Progressive Device Failure at Long Term Follow Up of the Nellix EndoVascular Aneurysm Sealing (EVAS) System.

OBJECTIVE: High rates of midterm failure of the Nellix EndoVascular Aneurysm Sealing (EVAS) System resulted in device withdrawal from the UK market. The study aim was to report long term Nellix EVAS outcomes and management of a failing device. METHODS: A retrospective review of EVAS procedures at a tertiary unit was performed. Device failure was defined as a triad of stent migration, stent separation, and secondary sac expansion, or any intervention for type 1 endoleak, device rupture, or explant. RESULTS: 161 (male n = 140, female n = 21) patients with a median follow up of 6.0 (IQR 5.0-6.6) years were included. Freedom from all cause mortality estimate at six years was 41.5%. There were 70 (43.5%) device failures with a freedom from device failure estimate at six years of 32.3%. Failure was the result of sac expansion (n = 41), caudal stent migration (n = 36), stent separation (n = 26), and secondary AAA rupture (n = 15). A substantial number of type 1 endoleaks was present (1a n = 33, 1b n = 11), but the type 2 endoleak rate was low at 3.7%. Some 36 (22.4%) patients required re-intervention. Twenty-one patients underwent explant with no 30 day deaths. Six patients underwent Nellix-in-Nellix application (NINA) with one early death from bowel ischaemia and one patient who died later from non-aneurysm related cause. Two NINA patients have ongoing sac expansion and two have had thrombosis of a Nellix limb or visceral stent. Proximal embolisation was only successful in one of six cases. CONCLUSION: The long term failure rate of Nellix EVAS is high. All patients with a device must be informed and be enrolled in enhanced surveillance. EVAS explant is an acceptable technique with favourable outcomes. Management by open explant, if the patient is fit, should be considered early and offered to those with device failure.

Long-term Outcomes Following Endovascular Aneurysm Repair for Ruptured Abdominal Aortic Aneurysms.

Purpose: To investigate the long-term outcomes of endovascular aneurysm repair (EVAR) for ruptured abdominal aortic aneurysm (rAAA) from a single center over an 11-year period. Materials and Methods: A retrospective analysis was conducted of 121 patients (median age 78 years; 100 men) with rAAA who underwent emergency EVAR at a single tertiary vascular center from January 2006 to December 2016. The study included only ruptures confirmed by evidence of hematoma on preoperative computed tomography; both iliac and aortic aneurysm ruptures were eligible. The primary outcome measures included mortality and reintervention rates. Kaplan-Meier estimates of survival and freedom from reintervention are reported with the 95% confidence interval (CI). Results: In-hospital and 30-day mortality rates for emergency EVAR were 16.5%; 90-day mortality was 24.0%. The mortality estimates were 27.3% (95% CI 20% to 36%) at 1 year and 61.7% (95% CI 51% to 72%) at 5 years. In the observation period to 2017, 63 reinterventions were performed on 37 patients (30.6%). Median time to the first reintervention was 3.2 years. Freedom from reintervention in surviving patients at 1 year was 86% (95% CI 72% to 94%) and 51% (95% CI 26% to 71%) at 5 years. Four patients (3.3%) had a secondary sac rupture over the study period. Conclusion: Emergency EVAR for ruptured AAA can be performed with acceptable short-term outcomes; however, long-term surveillance is necessary, and reintervention is common.

Tropical dead zones and mass mortalities on coral reefs.

Degradation of coastal water quality in the form of low dissolved oxygen levels (hypoxia) can harm biodiversity, ecosystem function, and human wellbeing. Extreme hypoxic conditions along the coast, leading to what are often referred to as "dead zones," are known primarily from temperate regions. However, little is known about the potential threat of hypoxia in the tropics, even though the known risk factors, including eutrophication and elevated temperatures, are common. Here we document an unprecedented hypoxic event on the Caribbean coast of Panama and assess the risk of dead zones to coral reefs worldwide. The event caused coral bleaching and massive mortality of corals and other reef-associated organisms, but observed shifts in community structure combined with laboratory experiments revealed that not all coral species are equally sensitive to hypoxia. Analyses of global databases showed that coral reefs are associated with more than half of the known tropical dead zones worldwide, with >10% of all coral reefs at elevated risk for hypoxia based on local and global risk factors. Hypoxic events in the tropics and associated mortality events have likely been underreported, perhaps by an order of magnitude, because of the lack of local scientific capacity for their detection. Monitoring and management plans for coral reef resilience should incorporate the growing threat of coastal hypoxia and include support for increased detection and research capacity.

