Multiomics links global surfactant dysregulation with airflow obstruction and emphysema in COPD

RATIONALE: Pulmonary surfactant is vital for lung homeostasis as it reduces surface tension to prevent alveolar collapse and provides essential immune-regulatory and antipathogenic functions. Previous studies demonstrated dysregulation of some individual surfactant components in COPD. We investigated relationships between COPD disease measures and dysregulation of surfactant components to gain new insights into potential disease mechanisms. METHODS: Bronchoalveolar lavage proteome and lipidome were characterised in ex-smoking mild/moderate COPD subjects (n=26) and healthy ex-smoking (n=20) and never-smoking (n=16) controls using mass spectrometry. Serum surfactant protein analysis was performed. RESULTS: Total phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, surfactant protein (SP)-B, SP-A and SP-D concentrations were lower in COPD versus controls (log2 fold change (log2FC) -2.0, -2.2, -1.5, -0.5, -0.7 and -0.5 (adjusted p<0.02), respectively) and correlated with lung function. Total phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, SP-A, SP-B, SP-D, napsin A and CD44 inversely correlated with computed tomography small airways disease measures (expiratory to inspiratory mean lung density) (r= -0.56, r= -0.58, r= -0.45, r= -0.36, r= -0.44, r= -0.37, r= -0.40 and r= -0.39 (adjusted p<0.05)). Total phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, SP-A, SP-B, SP-D and NAPSA inversely correlated with emphysema (% low-attenuation areas): r= -0.55, r= -0.61, r= -0.48, r= -0.51, r= -0.41, r= -0.31 and r= -0.34, respectively (adjusted p<0.05). Neutrophil elastase, known to degrade SP-A and SP-D, was elevated in COPD versus controls (log2FC 0.40, adjusted p=0.0390), and inversely correlated with SP-A and SP-D. Serum SP-D was increased in COPD versus healthy ex-smoking volunteers, and predicted COPD status (area under the curve 0.85). CONCLUSIONS: Using a multiomics approach, we demonstrate, for the first time, global surfactant dysregulation in COPD that was associated with emphysema, giving new insights into potential mechanisms underlying the cause or consequence of disease

The influence of both individual and area based socioeconomic status on temporal trends in Caesarean sections in Scotland 1980-2000

Background: Caesarean section rates have risen over the last 20 years. Elective Caesarean section rates have been shown to be linked to area deprivation in England, women in the most deprived areas were less likely to have an elective section than those in the most affluent areas. We examine whether individual social class, area deprivation or both are related to Caesarean sections in Scotland and investigate changes over time. Methods: Routine maternity discharge data from live singleton births in Scottish hospitals from three time periods were used; 1980-81 (n = 133,555), 1990-91 (n = 128,933) and 1999-2000 (n = 102,285). Multilevel logistic regression, with 3 levels (births, postcode sector and Health Board) was used to analyse emergency and elective Caesareans separately; analysis was further stratified by previous Caesarean section. The relative index of inequality (RII) was used to assess socioeconomic inequalities. Results: Between 1980-81 and 1999-2000 the emergency section rate increased from 6.3% to 11.9% and the elective rate from 3.6% to 5.5%. In 1980-81 and 1990-91 emergency Caesareans were more likely among women at the bottom of the social class hierarchy compared to those at the top (RII = 1.14, 95%CI 1.00-1.25 and RII = 1.13, 1.03-1.23 respectively) and also among women in the most deprived areas compared to those in the most affluent (RII = 1.18, 1.05-1.32 and RII = 1.13, 1.02-1.26 respectively). In 1999-2000 the odds of an elective section were lower for women at the bottom of the social class hierarchy than those at the top (RII = 0.87, 0.76-1.00) and also lower in women in the most deprived areas compared to those in the most affluent (RII = 0.85, 0.73-0.99). Conclusions: Both individual social class and area deprivation are independently associated with Caesarean sections in Scotland. The tendency for disadvantaged women to be more likely to receive emergency sections disappeared at the same time as the likelihood of advantaged groups receiving elective sections increased

SEGMA: an automatic SEGMentation Approach for human brain MRI using sliding window and random forests

Quantitative volumes from brain magnetic resonance imaging (MRI) acquired across the life course may be useful for investigating long term effects of risk and resilience factors for brain development and healthy aging, and for understanding early life determinants of adult brain structure. Therefore, there is an increasing need for automated segmentation tools that can be applied to images acquired at different life stages. We developed an automatic segmentation method for human brain MRI, where a sliding window approach and a multi-class random forest classifier were applied to high-dimensional feature vectors for accurate segmentation. The method performed well on brain MRI data acquired from 179 individuals, analyzed in three age groups: newborns (38–42 weeks gestational age), children and adolescents (4–17 years) and adults (35–71 years). As the method can learn from partially labeled datasets, it can be used to segment large-scale datasets efficiently. It could also be applied to different populations and imaging modalities across the life course

A hierarchical Bayesian model for understanding the spatiotemporal dynamics of the intestinal epithelium

