Search

From dynamic rupture simulations, we reveal under which conditions a rupture in the Groningen gas field stops along fault dip or along fault strike after it starts on a fault in the reservoir. The simulations focus on the capabilities of fault plane irregularities to arrest ruptures. Such irregularities can be recognised in sandstone outcrops. Fault planes in the Groningen field, extracted from the 3D seismic data by seismic attribute extraction methods, show similar irregularities. A detailed surface of a major fault plane in the field indicates that steps and jogs of tenths of metres are possible. Although these irregularities are close to seismic resolution and could be partially artificial, we investigated their effect on rupture arrest. For typical current stresses in the Groningen field, jogs and steps of this length scale are found to be remarkably effective to stop ruptures in the reservoir. Also, a significant increase in the fault dip along fault strike can stop these ruptures but a kink in the fault under a constant fault dip not. Including non-planar fault features and pressure diffusion in the Carboniferous, the simulations in this paper follow trends of previous simulations in the literature using 2D planar faults. In particular, the horizontal stress in this formation and the strength of the Carboniferous fault zone are important for rupture propagation. If the fault would have been reactivated in the Neogene or Quaternary and poorly healed in clay-rich parts, rupture propagation into the Carboniferous can only be prevented by jogs of sufficient size and lateral continuity under the present estimate of the horizontal field stress. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to determine the prevalence of ultrasound-detected tendon abnormalities in healthy subjects (HS) across the age range., Methods: Adult HS (age 18-80 years) were recruited in 23 international Outcome Measures in Rheumatology ultrasound centres and were clinically assessed to exclude inflammatory diseases or overt osteoarthritis before undergoing a bilateral ultrasound examination of digit flexors (DFs) 1-5 and extensor carpi ulnaris (ECU) tendons to detect the presence of tenosynovial hypertrophy (TSH), tenosynovial power Doppler (TPD) and tenosynovial effusion (TEF), usually considered ultrasound signs of inflammatory diseases. A comparison cohort of patients with rheumatoid arthritis (RA) was taken from the Birmingham Early Arthritis early arthritis inception cohort., Results: 939 HS and 144 patients with RA were included. The majority of HS (85%) had grade 0 for TSH, TPD and TEF in all DF and ECU tendons examined. There was a statistically significant difference in the proportion of TSH and TPD involvement between HS and subjects with RA (HS vs RA p<0.001). In HS, there was no difference in the presence of ultrasound abnormalities between age groups., Conclusions: Ultrasound-detected TSH and TPD abnormalities are rare in HS and can be regarded as markers of active inflammatory disease, especially in newly presenting RA., Competing Interests: Competing interests: There are no declared competing interests from authors except the following: CC declared grants from NIHR Versus Arthritis, Lilly sponsored EULAR conference travel, Modern Biosciences payment as DSM committee member, Roche consultancy fee and Novartis sponsored writing of one medical paper. KI declared a Mitsubishi-Tanabe research grant for RA; Abbvie, Eli Lilly, Mitsubishi-Tanabe, Bristol-Myers-Squib and Novartis speaker’s fees; and participation on a DSM board for Abbvie, Eli Lilly and Mitsubishi-Tanabe. RK declared support from Abbvie, Roche, Novartis and UCB with payments for travel to meetings/lectures, presentations, speakers’ bureaus, manuscript writing/educational events., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: An efficient diagnostic pathway and early stage diagnosis for cancer patients is widely pursued. This study aims to chart the duration of the diagnostic pathway for patients with symptomatic oesophageal and gastric cancer, to identify factors associated with long duration and to assess the association of duration with tumour stage at diagnosis., Methods: This was a retrospective cohort study, using electronic health records of six routine primary care databases covering about 640,000 patients, partly linked to the Netherlands Cancer Registry. Symptomatic patients with oesophageal and gastric cancer (2010-2015) that presented in primary care were included. Duration of four diagnostic intervals was determined: patient interval; first symptoms to primary care consultation, primary care interval; consultation to referral, secondary care interval; referral to diagnosis, and the diagnostic interval; consultation to diagnosis. Characteristics associated with 'long duration' (≥P75 duration) were assessed using log-binomial regression. Median durations were stratified for tumour stages., Results: Among 312 symptomatic patients with upper gastrointestinal cancer, median durations were: patient interval: 29 days (interquartile interval 15-73), primary care interval: 12 days (interquartile interval 1-43), secondary care interval: 13 days (interquartile interval 6-29) and diagnostic interval: 31 days (11-74). Patient interval duration was comparable for patients with and without alarm symptoms. Absence of cancer-specific alarm symptoms was associated with 'long duration' of primary care interval and secondary care interval: relative risk 5.0 (95% confidence interval 2.7-9.1) and 2.1 (95% confidence interval 1.3-3.7), respectively. Median diagnostic interval duration for local stage disease was 51 days (interquartile interval 13-135) versus 27 days (interquartile interval 11-71) for advanced stage ( p  = 0.07)., Conclusion: In the diagnostic pathway of upper gastrointestinal cancers, the longest interval is the patient interval. Reducing time to diagnosis may be achieved by improving patients' awareness of alarm symptoms and by diagnostic strategies which better identify cancer patients despite low suspicion.

