Turbidite reservoirs of the Sele Formation in the Central North Sea produce from fields such as Forties, Nelson, Montrose–Arbroath, Scoter, Pierce, the Gannet cluster, Guillemot A, Mirren and are under appraisal/development in fields such as Merganser, Phyllis, Starling and Blane. These reservoirs form part of the ‘Forties’ submarine fan system that was sourced from feeder channels in the northwest and west. Blanket 3D seismic coverage tied to wells shows that nearer their updip sources the turbidites are thicker, higher in net:gross, and more channelized. Downdip, the turbidite reservoirs are thinner bedded, finer grained and with depositional architectures that are characterized by stacked lobes and minor channels controlled by accommodation space and salt movement.In updip fields, such as Nelson and Forties, production is mature. High-quality reservoir channel sands are mostly drained. Recovery factors of 60–62% are achievable by application of water injection and 4D seismic technologies. The remaining challenge in these reservoirs is to (1) find by-passed oil in the channel facies and (2) to identify/model oil remaining in non-channelized facies, such as channel margin and interchannel facies. Portions of the channelized reservoirs have not been swept because of non-uniform water ascent and breakthrough or shale barriers. Non-channelized reservoirs have not been swept because their sands are thin bedded, interbedded with shales and of lower reservoir quality. Remaining oil zones are not correlatable between existing wells, emphasizing the uncertainties of lateral heterogeneities away from the wellbore and the importance of static reservoir modelling techniques to properly model, identify and plan infill targets with multiple realizations. Higher recovery factors (possibly as high as 70%) may be achievable with higher resolution seismic interpretations and reservoir models, application of enhanced oil recovery and sharpshooter drilling techniques and improved water management.In downdip fields, such as Scoter, Merganser, Pierce and Guillemot A, production is not as mature and wells are not as abundant. Consequently, development planning is more dependent on high-quality static and dynamic reservoir models to predict the interwell reservoir character, volumetrics and performance. In general, turbidite reservoir sandstones are thinner and finer grained. The thickest sands may be more correlatable as lobes/sheets. Permeability is lower than in updip reservoirs of equivalent porosity (tens of mD as opposed to hundreds or thousands of mD), probably due to reductions in mean grain size and textural maturity and a corresponding increase in detrital clay matrix. The greatest challenges lie in modelling lateral changes in net:gross, bed thickness, facies (especially shale bed architecture) and cementation. Where depositional slopes were oversteepened by the growth of salt diapirs, slumps and slides introduce lateral heterogeneities and reduce predictability in the reservoir section. Multiple faults radiate from such salt diapirs and may compartmentalize the reservoir. These effects may be mitigated by the construction of robust conceptual models of reservoir accumulation and architecture, supported by relevant field analogues and detailed biostratigraphy which may delineate multiple widespread marker horizons. For liquid hydrocarbons, recovery factors are typically 40–45%. Gas recovery factors are projected to be 60–65%.

Background Amyotrophic lateral sclerosis (ALS) is a universally fatal neurodegenerative disease. ALS is determined by gene-environment interactions and improved understanding of these interactions may lead to effective personalised medicine. The role of physical exercise in the development of ALS is currently controversial. Methods First, we dissected the exercise-ALS relationship in a series of two-sample Mendelian randomisation (MR) experiments. Next we tested for enrichment of ALS genetic risk within exercise-associated transcriptome changes. Finally, we applied a validated physical activity questionnaire in a small cohort of genetically selected ALS patients. Findings We present MR evidence supporting a causal relationship between genetic liability to frequent and strenuous leisure-time exercise and ALS using a liberal instrument (multiplicative random effects IVW, p=0.01). Transcriptomic analysis revealed that genes with altered expression in response to acute exercise are enriched with known ALS risk genes (permutation test, p=0.013) including C9ORF72 , and with ALS-associated rare variants of uncertain significance. Questionnaire evidence revealed that age of onset is inversely proportional to historical physical activity for C9ORF72 -ALS (Cox proportional hazards model, Wald test p=0.007, likelihood ratio test p=0.01, concordance=74%) but not for non -C9ORF72 -ALS. Variability in average physical activity was lower in C9ORF72 -ALS compared to both non -C9ORF72 -ALS (F-test, p=0.002) and neurologically normal controls (F-test, p=0.049) which is consistent with a homogeneous effect of physical activity in all C9ORF72 -ALS patients. Interpretation Our MR approach suggests a positive causal relationship between ALS and physical exercise. Exercise is likely to cause motor neuron injury only in patients with a risk-genotype. Consistent with this we have shown that ALS risk genes are activated in response to exercise. In particular, we propose that G4C2-repeat expansion of C9ORF72 predisposes to exercise-induced ALS. Funding We acknowledge support from the Wellcome Trust (JCK, 216596/Z/19/Z), NIHR (PJS, NF-SI-0617-10077; IS-BRC-1215-20017) and NIH (MPS, CEGS 5P50HG00773504, 1P50HL083800, 1R01HL101388, 1R01-HL122939, S10OD025212, P30DK116074, and UM1HG009442).

Amyotrophic lateral sclerosis (ALS) is a relatively common and rapidly progressive neurodegenerative disease which, in the majority of cases, is thought to be determined by a complex gene-environment interaction. Exponential growth in the number of performed genome-wide association studies (GWAS), combined with the advent of Mendelian randomization (MR) is opening significant new opportunities to identify environmental exposures which increase or decrease the risk of ALS. Each of these discoveries has the potential to shape new therapeutic interventions. However, to do so rigorous methodological standards must be applied in the performance of MR. We have performed a review of MR studies performed in ALS to date. We identified 20 MR studies, including evaluation of physical exercise, adiposity, cognitive performance, immune function, blood lipids, sleep behaviours, educational attainment, alcohol consumption, smoking and type 2 diabetes mellitus. We have evaluated each study using gold standard methodology supported by the MR literature and the STROBE-MR checklist. Where discrepancies exist between MR studies, we suggest the underlying reasons. A number of studies conclude that there is a causal link between blood lipids and risk of ALS; replication across different datasets and even different populations adds confidence. For other putative risk factors, such as smoking and immune function, MR studies have provided cause for doubt. We highlight the use of positive control analyses in choosing exposure SNPs to make up the MR instrument, use of SNP clumping to avoid false positive results due to SNPs in linkage, and the importance of multiple testing correction. We discuss the implications of survival bias for study of late age of onset diseases such as ALS, and make recommendations to mitigate this potentially important confounder. For MR to be useful to the ALS field, high methodological standards must be applied to ensure reproducibility. MR is already an impactful tool but poor quality studies will lead to incorrect interpretations by a field which includes non-statisticians, wasted resources and missed opportunities.

Genome-wide identification of the genetic basis of amyotrophic lateral sclerosisHighlights d Machine learning method identifies risk genes by integrating GWASs and epigenetic data d Discovered ALS risk genes lead to a 5-fold increase in recovered heritability d Genetic and experimental support for initiation of ALS pathogenesis in the distal axon d Convergent genetic and experimental data establish KANK1 as a new ALS gene

Amyotrophic lateral sclerosis (ALS) is an archetypal complex disease centered on progressive death of motor neurons. Despite heritability estimates of 52%, GWAS studies have discovered only seven genome-wide significant hits, which are relevant to <10% of ALS patients. To increase the power of gene discovery, we integrated motor neuron functional genomics with ALS genetics in a hierarchical Bayesian model called RefMap. Comprehensive transcriptomic and epigenetic profiling of iPSC-derived motor neurons enabled RefMap to systematically fine-map genes and pathways associated with ALS. As a significant extension of the known genetic architecture of ALS, we identified a group of 690 candidate ALS genes, which is enriched with previously discovered risk genes. Extensive conservation, transcriptome and network analyses demonstrated the functional significance of these candidate genes in motor neurons and disease progression. In particular, we observed a genetic convergence on the distal axon, which supports the prevailing view of ALS as a distal axonopathy. Of the new ALS genes we discovered, we further characterized KANK1 that is enriched with coding and noncoding, common and rare ALS-associated genetic variation. Modelling patient mutations in human neurons reduced KANK1 expression and produced neurotoxicity with disruption of the distal axon. RefMap can be applied broadly to increase the discovery power in genetic association studies of human complex traits and diseases.

