, and animal dose response data. FINDINGS:We estimated an average extra lifetime risk of cancer due to BaP from barbecued meat of 6.8 × 10-5 (95% uncertainty interval 2.6 × 10-7 - 7.0 × 10-4) in the Danish population. This corresponds to approximately one to 4,074 extra cancer cases over a lifetime, reflecting wide uncertainty. The impact per barbecuing event on the risk of cancer for men and women of low body weight was higher compared to higher bodyweight. However, the difference due to sex and bodyweight between subgroups are dwarfed by the uncertainty. INTERPRETATION:This study proposes a model that can be applied to other substances and routes of exposure, and allows for deriving the change in risk following a specific change in behaviour. The presented methodology can serve as a valuable tool for risk management, allowing for the formulation of behaviour advice targeted to specific sub-groups in the population.

The incidence of hepatocellular carcinoma (HCC), the most common primary liver cancer, is increasing in the US and tripled during the past two decades. The reasons for such phenomenon remain poorly understood. Texas is among continental states with the highest incidence of liver cancer with an annual increment of 5.7%. Established risk factors for HCC include Hepatitis B and C (HBV, HCV) viral infection, alcohol, tobacco and suspected risk factors include obesity and diabetes. While distribution of these risk factors in the state of Texas is similar to the national data and homogeneous, the incidence of HCC in this state is exceptionally higher than the national average and appears to be dishomogeneous in various areas of the state suggesting that other non-recognized risk factors might play a role. No population-based studies are currently available investigating the effect of exposure to Hazardous Air Pollutants (HAPs) as a contributing risk factor for liver cancer. Incidence rate of liver cancer in Texas by counties for the time period between 2002 and 2012 was obtained from the Texas Cancer Registry (TCR). Through Principal Component Analysis (PCA) a subgroup of pollutants, explaining almost all the dataset variability, were identified and used to cluster Texas counties. The analysis generated 4 clusters showing liver cancer rate either higher or lower than national average in association with either high or low levels of HAPs emission in the environment. The study shows that the selected relevant HAPs, 10 among 253 analyzed, produce a significant correlation (P = 0.01-0.05) and some of these have been previously identified as carcinogens. An association between the increased production and consequent exposure to these HAPs and a higher presence of liver cancer in certain counties is suggested. This study provides a new insight on this complex multifactorial disease suggesting that environmental substances might play a role in the etiology of this cancer.