Impact of intracoronary imaging-guided percutaneous coronary intervention on procedural outcomes among complex patient groups

Background Intracoronary imaging (ICI) has been previously shown to improve survival and clinical outcomes after percutaneous coronary intervention (PCI). However, whether this prognostic benefit is sustained across different indications/patient groups remains unclear. Methods All PCI procedures performed in England and Wales between 1st April 2014 and 31st March 2020 were retrospectively analysed. The association between ICI use and in-hospital MACCE (major adverse cardiovascular and cerebrovascular outcomes; composite of all-cause mortality, stroke and reinfarction) and mortality was examined using multivariable logistic regression analysis for each imaging-recommended indication (stent thrombosis (ST), in-stent restenosis, stent length>60mm, acute coronary syndrome (ACS) indications, chronic total occlusion, left main stem (LMS) intervention, renal failure and bioresorbable vascular scaffolds (BVS)). Results Of 555,398 PCI procedures, 10.8% (n=59,752) were performed under ICI guidance. ICI use doubled between 2014 (7.8%) and 2020 (17.5%). ICI use was highest for BVS (44.7%) and LMS PCI (41.2%) cases and lowest in ACS (9%). Overall, the odds ratios (OR) of in-hospital MACCE and mortality were only reduced with ICI-guided PCI in cases with an imaging-recommended indication (OR 0.75 95% confidence interval (CI) 0.69-0.81 and OR 0.69 95%CI 0.63-0.76, respectively). Only specific imaging-recommended indications were associated with reduced MACCE and mortality, including LMS PCI (OR 0.45 95%CI 0.39-0.52 and 0.41 95%CI 0.35-0.48, respectively), ACS (OR 0.76 95%CI 0.70-0.82 and 0.70 95%CI 0.63-0.77), stent length>60mm (OR 0.75 95%CI 0.59-0.94 and 0.72 95%CI 0.54-0.95). ST was only associated with lower mortality (OR: 0.69 95%CI 0.52-0.91) while renal failure was associated with reduced MACCE (OR 0.77 95%CI 0.60-0.99) but not mortality. (Figure 1) Conclusion The utilisation of ICI has more than doubled over a seven-year period at a national level but remains low, with less than 1-in-5 procedures performed under ICI guidance. In-hospital survival was better with ICI-guided than angiography-guided PCI, albeit only for specific indications.Figure

Filamin A (FLNA) mutation—A newcomer to the childhood interstitial lung disease (ChILD) classification

AIM: Interstitial lung disease (ILD) in infants represents a rare and heterogenous group of disorders, distinct from those occurring in adults. In recent years a new entity within this category is being recognized, namely filamin A (FLNA) mutation related lung disease. Our aims are to describe the clinical and radiological course of patients with this disease entity to aid clinicians in the prognostic counseling and management of similar patients they may encounter. METHOD: A retrospective case note review was conducted of all patients treated at our institution (a specialist tertiary referral childrens’ center) for genetically confirmed FLNA mutation related lung disease. The clinical presentation, evolution, management and radiological features were recorded and a medical literature review of Medline indexed articles was conducted. RESULTS: We present a case series of four patients with interstitial lung disease and genetically confirmed abnormalities within the FLNA gene. Their imaging findings all reveal a pattern of predominantly upper lobe overinflation, coarse pulmonary lobular septal thickening and diffuse patchy atelectasis. The clinical outcomes of our patients have been variable ranging from infant death, lobar resection and need for supplemental oxygen and bronchodilators. CONCLUSION: The progressive nature of the pulmonary aspect of this disorder and need for early aggressive supportive treatment make identification crucial to patient management and prognostic counseling

Impact of Intracoronary Imaging-Guided Percutaneous Coronary Intervention on Procedural Outcomes Among Complex Patient Groups.