Broccoli is rich in glucosinolates, which can be converted upon chewing and processing into Aryl hydrocarbon Receptor (AhR) ligands. Activation of AhR plays an important role in overall gut homeostasis but the role of broccoli processing on the generation of AhR ligands is still largely unknown. In this study, the effects of temperature, cooking method (steaming versus boiling), gastric pH and further digestion of broccoli on AhR activation were investigated in vitro and in ileostomy subjects. For the in vitro study, raw, steamed (t = 3 min and t = 6 min) and boiled (t = 3 min and t = 6 min) broccoli were digested in vitro with different gastric pH. In the in vivo ileostomy study, 8 subjects received a broccoli soup or a broccoli soup plus an exogenous myrosinase source. AhR activation was measured in both in vitro and in vivo samples by using HepG2-Lucia™ AhR reporter cells. Cooking broccoli reduced the AhR activation measured after gastric digestion in vitro, but no effect of gastric pH was found. Indole AhR ligands were not detected or detected at very low levels both after intestinal in vitro digestion and in the ileostomy patient samples, which resulted in no AhR activation. This suggests that the evaluation of the relevance of glucosinolates for AhR modulation in the gut cannot prescind from the way broccoli is processed, and that broccoli consumption does not necessarily produce substantial amounts of AhR ligands in the large intestine.

Objectives: Low-dose radiation therapy (LDRT) is widely used as treatment for osteoarthritis (OA) in some countries, while relatively unknown in others. Systematic literature review displayed a lack of high-level evidence for beneficial effects in clinical practice. The aim was to assess the efficacy of LDRT on symptoms and inflammation in hand OA patients in a randomised, blinded, sham-controlled trial, using validated outcome measures., Design: Hand OA patients, ≥50 years, with pain ≥5 (scale 0-10) and non-responding to conservative therapy were included and randomised 1:1 to receive LDRT (6 × 1 Gy in 2 weeks) or sham (6 × 0 Gy in 2 weeks). Primary outcome was the proportion of OMERACT-OARSI responders, 3 months post-intervention. Secondary outcomes were pain and functioning (Australian/Canadian Hand Osteoarthritis Index; AUSCAN), quality of life (Short Form Health Survey; SF36) and inflammatory outcomes: erythrocyte sedimentation rate and C-reactive protein serum levels, effusion, synovial thickening and power Doppler signal on ultrasound (range 0-3)., Results: Fifty-six patients were included. After 3 months, no significant difference in responders was observed between groups (LDRT: 8 (29%); sham: 10 (36%); difference -7% (95%CI -31-17%)). Also, differences in clinical and inflammatory outcomes between groups were small and not significant., Conclusions: We were unable to demonstrate a substantial beneficial effect of LDRT on symptoms and inflammation in patients with hand OA, compared to sham treatment. Although a small effect can not be excluded, a treatment effect exceeding 20% is very unlikely, given the confidence interval. Therefore, in the absence of other high-level evidence, we advise against the use LDRT as treatment for patients with hand OA., Clinical Trial Registration Number: NTR4574 (Dutch Trial Register)., (Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: Osteoarthritis in thumb base joints (first carpometacarpal (CMC-1), scaphotrapeziotrapezoid (STT)) is prevalent and disabling, yet focussed studies are scarce. Our aim was to investigate associations between ultrasonographic and magnetic resonance imaging (MRI) inflammatory features, radiographic osteophytes, and thumb base pain in hand osteoarthritis patients., Design: Cross-sectional analyses were performed in cohorts with MRI (n = 202) and ultrasound measurements (n = 87). Pain upon thumb base palpation was assessed. Radiographs were scored for CMC-1/STT osteophytes. Synovial thickening, effusion and power Doppler signal in CMC-1 joints were assessed with ultrasound. MRIs were scored for synovitis and bone marrow lesions (BMLs) in CMC-1 and STT joints using OMERACT-TOMS. Associations between ultrasound/MRI features, osteophytes, and thumb base pain were assessed. Interaction between MRI features and osteophytes was explored., Results: In 289 patients (mean age 60.2, 83% women) 139/376 thumb bases were painful. Osteophyte presence was associated with pain (MRI cohort: odds ratio (OR) 5.1 (2.7-9.8)). Ultrasound features were present in 25-33% of CMC-1 joints, though no associations were seen with pain. MRI-synovitis and BMLs grade ≥2 were scored in 25% and 43% of thumb bases, and positively associated with pain (OR 3.6 (95% CI 1.7-7.6) and 3.0 (1.6-5.5)). Associations attenuated after adjustment for osteophyte presence. Combined presence of osteophytes and MRI-synovitis had an additive effect., Conclusions: Ultrasonographic and MRI inflammatory features were often present in the thumb base. Osteophytes were more strongly associated with thumb base pain than inflammatory features, in contrast to findings in finger OA studies, supporting thumb base osteoarthritis as a distinct phenotype., (Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objectives: Evidence-based medicine (EBM) is an important element in the general practice (GP) specialty training. Studies show that integrating EBM training into clinical practice brings larger benefits than stand-alone modules. However, these studies have neither been performed in GP nor assessed EBM behaviour of former trainees in daily clinical practice., Setting: GP specialty training in the Netherlands., Participants: All 82 third year GP trainees who started their final third year in 2011 were approached for inclusion, of whom 79 (96%) participated: 39 in the intervention group and 40 in the control group., Intervention: Integrated EBM training, in which EBM is embedded closely within the clinical context by joint assignments for the trainee and supervisor in daily practice, and teaching sessions based on dilemmas from actual patient consultations., Comparison: Stand-alone EBM training at the institute only., Primary and Secondary Outcomes: Our primary outcome was EBM behaviour, assessed by measuring guideline adherence (incorporating rational, motivated deviation) and information-seeking behaviour. Our secondary outcomes were EBM attitude and EBM knowledge. Data were acquired using logbooks and questionnaires, respectively. Analyses were performed using mixed models., Results: Logbook data were available from 76 (96%) of the participating trainees at baseline (7614 consultations), 60 (76%) at the end of the third year (T1, 4973 consultations) and 53 (67%) 1 year after graduation (T2, 3307 consultations). We found no significant differences in outcomes between the 2 groups, with relative risks for guideline adherence varying between 0.96 and 0.99 (95% CI 0.86 to 1.11) at T1, and 0.99 and 1.10 (95% CI 0.92 to 1.25) at T2, and for information-seeking behaviour between 0.97 and 1.16 (95% CI 0.70 to 1.91) and 0.90 and 1.10 (95% CI 0.70 to 1.32), respectively., Conclusions: Integrated EBM training compared with stand-alone EBM training does not improve EBM behaviour, attitude or knowledge of (future) GPs., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: To assess sensitivity-to-change and validity of longitudinal quantitative semi-automatic joint space width (JSW) measurements and to compare this method with semi-quantitative joint space narrowing (JSN) scoring in hand osteoarthritis (OA) patients., Design: Baseline and 2-year follow-up radiographs of 56 hand OA patients (mean age 62 years, 86% women) were used. JSN was scored 0-3 using the Osteoarthritis Research Society International atlas and JSW was quantified in millimetres (mm) in the second to fifth distal, proximal interphalangeal and metacarpal joints (DIPJs, PIPJs, MCPJs). Sensitivity-to-change was evaluated by calculating Standardized Response Means (SRMs). Change in JSW or JSN above the Smallest Detectable Difference (SDD) defined progression on joint level. To assess construct validity, progressed joints were compared by cross-tabulation and by associating baseline ultrasound variables with progression (using generalized estimating equations, adjusting for age and sex)., Results: The JSW method detected statistically significant mean changes over 2.6 years (-0.027 mm (95%CI -0.01; -0.04), -0.024 mm (-0.01; -0.03), -0.021 mm (-0.01; -0.03) for DIPJs, PIPJs, MCPJs, respectively). Sensitivity-to-change was low (SRMs: 0.174, 0.168, 0.211, respectively). 9.1% (121/1336) of joints progressed in JSW, but 3.6% (48/1336) widened. 83 (6.2%) joints progressed in JSW only, 36 (2.7%) in JSN only and 37 (2.8%) in both methods. Progression in JSW showed weaker associations with baseline inflammatory ultrasound features than progression in JSN., Conclusions: Assessment of progression in hand OA defined by JSW measurements is possible, but performs less well than progression defined by JSN scoring. Therefore, the value of JSW measurements in hand OA clinical trials remains questionable., (Copyright © 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To study inflammatory ultrasound (US) features and pain over a 3-month period in hand osteoarthritis (HOA)., Design: In 25 consecutive HOA patients (mean age 60 years, 76% female), fulfilling the American College of Rheumatology (ACR) criteria, visual analogue scale (VAS) pain scores were collected at baseline and 3 months. In 750 [all first carpometacarpal (CMC), metacarpalphalangeal (MCP), proximal interphalangeal (PIP), distal interphalangeal (DIP) and first interphalangeal (IP)] joints, pain was assessed upon palpation and synovial thickening, effusion and power Doppler signal (PDS) were scored with standardized methods