Editor's Choice - Mid-term Migration and Device Failure Following Endovascular Aneurysm Sealing with the Nellix Stent Graft System - a Single Centre Experience.

OBJECTIVE: Endovascular aneurysm sealing (EVAS) with the Nellix stent graft system is a novel concept in the management of abdominal aortic aneurysm (AAA) that aims to reduce the prevalence of all endoleaks following endovascular repair. There are few data describing the longer-term durability of this approach. The aim was to report the longer-term outcomes following EVAS in a single centre. METHODS: This is a retrospective review of all patients that underwent Nellix at Cambridge University Hospitals Foundation Trust. Factors that are described as device failure include secondary sac rupture, graft explantation, further surgical procedures for Type 1 endoleak, or major migration of the stent grafts with pressurisation of the aortic sac. RESULTS: A total of 161 patients have been treated with Nellix. The indications included primary AAA (n = 115), ruptured AAA (n = 4), salvage of other aortic grafts (n = 18), primary iliac aneurysm (n = 6), and chimney EVAS (ChEVAS) for pararenal AAA (n = 18). In total there have been 42 graft failures in patients treated with EVAS for primary AAA. The 4 year freedom from graft failure was 42% in patients treated for primary AAA. Failures mostly occurred more than 2 years post-Nellix implant. There were eight secondary sac ruptures (incidence 2.4 per 100 person years) and there have been 14 graft explants. CONCLUSIONS: Failure of aneurysm sealing following treatment with Nellix has been more common than anticipated and can cause aortic rupture. Post-operative surveillance of Nellix stent grafts is crucial to identify features of failure.

Editor's Choice - Calcification of Thoracic and Abdominal Aneurysms is Associated with Mortality and Morbidity.

INTRODUCTION: Cardiovascular events are common in people with aortic aneurysms. Arterial calcification is a recognised predictor of cardiovascular outcomes in coronary artery disease. Whether calcification within abdominal and thoracic aneurysm walls is correlated with poor cardiovascular outcomes is not known. PATIENTS AND METHODS: Calcium scores were derived from computed tomography (CT) scans of consecutive patients with either infrarenal (AAA) or descending thoracic aneurysms (TAA) using the modified Agatston score. The primary outcome was subsequent all cause mortality during follow-up. Secondary outcomes were cardiovascular mortality and morbidity. RESULTS: A total of 319 patients (123 TAA and 196 AAA; median age 77 [71-84] years, 72% male) were included with a median follow-up of 30 months. The primary outcome occurred in 120 (37.6%) patients. In the abdominal aortic aneurysm group, the calcium score was significantly related to both all cause mortality and cardiac mortality (odds ratios (OR) of 2.246 (95% CI 1.591-9.476; p < 0.001) and 1.321 (1.076-2.762; p = 0.003)) respectively. In the thoracic aneurysm group, calcium score was significantly related to all cause mortality (OR 6.444; 95% CI 2.574-6.137; p < 0.001), cardiac mortality (OR 3.456; 95% CI 1.765-4.654; p = 0.042) and cardiac morbidity (OR 2.128; 95% CI 1.973-4.342; p = 0.002). CONCLUSIONS: Aortic aneurysm calcification, in either the thoracic or the abdominal territory, is significantly associated with both higher overall and cardiovascular mortality. Calcium scoring, rapidly derived from routine CT scans, may help identify high risk patients for treatment to reduce risk.

Intervention Associated Acute Kidney Injury and Long-Term Cardiovascular Outcomes.

BACKGROUND: Acute kidney injury (AKI) has been associated with all-cause short- and long-term mortality. However, its association with cardiovascular (CV) events remains unclear. We sought to investigate this in patients undergoing open (OAR) or endovascular (EVAR) abdominal aortic aneurysm repair, as they are likely to develop both AKI and CV morbidity. A meta-analysis was subsequently performed to confirm this in other CV-interventions. METHODS: AKI-incidence was assessed in a multicentre-cohort of 1,068 patients undergoing EVAR (947 individuals) or OAR electively using the 'Acute Kidney Injury Network' criteria. A composite-endpoint was used, consisting of non-fatal myocardial infarction (MI), stroke, vascular event, hospitalisation due to heart failure and CV death. A systematic literature review identified studies reporting AKI-incidence and CV events. Risk ratios (RRs) at 1 and 5 years were combined using meta-analysis. RESULTS: During a median follow-up of 62 months (range 11-121), AKI was associated with CV events on adjusted (for CV risk-factors) analyses (Incidence 36% of EVAR, 32% of OAR patients; hazard ratio 1.73, 95% CI 1.06-3.39, p=0.03) for the overall population. In the meta-analysis, 7 studies reported incidence of MI on 23,936 patients 1-year after coronary intervention (PCI) with a pooled RR of 1.76 (95% CI 1.45-2.83, p<0.001); at 2 years, 3 studies reported MI incidence on 17,773 patients after PCI with a pooled RR of 1.34 (95% CI 1.10-1.63, p=0.003). MI-incidence was reported 5 years after cardiac surgery by 3 studies (33,701 patients) with a pooled RR of 1.60 (95% CI 1.43-1.81). CONCLUSION: AKI is associated with long-term CV events after surgery or endovascular intervention.

Impact of Fenestrated Endovascular Abdominal Aortic Aneurysm Repair on Renal Function.

PURPOSE: To investigate the impact of fenestrated endovascular aneurysm repair (fEVAR) on renal function perioperatively and at midterm. METHODS: A case-controlled study was performed involving 58 patients (mean age 75±7 years; 51 men) who underwent elective fEVAR for a juxtarenal or short-necked abdominal aortic aneurysm (AAA) matched on age, sex, smoking, diabetes, and baseline estimated glomerular filtration rate (eGFR) with a contemporaneous group undergoing open aneurysm repair (OAR) for the same indications. Perioperative incidence of acute kidney injury (AKI) and levels of eGFR at 30 days and 1 year were compared. A systematic literature review was performed to identify studies that had used eGFR as renal outcome after fEVAR; the pooled data were meta-analyzed using an eGFR drop >30% at 1 month and the latest follow-up as endpoints. Results are reported as the pooled proportion and 95% confidence interval (CI). RESULTS: The incidence of AKI after fEVAR was 28% compared to 10% after OAR (p=0.03). Following fEVAR, the mean eGFR dropped from 78±8 to 74±9 mL/min/1.73 m(2) at 30 days compared to a change from 79±8 to 80±16 mL/min/1.73 m(2) after OAR (p<0.01). However, the absolute drop in eGFR between fEVAR and OAR at 1 year was similar (7 mL/min/1.73 m(2); p=0.53); 7% of the fEVAR patients had an eGFR drop >30% at that point compared with none for OAR (p=0.12). The systematic literature review identified eGFR outcomes for 193 fEVAR patients. Combining these patients with the 58 from our cohort study, the pooled proportions of eGFR drop >30% were 20% (95% CI 9% to 39%) at 30 days and 8% (95% CI 0.5% to 13%) at the end of follow-up. CONCLUSION: fEVAR has a significant perioperative impact on renal function, but 1-year results are similar to OAR. fEVAR patients may benefit from targeted AKI prevention strategies that need to be assessed in relevant studies.

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1.

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression.

Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study.

BACKGROUND: Familial hypercholesterolaemia is a common autosomal-dominant disorder caused by mutations in three known genes. DNA-based cascade testing is recommended by UK guidelines to identify affected relatives; however, about 60% of patients are mutation-negative. We assessed the hypothesis that familial hypercholesterolaemia can also be caused by an accumulation of common small-effect LDL-C-raising alleles. METHODS: In November, 2011, we assembled a sample of patients with familial hypercholesterolaemia from three UK-based sources and compared them with a healthy control sample from the UK Whitehall II (WHII) study. We also studied patients from a Belgian lipid clinic (Hôpital de Jolimont, Haine St-Paul, Belgium) for validation analyses. We genotyped participants for 12 common LDL-C-raising alleles identified by the Global Lipid Genetics Consortium and constructed a weighted LDL-C-raising gene score. We compared the gene score distribution among patients with familial hypercholesterolaemia with no confirmed mutation, those with an identified mutation, and controls from WHII. FINDINGS: We recruited 321 mutation-negative UK patients (451 Belgian), 319 mutation-positive UK patients (273 Belgian), and 3020 controls from WHII. The mean weighted LDL-C gene score of the WHII participants (0.90 [SD 0.23]) was strongly associated with LDL-C concentration (p=1.4 x 10(-77); R(2)=0.11). Mutation-negative UK patients had a significantly higher mean weighted LDL-C score (1.0 [SD 0.21]) than did WHII controls (p=4.5 x 10(-16)), as did the mutation-negative Belgian patients (0.99 [0.19]; p=5.2 x 10(-20)). The score was also higher in UK (0.95 [0.20]; p=1.6 x 10(-5)) and Belgian (0.92 [0.20]; p=0.04) mutation-positive patients than in WHII controls. 167 (52%) of 321 mutation-negative UK patients had a score within the top three deciles of the WHII weighted LDL-C gene score distribution, and only 35 (11%) fell within the lowest three deciles. INTERPRETATION: In a substantial proportion of patients with familial hypercholesterolaemia without a known mutation, their raised LDL-C concentrations might have a polygenic cause, which could compromise the efficiency of cascade testing. In patients with a detected mutation, a substantial polygenic contribution might add to the variable penetrance of the disease. FUNDING: British Heart Foundation, Pfizer, AstraZeneca, Schering-Plough, National Institute for Health Research, Medical Research Council, Health and Safety Executive, Department of Health, National Heart Lung and Blood Institute, National Institute on Aging, Agency for Health Care Policy Research, John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health, Unilever, and Departments of Health and Trade and Industry.

Interleukin-6 receptor pathways in abdominal aortic aneurysm.

METHODS: We conducted a systematic review and meta-analysis of studies reporting circulating IL-6 in AAA, and new investigations of the association between a common non-synonymous functional variant (Asp358Ala) in the IL-6R gene (IL6R) and AAA, followed the analysis of the variant both in vitro and in vivo. Inflammation may play a role in the development of abdominal aortic aneurysms (AAA). Interleukin-6 (IL-6) signalling through its receptor (IL-6R) is one pathway that could be exploited pharmacologically. We investigated this using a Mendelian randomization approach. RESULTS: Up to October 2011, we identified seven studies (869 cases, 851 controls). Meta-analysis demonstrated that AAA cases had higher levels of IL-6 than controls [standardized mean difference (SMD) = 0.46 SD, 95% CI = 0.25-0.66, I(2) = 70%, P = 1.1 × 10-5 random effects]. Meta-analysis of five studies (4524 cases/15 710 controls) demonstrated that rs7529229 (which tags the non-synonymous variant Asp358Ala, rs2228145) was associated with a lower risk of AAA, per Ala358 allele odds ratio 0.84, 95% CI: 0.80-0.89, I(2) = 0%, P = 2.7 × 10-11). In vitro analyses in lymphoblastoid cell lines demonstrated a reduction in the expression of downstream targets (STAT3, MYC and ICAM1) in response to IL-6 stimulation in Ala358 carriers. CONCLUSIONS: A Mendelian randomization approach provides robust evidence that signalling via the IL-6R is likely to be a causal pathway in AAA. Drugs that inhibit IL-6R may play a role in AAA management.

A polygenic risk score added to a QRISK®2 cardiovascular disease risk calculator demonstrated robust clinical acceptance and clinical utility in the primary care setting.

AIMS: The aim of the study was to assess the real-world feasibility, acceptability, and impact of an integrated risk tool for cardiovascular disease (CVD IRT, combining the standard QRISK®2 risk algorithm with a polygenic risk score), implemented within routine primary practice in the UK National Health Service. METHODS AND RESULTS: The Healthcare Evaluation of Absolute Risk Testing Study (NCT05294419) evaluated participants undergoing primary care health checks. Both QRISK2 and CVD IRT scores were returned to the healthcare providers (HCPs), who then communicated the results to participants. The primary outcome of the study was feasibility of CVD IRT implementation. Secondary outcomes included changes in CVD risk (QRISK2 vs. CVD IRT) and impact of the CVD IRT on clinical decision-making. A total of 832 eligible participants (median age 55 years, 62% females, 97.5% White ethnicity) were enrolled across 12 UK primary care practices. Cardiovascular disease IRT scores were obtained on 100% of the blood samples. Healthcare providers stated that the CVD IRT could be incorporated into routine primary care in a straightforward manner in 90.7% of reports. Participants stated they were 'likely' or 'very likely' to recommend the use of this test to their family or friends in 86.9% of reports. Participants stated that the test was personally useful (98.8%) and that the results were easy to understand (94.6%). When CVD IRT exceeded QRISK2, HCPs planned changes in management for 108/388 (27.8%) of participants and 47% (62/132) of participants with absolute risk score changes of >2%. CONCLUSION: Amongst HCPs and participants who agreed to the trial of genetic data for refinement of clinical risk prediction in primary care, we observed that CVD IRT implementation was feasible and well accepted. The CVD IRT results were associated with planned changes in prevention strategies.