Background Intracoronary imaging (ICI) has been shown to improve survival after percutaneous coronary intervention (PCI). Whether this prognostic benefit is sustained across different indications remains unclear. Methods and Results All PCI procedures performed in England and Wales between April, 2014 and March 31, 2020, were retrospectively analyzed. The association between ICI use and in-hospital major acute cardiovascular and cerebrovascular events; composite of all-cause mortality, stroke, and reinfarction and mortality was examined using multivariable logistic regression analysis for different imaging-recommended indications as set by European Association for Percutaneous Cardiovascular Interventions consensus. Of 555 398 PCI procedures, 10.8% (n=59 752) were ICI-guided. ICI use doubled between 2014 (7.8%) and 2020 (17.5%) and was highest in left main PCI (41.2%) and lowest in acute coronary syndrome (9%). Only specific European Association for Percutaneous Cardiovascular Interventions imaging-recommended indications were associated with reduced major acute cardiovascular and cerebrovascular events and mortality, including left main PCI (odds ratio [OR], 0.45 [95% CI, 0.39-0.52] and 0.41 [95% CI, 0.35-0.48], respectively), acute coronary syndrome (OR, 0.76 [95% CI, 0.70-0.82] and 0.70 [95% CI, 0.63-0.77]), and stent length >60 mm (OR, 0.75 [95% CI, 0.59-0.94] and 0.72 [95% CI, 0.54-0.95]). Stent thrombosis and renal failure were associated with lower mortality (OR, 0.69 [95% CI, 0.52-0.91]) and major acute cardiovascular and cerebrovascular events (OR, 0.77 [95% CI, 0.60-0.99]), respectively. Conclusions ICI use has more than doubled over a 7-year period at a national level but remains low, with <1 in 5 procedures performed under ICI guidance. In-hospital survival was better with ICI-guided than angiography-guided PCI, albeit only for specific indications

Adoption incentives and environmental policy timing under asymmetric information and strategic firm behaviour

We consider the incentives of a single firm to invest in a cleaner technology under emission quotas and emission taxation. We assume asymmetric information about the firm's cost of employing the new technology. Policy is set either before the firm invests (commitment) or after (time consistency). Contrary to conventional wisdom, we find that with commitment (time consistency), quotas give higher (lower) investment incentives than taxes. With quotas (taxes), commitment generally leads to higher (lower) welfare than time consistency. Under commitment with quadratic abatement costs and environmental damages, a modified Weitzman rule applies and quotas usually lead to higher welfare than taxes

A systematic analysis of splicing variants identifies new diagnoses in the 100,000 Genomes Project

Background Genomic variants which disrupt splicing are a major cause of rare genetic diseases. However, variants which lie outside of the canonical splice sites are difficult to interpret clinically. Improving the clinical interpretation of non-canonical splicing variants offers a major opportunity to uplift diagnostic yields from whole genome sequencing data. Methods Here, we examine the landscape of splicing variants in whole-genome sequencing data from 38,688 individuals in the 100,000 Genomes Project and assess the contribution of non-canonical splicing variants to rare genetic diseases. We use a variant-level constraint metric (the mutability-adjusted proportion of singletons) to identify constrained functional variant classes near exon–intron junctions and at putative splicing branchpoints. To identify new diagnoses for individuals with unsolved rare diseases in the 100,000 Genomes Project, we identified individuals with de novo single-nucleotide variants near exon–intron boundaries and at putative splicing branchpoints in known disease genes. We identified candidate diagnostic variants through manual phenotype matching and confirmed new molecular diagnoses through clinical variant interpretation and functional RNA studies. Results We show that near-splice positions and splicing branchpoints are highly constrained by purifying selection and harbour potentially damaging non-coding variants which are amenable to systematic analysis in sequencing data. From 258 de novo splicing variants in known rare disease genes, we identify 35 new likely diagnoses in probands with an unsolved rare disease. To date, we have confirmed a new diagnosis for six individuals, including four in whom RNA studies were performed. Conclusions Overall, we demonstrate the clinical value of examining non-canonical splicing variants in individuals with unsolved rare diseases

Technology Diffusion, Abatement Cost and Transboundary Pollution

This paper studies countries' incentives to develop advanced pollution abatement technology when technology may spillover across countries and pollution abatement is a global public good. We are motivated in part by the problem of global warming: a solution to this involves providing a global public good, and will surely require the development and implementation of new technologies. We show that at the Nash equilibrium of a simultaneous-move game with R&D investment and emission abatement, whether the free rider effect prevails and under-investment and excess emissions occur depends on the degree of technology spillovers and the effect of R&D on the marginal abatement costs. There are cases in which, contrary to conventional wisdom, Nash equilibrium investments in emissions reductions exceed the first-best case

De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures.

Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability

Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.JW is supported by a Cancer Research UK Cambridge Cancer Centre Clinical Research Training Fellowship. Funding for the NIHR BioResource – Rare diseases project was provided by the National Institute for Health Research (NIHR, grant number RG65966). ERM acknowledges support from the European Research Council (Advanced Researcher Award), NIHR (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre), Cancer Research UK Cambridge Cancer Centre and Medical Research Council Infrastructure Award. The University of Cambridge has received salary support in respect of EM from the NHS in the East of England through the Clinical Academic Reserve. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. DGE is an NIHR Senior Investigator and is supported by the all Manchester NIHR Biomedical Research Centre

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre