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BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

Zusammenfassung Hintergrund Regelmäßige Bewegung und spezifisches Training sind wichtige Bausteine in der Therapie rheumatischer Erkrankungen, weil ein gesundheitlicher Nutzen für die Patient*innen nachgewiesen ist. Basierend auf den internationalen Empfehlungen der WHO für Gesunde, geben die „2018 EULAR Empfehlungen zu körperlicher Aktivität von Menschen mit entzündlich-rheumatischen und degenerativen Erkrankungen“ erstmals evidenzbasierte Empfehlungen zu Gestaltung, Durchführung und Implementierung von Bewegungsübungen bei diesen Patient*innen. Ziel Übersetzung ins Deutsche und sprachliche Validierung in Deutschland, Österreich und der Schweiz. Methoden Eine professionelle Übersetzung der EULAR Bewegungsempfehlungen ins Deutsche wurde durch deutschsprachige Experten*innen aus allen 3 Ländern überarbeitet. Die Validierung erfolgte in einem Feldtest mit Rheumatolog*innen, Ergo- und Physiotherapeut*innen, Pflegefachpersonen und medizinischen Fachangestellten aus der Rheumatologie. In den 3 Ländern wurden jeweils 8 strukturierte Interviews zu Verständlichkeit, Wortwahl, Vollständigkeit und Umsetzbarkeit durchgeführt. Die Experten*innen diskutierten die Änderungsvorschläge, bis jeweils ein Konsens erreicht wurde. Zuletzt gaben sie den Grad ihrer Zustimmung zu der finalen Übersetzungsversion an. Ergebnisse Die professionelle Übersetzung wurde substanziell überarbeitet. Aufgrund der Ergebnisse der Feldtests wurden verschiedene Änderungen einzelner Worte sowie Umformulierungen zur besseren Verständlichkeit vorgenommen. Der Grad der Zustimmung lag mit durchschnittlichen Bewertungen zwischen 10 (SD 0,0) und 8,9 (SD 1,5) insgesamt sehr hoch. Diskussion Die vorliegende sprachlich validierte deutschsprachige Version der 2018 EULAR Bewegungsempfehlungen kann und soll dazu beitragen, Fachpersonal darin zu unterstützen, körperliche Aktivität bei Menschen mit entzündlich-rheumatischen und degenerativen Erkrankungen zu fördern.

Objectives To compare the diagnostic value of ultrashort echo time (UTE) magnetic resonance imaging (MRI) for the lung versus the gold standard computed tomography (CT) and two T1-weighted MRI sequences in children. Methods Twenty-three patients with proven oncologic disease (14 male, 9 female; mean age 9.0 + / − 5.4 years) received 35 low-dose CT and MRI examinations of the lung. The MRI protocol (1.5-T) included the following post-contrast sequences: two-dimensional (2D) incoherent gradient echo (GRE; acquisition with breath-hold), 3D volume interpolated GRE (breath-hold), and 3D high-resolution radial UTE sequences (performed during free-breathing). Images were evaluated by considering image quality as well as distinct diagnosis of pulmonary nodules and parenchymal areal opacities with consideration of sizes and characterisations. Results The UTE technique showed significantly higher overall image quality, better sharpness, and fewer artefacts than both other sequences. On CT, 110 pulmonary nodules with a mean diameter of 4.9 + / − 2.9 mm were detected. UTE imaging resulted in a significantly higher detection rate compared to both other sequences (p p Conclusion The UTE technique for lung MRI is favourable in children with generally high diagnostic performance compared to standard T1-weighted sequences as well as CT. Key Points • Due to the possible acquisition during free-breathing of the patients, the UTE MRI sequence for the lung is favourable in children. • The UTE technique reaches higher overall image quality, better sharpness, and lower artefacts, but not higher contrast compared to standard post-contrast T1-weighted sequences. • In comparison to the gold standard chest CT, the detection rate of small pulmonary nodules small nodules ≤ 4 mm and subtle parenchymal areal opacities is higher with the UTE imaging than standard T1-weighted sequences.

Static checker frameworks support software developers by automatically discovering bugs that fit general-purpose bug patterns. These frameworks ship with hundreds of detectors for such patterns and allow developers to add custom detectors for their own projects. However, existing frameworks generally encode detectors in imperative specifications, with extensive details of not only what to detect but also how . These details complicate detector maintenance and evolution, and also interfere with the framework’s ability to change how detection is done, for instance, to make the detectors incremental. In this paper, we present JavaDL, a Datalog-based declarative specification language for bug pattern detection in Java code. JavaDL seamlessly supports both exhaustive and incremental evaluation from the same detector specification. This specification allows developers to describe local detector components via syntactic pattern matching , and nonlocal (e.g., interprocedural) reasoning via Datalog-style logical rules . We compare our approach against the well-established SpotBugs and Error Prone tools by re-implementing several of their detectors in JavaDL. We find that our implementations are substantially smaller and similarly effective at detecting bugs on the Defects4J benchmark suite, and run with competitive runtime performance. In our experiments, neither incremental nor exhaustive analysis can consistently outperform the other, which highlights the value of our ability to transparently switch execution modes. We argue that our approach showcases the potential of clear-box static checker frameworks that constrain the bug detector specification language to enable the framework to adapt and enhance the detectors.

In the context of blue-collar work, digital technologies and robotic systems are introduced at a rapid speed. However, employees are not always motivated to adopt such new technologies. Thus, it is...

Airborne grass (Poaceae) pollen measurements are used in public warning systems to inform people about the risk of allergic symptoms. However, there is no consensus about which exact thresholds of pollen concentrations provoke the allergic symptoms. The aim of this study was to review the relevant scientific information on the relationship between grass pollen concentrations and the occurrence of emergency department (ED) visits, hospital admissions (HA), drug consumption and allergic symptoms. Literature search was conducted by experts’ consultation and snowball strategy. Studies meeting the criteria for inclusion were assessed regarding their risk of bias (RoB). A high RoB resulted in exclusion of the study from data synthesis. Extensive data were extracted and qualitatively compared. The review is registered in PROSPERO. 32 Studies were eligible while 18 showed a low RoB and were qualitatively synthesised. Emergency department visits and hospital admissions were mostly investigated. Threshold values of 10 grains/m3 and 12 grains/m3 were reported for ED visits and HA. Evidence exists that an increase of 10 grains/m3 of air leads to a significant increase in adverse health outcomes. Especially at a three-day lag, adverse health effects were shown. Variations in exposure and outcome measurement make the definition of pollen thresholds difficult. As a consequence, no defined pollen threshold values could be identified. Studies with uniform exposure measures and statistical methods are necessary to gain a better understanding of the impact of grass pollen on human health. Determining personal thresholds could be beneficial for affected people.

Objective: The present study’s purpose is to evaluate the economic context in which the Brazilian public health system, the only universal public health system with more than 200 million users, stands out. This evaluation will be made through the lens of the execution of gestational health care services in a city of approximately 500 thousand inhabitants in southern Brazil. The care costs of patients with gestational diabetes mellitus (GDM) will be compared to those of patients without GDM, analyzing the different economic valuation methods. And lastly, there was an intent to explore the generated costs in the context of economic valuation applied to health to comprehend better the complexity of the union of the financial and health areas to optimize the services offered. Methods: For the economic context in health, an analysis of health investments was performed through the Transparency Portal. The costs involved in preventing GDM were raised by the Sistema Único de Saúde (SUS) table of procedures performed ordinarily in low-risk pregnancies. The expenses involved in DMG patients were increased at the High-Risk Pregnancy and Fetal Medicine Clinic of DMG patients. Results: Preventing GDM is more cost-effective, cost-minimizing, and cost-useful than treating patients diagnosed with GDM. Conclusion: The result is an extremely interesting costopportunity, given the economic context in which it is presented