by US. Associations between inflammatory features and painful joints were analysed using generalized estimated equations to account for patient effects, adjusting for confounders, and presented as odds ratios (ORs) with 95% confidence intervals (95%CI)., Results: Inflammatory US features were seen in (nearly) all patients. The median number (range) of inflammatory joints per patient did not change over time: 9 (0-16) to 9 (2-18). In 18.7% of joints inflammatory features were present at both time points; in 20.5% inflammatory features occurred only at baseline or follow-up. Pain decreased over time: median VAS pain 49-39 mm; median number of painful joints 8-3. Synovial thickening, effusion and PDS were associated with pain upon palpation both at baseline and follow-up: OR 2.9 (1.4, 5.7), 2.7 (1.7, 4.3), 3.6 (2.1, 6.3) and 7.3 (3.2, 16.5), 3.3 (2.3, 4.7), 4.1 (2.1, 7.9). respectively., Conclusions: In HOA inflammatory US features are stable over time at patient level, but vary on joint level. Pain diminished after 3 months, while associations between painful joints and inflammation seem to increase, emphasizing the multifactorial aetiology of pain., (Copyright © 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Hypoxia, a growing worldwide problem, has been intermittently present in the modern Baltic Sea since its formation ca. 8000 cal. yr BP. However, both the spatial extent and intensity of hypoxia have increased with anthropogenic eutrophication due to nutrient inputs. Physical processes, which control stratification and the renewal of oxygen in bottom waters, are important constraints on the formation and maintenance of hypoxia. Climate controlled inflows of saline water from the North Sea through the Danish Straits is a critical controlling factor governing the spatial extent and duration of hypoxia. Hypoxia regulates the biogeochemical cycles of both phosphorus (P) and nitrogen (N) in the water column and sediments. Significant amounts of P are currently released from sediments, an order of magnitude larger than anthropogenic inputs. The Baltic Sea is unique for coastal marine ecosystems experiencing N losses in hypoxic waters below the halocline. Although benthic communities in the Baltic Sea are naturally constrained by salinity gradients, hypoxia has resulted in habitat loss over vast areas and the elimination of benthic fauna, and has severely disrupted benthic food webs. Nutrient load reductions are needed to reduce the extent, severity, and effects of hypoxia.

Plasma cells secreting antibodies directed to myelin components are present in CNS of MS patients and although the pathogenic role of such antibodies has yet to be established it is apparent from animal studies that anti-myelin antibodies are involved in myelin damage. In this study, we have investigated the effect of disease-promoting anti-myelin mAb on the phagocytosis of myelin by macrophages. Monoclonal antibodies directed to myelin basic protein (MBP)--clones 1, 12, 17, 22, 26, proteolipid protein (PLP), galactocerebroside (GalC) and myelin oligodendrocyte glycoprotein (MOG)--clones Y1, Y4, Y6, Y7, Y9, Y10, Y11 and Z12 were incubated with purified murine myelin labeled with DiI. The degree of phagocytosis of antibody-treated myelin by murine macrophages in vitro was determined using a quantitative flow cytometric assay. In comparison to untreated myelin pretreatment with myelin-specific mAb modified the degree of phagocytosis. The degree of opsonization of myelin was dependent on the isotype of antibody and the epitope recognized in addition to the ability of the mAb to fix complement. The greatest degree of opsonization of myelin was observed with the monoclonal antibody MOG Z12 that has previously been shown to enhance EAE and augment demyelination. These findings suggest a major role for anti-myelin antibodies, in particular antibodies directed to MOG, for the phagocytosis of myelin by macrophages in vitro. This may have relevance to the pathogenesis of myelin damage in vivo and provide a helpful tool for the classification of heterogeneous diseases such as MS.

The discovery of a naturally occurring missense point mutation in the gene encoding Fas-ligand (FasL/CD95L) in generalized lymphoproliferative disease (gld) mice has lead to the characterization of FasL as an important mediator of apoptosis. Further analysis of FasL function can be facilitated by crossing the gld mutation onto other mouse-strains, for example those carrying mutations affecting other molecules involved in apoptosis, or disease-prone genetic backgrounds. The success of this is dependent on a quick and reliable screening method. Here we report an allele-specific PCR for detection of the gld mutation. This approach permits the screening of back-crossed F1 progeny within one day, using whole blood samples as a source of genomic DNA. The technique is fast, robust, easily learnt, and unambiguous.