Our work addresses two key challenges, one biological and one methodological. First, we aim to understand how proliferation and cell migration rates in the intestinal epithelium are related under healthy, damaged (Ara-C treated) and recovering conditions, and how these relations can be used to identify mechanisms of repair and regeneration. We analyse new data, presented in more detail in a companion paper, in which BrdU/IdU cell-labelling experiments were performed under these respective conditions. Second, in considering how to more rigorously process these data and interpret them using mathematical models, we use a probabilistic, hierarchical approach. This provides a best-practice approach for systematically modelling and understanding the uncertainties that can otherwise undermine the generation of reliable conclusions-uncertainties in experimental measurement and treatment, difficult-to-compare mathematical models of underlying mechanisms, and unknown or unobserved parameters. Both spatially discrete and continuous mechanistic models are considered and related via hierarchical conditional probability assumptions. We perform model checks on both in-sample and out-of-sample datasets and use them to show how to test possible model improvements and assess the robustness of our conclusions. We conclude, for the present set of experiments, that a primarily proliferation-driven model suffices to predict labelled cell dynamics over most time-scales

The FAIR Guiding Principles for scientific data management and stewardship

There is an urgent need to improve the infrastructure supporting the reuse of scholarly data. A diverse set of stakeholders—representing academia, industry, funding agencies, and scholarly publishers—have come together to design and jointly endorse a concise and measureable set of principles that we refer to as the FAIR Data Principles. The intent is that these may act as a guideline for those wishing to enhance the reusability of their data holdings. Distinct from peer initiatives that focus on the human scholar, the FAIR Principles put specific emphasis on enhancing the ability of machines to automatically find and use the data, in addition to supporting its reuse by individuals. This Comment is the first formal publication of the FAIR Principles, and includes the rationale behind them, and some exemplar implementations in the community

Mismatches in Scale Between Highly Mobile Marine Megafauna and Marine Protected Areas

Marine protected areas (MPAs), particularly large MPAs, are increasing in number and size around the globe in part to facilitate the conservation of marine megafauna under the assumption that large-scale MPAs better align with vagile life histories; however, this alignment is not well established. Using a global tracking dataset from 36 species across five taxa, chosen to reflect the span of home range size in highly mobile marine megafauna, we show most MPAs are too small to encompass complete home ranges of most species. Based on size alone, 40% of existing MPAs could encompass the home ranges of the smallest ranged species, while only \u3c 1% of existing MPAs could encompass those of the largest ranged species. Further, where home ranges and MPAs overlapped in real geographic space, MPAs encompassed \u3c 5% of core areas used by all species. Despite most home ranges of mobile marine megafauna being much larger than existing MPAs, we demonstrate how benefits from MPAs are still likely to accrue by targeting seasonal aggregations and critical life history stages and through other management techniques

Mismatches in Scale Between Highly Mobile Marine Megafauna and Marine Protected Areas

Marine protected areas (MPAs), particularly large MPAs, are increasing in number and size around the globe in part to facilitate the conservation of marine megafauna under the assumption that large-scale MPAs better align with vagile life histories; however, this alignment is not well established. Using a global tracking dataset from 36 species across five taxa, chosen to reflect the span of home range size in highly mobile marine megafauna, we show most MPAs are too small to encompass complete home ranges of most species. Based on size alone, 40% of existing MPAs could encompass the home ranges of the smallest ranged species, while only \u3c 1% of existing MPAs could encompass those of the largest ranged species. Further, where home ranges and MPAs overlapped in real geographic space, MPAs encompassed \u3c 5% of core areas used by all species. Despite most home ranges of mobile marine megafauna being much larger than existing MPAs, we demonstrate how benefits from MPAs are still likely to accrue by targeting seasonal aggregations and critical life history stages and through other management techniques

A randomised controlled trial of losartan as an anti-fibrotic agent in non-alcoholic steatohepatitis.

Introduction: Non-alcoholic fatty liver disease (NAFLD) is a common liver disease worldwide. Experimental and small clinical trials have demonstrated that angiotensin II blockers (ARB) may be anti-fibrotic in the liver. The aim of this randomised controlled trial was to assess whether treatment with Losartan for 96 weeks slowed, halted or reversed the progression of fibrosis in patients with non-alcoholic steatohepatitis (NASH). Methods: Double-blind randomised-controlled trial of Losartan 50 mg once a day versus placebo for 96 weeks in patients with histological evidence of NASH. The primary outcome for the study was change in histological fibrosis stage from pre-treatment to end-of-treatment. Results: The study planned to recruit 214 patients. However, recruitment was slower than expected, and after 45 patients were randomised (median age 55; 56% male; 60% diabetic; median fibrosis stage 2), enrolment was suspended. Thirty-two patients (15 losartan and 17 placebo) completed follow up period: one patient (6.7%) treated with losartan and 4 patients (23.5%) in the placebo group were “responders” (lower fibrosis stage at follow up compared with baseline). The major reason for slow recruitment was that 39% of potentially eligible patients were already taking an ARB or angiotensin converting enzyme inhibitor (ACEI), and 15% were taking other prohibited medications. Conclusions: Due to the widespread use of ACEI and ARB in patients with NASH this trial failed to recruit sufficient patients to determine whether losartan has anti-fibrotic effects in the liver