Objectives Giant cell arteritis (GCA) may lead to vision loss. To what extent tocilizumab (TCZ) is able to prevent vision loss is unknown. The aim was to analyze the occurrence of vision loss in a large GCA cohort treated with TCZ. Methods In this observational monocentric study, GCA patients treated with TCZ between the years 2010 and 2018 were studied. Demographic, clinical, and laboratory data were analyzed. Results A total of 186 patients were included (62% female); 109 (59%) fulfilled the American College of Rheumatology (ACR) criteria, in 123 (66%) patients, large vessel vasculitis was diagnosed by magnetic resonance-angiography (MRA). Cumulative duration of TCZ treatment was 224 years, median treatment duration was 11.1 (IQR 5.6–17.9) months. Glucocorticoids (GC) were tapered over a median of 5.8 (IQR 3.0–8.5) months. At baseline, visual symptoms were present in 70 (38%) and vision loss in 21 (11%) patients. Patients with vision loss at baseline were older (p = 0.032), had a lower C-reactive protein (p = 0.002), and showed a negative association with MRA of the aorta (p = 0.006). Two patients (1.1%) developed vision loss, both at the initiation of TCZ treatment. Conclusion Our data show a very low incidence of vision loss in TCZ-treated patient. The two cases of AION occurred at the initiation of therapy, they support the hypothesis that advanced, and established structural changes of arteries are key factors for this accident. Whether a shorter duration of concomitant GC treatment is risky regarding vision loss needs to be studied.

Background The ultra-high risk (UHR) paradigm allows early contact with patients developing acute psychosis and the study of treatment effects on the underlying pathology. Methods 29 patients with first acute psychosis according to CAARMS criteria (transition patients, TP) (T0) and thereof 22 patients after two-year follow-up (mean 788 d) (T1) underwent 1H-/31P-MR spectroscopy of the prefrontal (DLPFC) and anterior midcingulate (aMCC) cortices and the thalamus. N-acetylaspartate (NAA), glutamate (Glu, Glx), energy (PCr, ATP) and phospholipid metabolites (PME, PDE) were compared to 27 healthy controls by ANCOVA and correlated with patients' symptom ratings (BPRS-E, SCL-90R). For longitudinal analysis, linear mixed model (LMM) and ANCOVA for repeated measures were used. Results DLPFC : In patients, NAA and PME were decreased bilaterally and Glu on the left side at T0. Left-sided Glu and NAA (trend) and bilateral Glx increased during follow-up. Thalamus : In TP, bilateral NAA, left-sided Glu and right-sided Glx were decreased at T0; bilateral NAA and left-sided Glx increased during follow-up. aMCC : In TP, bilateral NAA, right-sided Glu, and bilateral PME and PDE were decreased, while left-sided PCr was increased at T0. No changes were observed during follow-up. Conclusion Regardless of the long-term diagnosis, the psychotic state of illness includes disturbed neuronal function in the DLPFC, thalamus and aMCC. Treatment-as-usual (TAU), including antipsychotic/antidepressant medication and supportive psychotherapy, had an effect on the thalamo-frontal area but not or less pronounced on the neurometabolic deficits of the aMCC.

Electronic nicotine delivery systems (often known as e-cigarettes) are a novel tobacco product with growing popularity, particularly among younger demographics. The implications for public health are twofold, as these products may represent a novel source of tobacco-associated disease but may also provide a harm reduction strategy for current tobacco users. There is increasing recognition that e-cigarettes impact vascular function across multiple organ systems. Herein, we provide a comparison of evidence regarding the role of e-cigarettes versus combustible tobacco in vascular disease and implications for blood-brain barrier dysfunction and cognitive decline. Multiple non-nicotinic components of tobacco smoke have been identified in e-cigarette aerosol, and their involvement in vascular disease is discussed. In addition, nicotine and nicotinic signaling may modulate peripheral immune and endothelial cell populations in a highly context-dependent manner. Direct preclinical evidence for electronic nicotine delivery system–associated neurovascular impairment is provided, and a model is proposed in which non-nicotinic elements exert a proinflammatory effect that is functionally antagonized by the presence of nicotine.

