Evaluation of Polycyclic Aromatic Hydrocarbon Pollution From the HMS Royal Oak Shipwreck and Effects on Sediment Microbial Community Structure

Despite many shipwrecks containing oil there is a paucity of studies investigating their impact on surrounding environments. This study evaluates any potential effect the World War II shipwreck HMS Royal Oak is having on surrounding benthic sediments in Scapa Flow, Scotland. HMS (Her Majesty’s Ship) Royal Oak sank in 1939, subsequently leaked oil in the 1960s and 1990s, and is estimated to still hold 697 tonnes of fuel oil. In this study, sediments were analysed, over a 17.5 cm depth profile, along a 50–950 m cruciform transect away from the shipwreck. Analysis of polycyclic aromatic hydrocarbons (PAHs) revealed low concentrations (205.91 ± 50.15 μg kg‾¹ of dry sediment), which did not significantly differ with either distance from the shipwreck or sediment depth. PAH concentrations were well below the effects-range low (ERL) for the OSPAR (Oslo/Paris convention for the Protection of the Marine Environment of the North-East Atlantic) maritime area. The average Pyrogenic Index, in sediments around HMS Royal Oak, was 1.06 (±0.34), indicating PAHs were pyrogenic rather than petrogenic. Moreover, analysis of sediment microbiomes revealed no significant differences in bacterial community structure with distance from the shipwreck, with extremely low levels of obligate hydrocarbonoclastic bacteria (OHCB; 0.21% ± 0.54%). Both lines of evidence suggest that sampled sediments are not currently being impacted by petrogenic hydrocarbons and show no long-term impact by previous oil-spills from HMS Royal Oa

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Rehabilitation versus surgical reconstruction for non-acute anterior cruciate ligament injury (ACL SNNAP): a pragmatic randomised controlled trial

BackgroundAnterior cruciate ligament (ACL) rupture is a common debilitating injury that can cause instability of the knee. We aimed to investigate the best management strategy between reconstructive surgery and non-surgical treatment for patients with a non-acute ACL injury and persistent symptoms of instability.MethodsWe did a pragmatic, multicentre, superiority, randomised controlled trial in 29 secondary care National Health Service orthopaedic units in the UK. Patients with symptomatic knee problems (instability) consistent with an ACL injury were eligible. We excluded patients with meniscal pathology with characteristics that indicate immediate surgery. Patients were randomly assigned (1:1) by computer to either surgery (reconstruction) or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment), stratified by site and baseline Knee Injury and Osteoarthritis Outcome Score—4 domain version (KOOS4). This management design represented normal practice. The primary outcome was KOOS4 at 18 months after randomisation. The principal analyses were intention-to-treat based, with KOOS4 results analysed using linear regression. This trial is registered with ISRCTN, ISRCTN10110685, and ClinicalTrials.gov, NCT02980367.FindingsBetween Feb 1, 2017, and April 12, 2020, we recruited 316 patients. 156 (49%) participants were randomly assigned to the surgical reconstruction group and 160 (51%) to the rehabilitation group. Mean KOOS4 at 18 months was 73·0 (SD 18·3) in the surgical group and 64·6 (21·6) in the rehabilitation group. The adjusted mean difference was 7·9 (95% CI 2·5–13·2; p=0·0053) in favour of surgical management. 65 (41%) of 160 patients allocated to rehabilitation underwent subsequent surgery according to protocol within 18 months. 43 (28%) of 156 patients allocated to surgery did not receive their allocated treatment. We found no differences between groups in the proportion of intervention-related complications.InterpretationSurgical reconstruction as a management strategy for patients with non-acute ACL injury with persistent symptoms of instability was clinically superior and more cost-effective in comparison with rehabilitation management

Longitudinal changes in sputum and blood inflammatory mediators during FeNO suppression testing

To explore whether exhaled nitric oxide (FeNO) non-suppression identifies corticosteroid resistance, we analysed inflammatory mediator changes during a FeNO suppression test with monitored high-intensity corticosteroid therapy. In linear mixed-effects models analysed over time, the 15 clinically-distinct ‘suppressors’ (i.e. ≥42% FeNO suppression) normalised asthma control questionnaire scores (mean±SD: 2.8±1.4 to 1.4±0.9, p<0.0001) and sputum eosinophil counts (median [IQR]: 29 [6-41] to 1 [1-5]%, p=0.0003) while significantly decreasing sputum prostaglandin D2 (254 [89-894] to 93 [49-209] pg/mL, p=0.004) and numerically decreasing other type-2 cytokine, chemokine and alarmin levels. In comparison, the 19 non-suppressors had persistent sputum eosinophilia (10 [1-67]% despite high-intensity therapy) with raised end-test inflammatory mediator levels (1.9 [0.9-2.8]-fold greater than suppressors). FeNO non-suppression during monitored treatment implies biological corticosteroid resistance

Automated Tumour Recognition and Digital Pathology Scoring Unravels New Role for PD-L1 in Predicting Good Outcome in ER-/HER2+ Breast Cancer

The role of PD-L1 as a prognostic and predictive biomarker is an area of great interest. However, there is a lack of consensus on how to deliver PD-L1 as a clinical biomarker. At the heart of this conundrum is the subjective scoring of PD-L1 IHC in most studies to date. Current standard scoring systems involve separation of epithelial and inflammatory cells and find clinical significance in different percentages of expression, e.g., above or below 1%. Clearly, an objective, reproducible and accurate approach to PD-L1 scoring would bring a degree of necessary consistency to this landscape. Using a systematic comparison of technologies and the application of QuPath, a digital pathology platform, we show that high PD-L1 expression is associated with improved clinical outcome in Triple Negative breast cancer in the context of standard of care (SoC) chemotherapy, consistent with previous findings. In addition, we demonstrate for the first time that high PD-L1 expression is also associated with better outcome in ER- disease as a whole including HER2+ breast cancer. We demonstrate the influence of antibody choice on quantification and clinical impact with the Ventana antibody (SP142) providing the most robust assay in our hands. Through sampling different regions of the tumour, we show that tumour rich regions display the greatest range of PD-L1 expression and this has the most clinical significance compared to stroma and lymphoid rich areas. Furthermore, we observe that both inflammatory and epithelial PD-L1 expression are associated with improved survival in the context of chemotherapy. Moreover, as seen with PD-L1 inhibitor studies, a low threshold of PD-L1 expression stratifies patient outcome. This emphasises the importance of using digital pathology and precise biomarker quantitation to achieve accurate and reproducible scores that can discriminate low PD-L1 expression