Purpose of review Amyotrophic lateral sclerosis (ALS) is an archetypal complex disease where disease risk and severity are, for the majority of patients, the product of interaction between multiple genetic and environmental factors. We are in a period of unprecedented discovery with new large-scale genome-wide association study (GWAS) and accelerating discovery of risk genes. However, much of the observed heritability of ALS is undiscovered and we are not yet approaching elucidation of the total genetic architecture which will be necessary for comprehensive disease subclassification. Recent findings We summarise recent developments and discuss the future. New machine learning models will help to address nonlinear genetic interactions. Statistical power for genetic discovery may be boosted by reducing the search-space using cell-specific epigenetic profiles and expanding our scope to include genetically correlated phenotypes. Structural variation, somatic heterogeneity and consideration of environmental modifiers represent significant challenges which will require integration of multiple technologies and a multidisciplinary approach including clinicians, geneticists and pathologists. Summary The move away from fully penetrant Mendelian risk genes necessitates new experimental designs and new standards for validation. The challenges are significant but the potential reward for successful disease subclassification is large-scale and effective personalized medicine.

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A 4-year-old, female spayed, Standard Poodle was examined for evaluation of presumed immunemediated hemolytic anemia (IMHA) that had been refractory to therapy. Before referral, weakness and lethargy had been noted and a CBC performed by the referring veterinarian had shown a regenerative anemia with autoagglutination and spherocytosis. The hemoglobin concentration had been markedly reduced at 69 g/L (reference range, 120-180 g/L) and the reticulocyte count had been 35.3%. A PCV measurement taken by the referring veterinarian the same day that the CBC had been submitted was 24% (reference range, 37-55%). Serum biochemistry results revealed a slightly increased creatine kinase activity (611 U/L; reference range, 0-506 U/L), an increased aspartate aminotransferase activity (86 U/L; reference range, 15-55 U/L), an increased amylase activity (1,283 U/L; reference range, 250-1,060 U/L), and an increased bilirubin concentration (1.6 mg/dL; reference range, 0-0.24 mg/dL). There was no history of recent vaccination or drug administration before the onset of anemia. Treatment was with prednisone a (2 mg/kg PO q12h). However, after 1 week of treatment there was no significant improvement and the dog was referred.On physical examination, the dog was weak and had pale mucous membranes. Abdominal palpation and ultrasonography detected hepatosplenomegaly. Thoracic radiography did not reveal any abnormalities. A urine sample obtained by cystocentesis did not yield any growth on bacterial culture. A CBC revealed the hemoglobin concentration was 76 g/L (reference range, 120-180 g/L) and PCV 24% (reference range, 37-55%). A diagnosis of idiopathic IMHA was made and additional immunosuppressive therapy was added to the treatment regime (azathioprine b 1 mg/kg PO q24h and cyclosporin c at 10 mg/kg PO q24h). In an attempt to reduce the risk of thromboembolic disease, aspirin d was also administered at 0.5 mg/kg PO q24h. The dog responded well to treatment and medications were gradually withdrawn. The cyclosporin was completely withdrawn after 9 weeks of treatment. At that stage, treatment was prednisone (0.7 mg/kg PO q24h) and azathioprine (1 mg/kg PO q48h). The aspirin dose was unchanged. All medications were discontinued after 1 year at which time the CBC was within normal limits.Approximately 2 months after discontinuing treatment, the dog once again had lethargy and pale mucous membranes. A CBC showed a hemoglobin concentration of 71 g/L (reference range, 120-180 g/L) and a PCV was 24% (reference range 37-55%). Autoagglutination and spherocytosis were present. Serum biochemistry was within normal limits apart from an increase in bilirubin concentration (1.4 mg/dL; reference range, 0-0.24 mg/ dL). A diagnosis of a relapse of the idiopathic IMHA was made and immunosuppressive therapy was reinstituted with prednisone (1.7 mg/kg PO q12h), azathioprine (0.9 mg/kg PO q12h), aspirin (0.5 mg/kg PO q24h), and cyclosporin (8.5 mg/kg PO q24h). After 10 days of therapy, there had been a clinical improvement. The dose of prednisone was reduc...