Due to the ongoing slowdown of Dennard scaling, heterogeneous hardware architectures are inevitable to meet the increasing demand for energy efficient systems. However, one of the most important aspects that shape today’s computing landscape is the wide availability of software that can run on any system. Current applications that use accelerators, in contrast, are often especially tailored to a specific hardware setup and therefore not universally deployable. This is particularly true for reconfigurable logic as their internal structure requires the circuits and their integration to be designed as well. This makes them inherently difficult to use and therefore less accessible for a general audience. Nevertheless, their balance of flexibility and efficiency puts reconfigurable accelerators in a unique position between CPUs, GPUs, and ASICs. Therefore, one of the main challenges of future heterogeneous systems is to foster collaborative computing between these vastly different components while still being simple to use. Previous approaches mostly focused on subproblems instead of a holistic view of hardware and software in the context of commonplace usability. This paper analyzes the general demands on a reconfigurable platform and derives their requirements regarding accessibility and security. Hereby, we investigate several key features like hardware virtualization, system shared virtual memory, and the use of wide-spread programming paradigms. Then, we systematically build up such a platform based on the established ROCm GPU framework and its internal HSA standard. This new common HERA methodology is finally also demonstrated as a prototype.

The increasing availability of free-access satellite data represents a relevant opportunity for the analysis and assessment of natural hazards. The systematic acquisition of spaceborne imagery allows for monitoring areas prone to geohydrological disasters, providing relevant information for risk evaluation and management. In cases of major landslide events, for example, spaceborne radar data can provide an effective solution for the detection of slope failures, even in cases with persistent cloud cover. The information about the extension and location of the landslide-affected areas may support decision-making processes during emergency responses. In this paper, we present an automatic procedure based on Sentinel-1 Synthetic Aperture Radar (SAR) images, aimed at facilitating the detection of landslides over wide areas. Specifically, the procedure evaluates changes of radar backscattered signals associated with land cover modifications that may be also caused by mass movements. After a one-time calibration of some parameters, the processing chain is able to automatically execute the download and preprocessing of images, the detection of SAR amplitude changes, and the identification of areas potentially affected by landslides, which are then displayed in a georeferenced map. This map should help decision makers and emergency managers to organize field investigations. The process of automatization is implemented with specific scripts running on a GNU/Linux operating system and exploiting modules of open-source software. We tested the processing chain, in back analysis, on an area of about 3000 km2 in central Papua New Guinea that was struck by a severe seismic sequence in February–March 2018. In the area, we simulated a periodic survey of about 7 months, from 12 November 2017 to 6 June 2018, downloading 36 Sentinel-1 images and performing 17 change detection analyses automatically. The procedure resulted in statistical and graphical evidence of widespread land cover changes that occurred just after the most severe seismic events. Most of the detected changes can be interpreted as mass movements triggered by the seismic shaking.

Stroke is a debilitating disease, accounting for almost 20% of all hospital visits, and 8% of all fatalities in the United States in 2017. Following an ischemic attack, inflammatory processes originating from endothelial cells within the brain microvasculature can induce many toxic effects into the impacted area, from both sides of the blood brain barrier (BBB). In addition to increased BBB permeability, impacted brain microvascular endothelial cells can recruit macrophages and other immune cells from the periphery and can also trigger the activation of microglia and astrocytes within the brain. We have identified a key microRNA, let-7g, which levels were drastically diminished as consequence of transient middle cerebral artery occlusion (tMCAO) in vivo and oxygen-glucose deprivation (OGD) in vitro ischemia/reperfusion conditions, respectively. We have observed that let-7g* liposome-based delivery is capable of attenuating inflammation after stroke, reducing BBB permeability, limiting brain infiltration by CD3+CD4+ T-cells and Ly6G+ neutrophils, lessening microglia activation and neuronal death. These effects consequently improved clinical outcomes, shown by mitigating post-stroke gait asymmetry and extremity motor function. Due to the role of the endothelium in propagating the effects of stroke and other inflammation, treatments which can reduce endothelial inflammation and limit ischemic damage and improving recovery after a stroke are required. Our findings demonstrate a critical link between the CNS inflammation and the immune system reaction and lay important groundwork for future stroke pharmacotherapies.

Background Outcome prediction after out-of-hospital cardiac arrest (OHCA) may lead to withdrawal of life-sustaining therapy if the prognosis is perceived negative. Single use of uncertain prognostic tools may lead to self-fulfilling prophecies and death. We evaluated prognostic tests, blinded to clinicians and without calls for hasty outcome prediction, in a prospective study. Methods Comatose, sedated TTM 33-treated OHCA patients of all causes were included. Clinical-neurological/-neurophysiological/-biochemical predictors were registered. Patients were dichotomized into good/poor outcome using cerebral performance category (CPC) six months and > four years post-arrest. Prognostic tools were evaluated using false positive rates (FPR). Results We included 259 patients; 49 % and 42 % had good outcome (CPC 1–2) after median six months and 5.1 years. Unwitnessed arrest, non-shockable rhythms, and no-bystander-CPR predicted poor outcome with FPR (CI) 0.05 (0.02–0.10), 0.13 (0.08–0.21), and 0.13 (0.07–0.20), respectively. Time to awakening was median 6 (0–25) days in good outcome patients. Among patients alive with sedation withdrawal >72 h, 49 % were unconscious, of whom 32 % still obtained good outcome. Only absence of pupillary light reflexes (PLR) -and N20-responses in somato-sensory evoked potentials (SSEP), as well as increased neuron-specific enolase (NSE) later than 24 h to >80 μg/L, had FPR 0. Malignant EEG (burst suppression/epileptic activity/flat) differentiated poor/good outcome with FPR 0.05 (0.01–0.15). Conclusion Time to awakening was over six days in good outcome patients. Most clinical parameters had too high FPRs for prognostication, except for absent PLR and SSEP-responses >72 h after sedation withdrawal, and increased NSE later than 24 h to >80 μg/L.

In this paper, we present a novel method for utilising wearable devices with Convolutional Neural Networks (CNN) trained on acoustic and accelerometer signals in smart manufacturing environments in order to provide real-time quality inspection during manual operations. We show through our framework how recorded or streamed sound and accelerometer data gathered from a wrist-attached device can classify certain user actions as successful or unsuccessful. The classification is designed with a Deep CNN model trained on Mel-frequency Cepstral Coefficients (MFCC) from the acoustic input signals. The wearable device provides feedback on three different modalities: audio, visual and haptic; thus ensuring the worker’s awareness at all time. We validate our findings through deployments of the complete AI-enabled device in production facilities of Mercedes-Benz AG. From the conducted experiments it is concluded that the use of acoustic and accelerometer data is valuable to train a classifier with the purpose of action examination during industrial assembly operations, and provides an intuitive interface for ensuring continued and improved quality inspection.

Customer orientation is crucial for business success, especially in innovation and product development processes. Considering its limited resources, an organisation must recognise which product attributes generate value for customers. A key to successful product development is the identification of customer needs and expectations. One of the most popular approaches to discover the characteristics of customer needs is Kano's two-dimensional model. It considers customer satisfaction as a multi-factorial construct implying that certain quality attributes are more important in ensuring customer satisfaction than others. Recently, various regression approaches have been developed to simplify the process of data collection and allow a deeper quantitative understanding of the asymmetric and nonlinear relationships between attribute performance and customer satisfaction. However, the usefulness of these approaches is currently under debate due to the lack of validity testing. This study assesses different regression approaches theoretically and empirically. Moreover, a regression approach based on the elastic net regression and the squared multiple correlation analysis is proposed. This newly developed regression approach outperforms the other regression approaches in terms of classification performance. This paper provides guidance to scholars and managers in selecting the appropriate approach to analyse customer quality requirements and satisfaction.

Objectives To characterize the effect of ultra-short glucocorticoids followed by Tocilizumab monotherapy on the intima-media thickness (IMT) in GCA. Methods Eighteen GCA patients received 500 mg for 3 consecutive days (total of 1500mg) i.v. methylprednisolone on days 0–2, followed by i.v. Tocilizumab (8 mg/kg) on day 3 and thereafter weekly s.c. Tocilizumab injections (162 mg) over 52 weeks. US of temporal (TAs), axillary (AAs) and subclavian (SAs) arteries was performed at baseline, on days 2–3, and at weeks 4, 8, 12, 24 and 52. The largest IMT of all segments and IMT at landmarks of AA/SA were recorded. IMT was scaled by mean normal values and averaged. Each segment was classified according to diagnostic cut-offs. Results Of the 18 GCA patients, 16 patients had TA and 6 had extracranial large artery involvement. The IMT showed a sharp decline on day 2/3 in the TAs and AAs/SAs. In TAs, this was followed by an increase to baseline levels at week 4 and a subsequent slow decrease, which was paralleled by decreasing symptoms and achievement of clinical remission. The AAs/SAs showed a new signal of vasculitis at week 4 in three patients, with an IMT increase up to week 8. Conclusion Glucocorticoid pulse therapy induced a transient decrease of the IMT in TAs and AAs/SAs. Tocilizumab monotherapy resulted in a slow and steady decrease in IMT of the TAs and a smaller and delayed effect on the AAs/SAs. The data strongly support a remission-inducing effect of Tocilizumab and argue the case for US having an important role in monitoring disease activity in GCA. Trial registration ClinicalTrials.gov, www.clinicaltrials.gov, NCT03745586.

BACKGROUND Allergic diseases pose a health problem worldwide. Pollen are widespread aeroallergens which can cause symptoms like shortness of breath, cough, itchy eyes, or rhinitis. Apart from preventive measures and pharmacological treatment, also non-pharmacological interventions have been suggested to reduce symptoms. The objective of this work was to review studies investigating the effectiveness of non-pharmacologic interventions to reduce allergic symptoms. METHODS PubMed, EMBASE, and CENTRAL were systematically reviewed in July 2018 and April 2020. Several authors worked on the screening of titles, abstracts, and full texts. One author for each literature search performed the data extraction and the risk of bias assessment. Studies were included if they met the inclusion criteria defined by the PECOs. Studies which investigating the effect of non-pharmacologic interventions on patients with allergic rhinitis were included. RESULTS Twenty-nine studies investigating eleven types of non-pharmacologic interventions to avoid and reduce allergic symptoms due to pollen exposure were included in this review. Out of all studies, seven studies addressed nasal rinsing and 22 included acupuncture, air filtering, artisanal tears, individual allergen avoidance advice, various nasal applications, self-hypnosis, rhinophototherapy, and wraparound sunglasses. CONCLUSION Most studies had a high risk of bias and small sample sizes. There were only a few high-quality studies that give hints about the effectiveness of non-pharmacological interventions. For future research, more high-quality studies are required to confirm the effectiveness of simple, safe, and cost-effective interventions.

BackgroundArthroscopic surgery for femoroacetabular impingement syndrome (FAI) is known to lead to self-reported symptom improvement. In the context of surgical interventions with known contextual effects and no true sham comparator trials, it is important to ascertain outcomes that are less susceptible to placebo effects. The primary aim of this trial was to determine if study participants with FAI who have hip arthroscopy demonstrate greater improvements in delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) index between baseline and 12 months, compared to participants who undergo physiotherapist-led management.MethodsMulti-centre, pragmatic, two-arm superiority randomised controlled trial comparing physiotherapist-led management to hip arthroscopy for FAI. FAI participants were recruited from participating orthopaedic surgeons clinics, and randomly allocated to receive either physiotherapist-led conservative care or surgery. The surgical intervention was arthroscopic FAI surgery. The physiotherapist-led conservative management was an individualised physiotherapy program, named Personalised Hip Therapy (PHT). The primary outcome measure was change in dGEMRIC score between baseline and 12 months. Secondary outcomes included a range of patient-reported outcomes and structural measures relevant to FAI pathoanatomy and hip osteoarthritis development. Interventions were compared by intention-to-treat analysis.ResultsNinety-nine participants were recruited, of mean age 33 years and 58% male. Primary outcome data were available for 53 participants (27 in surgical group, 26 in PHT). The adjusted group difference in change at 12 months in dGEMRIC was -59 ms (95%CI − 137.9 to - 19.6) (p = 0.14) favouring PHT. Hip-related quality of life (iHOT-33) showed improvements in both groups with the adjusted between-group difference at 12 months showing a statistically and clinically important improvement in arthroscopy of 14 units (95% CI 5.6 to 23.9) (p = 0.003).ConclusionThe primary outcome of dGEMRIC showed no statistically significant difference between PHT and arthroscopic hip surgery at 12 months of follow-up. Patients treated with surgery reported greater benefits in symptoms at 12 months compared to PHT, but these benefits are not explained by better hip cartilage metabolism.Trial registration detailsAustralia New Zealand Clinical Trials Registry reference:ACTRN12615001177549. Trial registered 2/11/2015.

Most neurological diseases, including stroke, lead to some degree of blood–brain barrier (BBB) dysfunction. A significant portion of BBB injury is caused by inflammation, due to pro-inflammatory factors produced in the brain, and by leukocyte engagement of the brain endothelium. Recently, microRNAs (miRNAs) have appeared as major regulators of inflammation-induced changes to gene expression in the microvascular endothelial cells (BMVEC) that comprise the BBB. However, miRNAs’ role during cerebral ischemia/reperfusion is still underexplored. Endothelial levels of miR-98 were significantly altered following ischemia/reperfusion insults, both in vivo and in vitro, transient middle cerebral artery occlusion (tMCAO), and oxygen–glucose deprivation (OGD), respectively. Overexpression of miR-98 reduced the mouse’s infarct size after tMCAO. Further, miR-98 lessened infiltration of proinflammatory Ly6CHI leukocytes into the brain following stroke and diminished the prevalence of M1 (activated) microglia within the impacted area. miR-98 attenuated BBB permeability, as demonstrated by changes to fluorescently-labeled dextran penetration in vivo and improved transendothelial electrical resistance (TEER) in vitro. Treatment with miR-98 improved significantly the locomotor impairment. Our study provides identification and functional assessment of miRNAs in brain endothelium and lays the groundwork for improving therapeutic approaches for patients suffering from ischemic attacks.

Magnetic resonance imaging (MRI) of the lung remains challenging due to the low tissue density, susceptibility artefacts, unfavourable relaxation times and motion. Previously, we demonstrated in vivo that one-lung flooding (OLF) with saline is a viable and safe approach. This study investigates the feasibility of OLF in an MRI environment and evaluates the flooding process on MR images. OLF of the left lung was performed on five animals using a porcine model. Before, during and after OLF, standard T2w and T1w spin-echo (SE) and gradient-echo (GRE) sequences were applied at 3 T. The procedure was successfully performed in all animals. On T1w MRI, the flooded lung appeared homogenous and isointense with muscle tissue. On T2w images, vascular structures were highly hypointense, while the bronchi were clearly demarcated with hypointense wall and hyperintense lumen. The anatomical demarcation of the flooded lung from the surrounding organs was superior on T2w images. No outflow effects were seen, and no respiration triggering was required. OLF can be safely performed in an MR scanner with highly detailed visualization of the pulmonary structures on T2w images. The method provides new approaches to MRI-based image-guided pulmonary interventions using the presented experimental model.

Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations of the phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Autosomal recessive p47phox-deficient CGD (p47phox CGD) is the second most frequent form of the disease in western countries, and more than 94% of patients have a disease-causing dinucleotide deletion (ΔGT) in the neutrophil cytosolic factor 1 (NCF1) gene. The ΔGT mutation is most likely transferred onto the NCF1 from one of its two pseudogenes co-localized on the same chromosome. The presence of NCF1 pseudogenes in healthy individuals makes the genetic diagnostics of ΔGT p47phox CGD challenging, as it requires the distinction between ΔGT in NCF1 and in the two pseudogenes. We have developed a diagnostic tool for the identification of p47phox CGD based on PCR co-amplification of NCF1 and its pseudogenes, followed by band intensity quantification of restriction fragment length polymorphism products. The single-day, reliable p47phox CGD diagnostics allow for robust discrimination of homozygous ΔGT p47phox CGD patients from heterozygous carriers and healthy individuals, as well as for monitoring gene therapy efficacy. Keywords: chronic granulomatous disease, CGD, NCF1, NCF1B, NCF1C, pseudogene, genetic diagnostics

Assessment of bone graft material efficacy is difficult in humans, since invasive methods like staged CT scans or biopsies are ethically unjustifiable. Therefore, we developed a novel large animal model for the verification of a potential transformation of synthetic bone graft substitutes into vital bone. The model combines multiple imaging methods with corresponding histology in standardized critical sized cancellous bone defect. Cylindrical bone voids (10 ml) were created in the medial femoral condyles of both hind legs (first surgery at right hind leg, second surgery 3 months later at left hind leg) in three merino-wool sheep and either (i) left empty, filled with (ii) cancellous allograft bone or (iii) a synthetic, gentamicin eluting bone graft substitute. All samples were analysed with radiographs, MRI, μCT, DEXA and histology after sacrifice at 6 months. Unfilled defects only showed ingrowth of fibrous tissue, whereas good integration of the cancellous graft was seen in the allograft group. The bone graft substitute showed centripetal biodegradation and new trabecular bone formation in the periphery of the void as early as 3 months. μCT gave excellent insight into the structural changes within the defects, particularly progressive allograft incorporation and the bone graft substitute biodegradation process. MRI completed the picture by clearly visualizing soft tissue ingrowth into unfilled bone voids and presence of fluid collections. Histology was essential for verification of trabecular bone and osteoid formation. Conventional radiographs and DEXA could not differentiate details of the ongoing transformation process. This model appears well suited for detailed in vivo and ex vivo evaluation of bone graft substitute behaviour within large bone defects.

To further extent our understanding of aquatic vision, we introduce a complete optical model of a goldfish eye, which comprises all important optical parameters for the first time. Especially a spherical gradient index structure for the crystalline lens was included, thus allowing a detailed analysis of image quality, regarding spot size, and wavelength dependent aberration. The simulation results show, that our realistic eye model generates a sufficient image quality, with a spot radius of 4.9 mm which is below the inter cone distance of 5.5 mm. Furthermore, we optically simulate potential mechanical processes of accommodation and compare the results with contradictory findings of previous experimental studies. The quantitative simulation of the accommodation capacity shows that the depth of field is strongly dependent on the resting position and becomes significantly smaller when shorter resting positions are assumed. That means, to enable an extended depth perception with high acuity for the goldfish an adaptive, lens shifting mechanism would be required. In addition, our model allows a clear prediction of the expected axial lens-shift, which is necessary to ensure a sufficient resolution over a large object range.

The algorithm for a collision-free trajectory generation is proposed and its implementation in on-line supervisory control of FMS is described. The algorithm makes the use of a collision detection engine applied in computer graphics and the change in a manipulator kinematics related to the virtual model of the FMS and exact position of the collision point. Virtual model surfaces are used as contact sensors to prevent objects from colliding. Any point of the robot’ s surface can be controlled and its trajectory planned. The exact 3D model is not a prerequisite for successful collision avoidance ; however, with a better model more precise collision avoidance is possible. The algorithm is also very adaptable when planning trajectories for manipulators with different end-effectors or manipulators carrying various objects.

Software bugs cost time, money, and lives. They drive software research and development efforts, and are central to modern software engineering. Yet we lack a clear and general definition of what bugs are. Some bugs are defects, clearly defined as failures to meet some requirement or specification. However, there are many forms of undesirable program behaviour that are completely compatible with a typical program's specification. In this paper, we argue that the lack of a criterion for identifying non-defect bugs is hampering the development of tools that find and fix bugs. We propose such a criterion, based on the idea of wasted effort, discuss how bugs that meet our definition of software ticks can complement defects, and sketch how our definition can help guide future work on software tools.