When a standard cardiovascular risk tool, as currently used in National Health Service Health Checks, was expanded to include genetic risk information, it was well accepted by both participants and healthcare providers and generated impactful changes in planned clinical decision-making.Most participants found the test useful and easy to understand, and healthcare providers found it straightforward to use in most cases.When risk was increased by the addition of genetic information, this influenced planned management decisions.

Association of a sequence variant in DAB2IP with coronary heart disease.

AIMS: A sequence variant, rs7025486[A], in DAB2IP on chromosome 9q33 has recently been associated with coronary heart disease (CHD). We sought to replicate this finding and to investigate associations with a panel of inflammatory and haemostatic biomarkers. We also sought to examine whether this variant, in combination with a chromosome 9p21 CHD variant (rs10757278) and the Framingham risk score (FRS), could improve the prediction of events compared with the FRS alone. METHODS AND RESULTS: rs7025486 was genotyped in 1386 CHD cases and 3532 controls and was associated with CHD [odds ratio (OR) of 1.16, 95% confidence interval (CI) 1.05-1.29, P= 0.003]. Meta-analysis, using data from the original report and from genome-wide association studies in both the Wellcome Trust Case Control Consortium and the Cardiovascular Health Study, comprising 9968 cases and 20 048 controls, confirmed the association (OR of 1.10, 95% CI 1.06-1.14, P= 3.2 × 10(-6)). There was no association with a panel of CHD biomarkers, including any lipid, inflammation, or coagulation trait, nor with telomere length. Addition to the FRS of this variant plus rs10757278 on chromosome 9p21 improved the area under the receiver-operating characteristic curve (A(ROC)) from 0.61 to 0.64 (P= 0.03) as well as improving the reclassification (net reclassification index = 11.1%, P= 0.007). CONCLUSION: This study replicates a previous association of a variant in DAB2IP with CHD. Addition of multiple variants improves the performance of predictive models based upon classical cardiovascular risk factors.

The genetics of coronary heart disease.

BACKGROUND: Coronary heart disease (CHD) is a leading cause of death worldwide, yet many areas of its pathogenesis remain unknown or poorly understood, leaving potential for novel preventive and therapeutic interventions. Recent major advances in genomic science and technology have opened new avenues of investigation in the pathogenesis of CHD, some of which are leading to clinical translation. SOURCES OF DATA: The published literature in CHD genetics has burgeoned in the last 5 years with the reporting of genome-wide association studies (GWASs) and many other findings. AREAS OF AGREEMENT: Identification of many genetic variants with small effects on CHD risk has been a common finding. These have included several predicted loci, such as those involved in conventional CHD risk factors (e.g. plasma lipids) and many novel loci, where their mechanism of action is unclear. The need for large, collaborative approaches to research has also become clear and is now an accepted modus operandi. AREAS OF CONTROVERSY: The clinical utility of novel GWAS findings remains uncertain. In particular, the relative contribution of common variants of modest effect and rare variants of larger effects to risk of CHD or response to drugs is unclear. GROWING POINTS: As a greater number of larger GWASs are conducted in CHD and its related phenotypes, much effort is being made to find translational applications for their findings. Therapeutics, prediction and pathology are major areas of research endeavour.

Elective sac perfusion to reduce the risk of neurologic events following endovascular repair of thoracoabdominal aneurysms.

Spinal cord ischemia (SCI) is a catastrophic complication of thoracoabdominal aortic aneurysm (TAAA) repair. This article describes our early experience with a technique for maintaining perfusion of segmental vessels (intercostals and lumbars) in the early postoperative period after endovascular repair of a TAAA, with "sac perfusion branches" added to custom-made stent grafts. These are closed 7 to 10 days after the first procedure to complete exclusion of the aneurysm. We have used this technique in 10 patients with type II TAAAs. One developed monoparesis of the right leg during a period of hypotension secondary to a cardiac event and died within 30 days. Two patients developed lower limb weakness after closure of the perfusion branches, both with full recovery. Controlled perfusion of segmental vessels with perfusion branches is feasible and may be a useful adjunct to prevent SCI, providing protection to spinal cord perfusion during the immediate postoperative period when risk of SCI is greatest.

Heterogeneity within and among co-occurring foundation species increases biodiversity.

Habitat heterogeneity is considered a primary causal driver underpinning patterns of diversity, yet the universal role of heterogeneity in structuring biodiversity is unclear due to a lack of coordinated experiments testing its effects across geographic scales and habitat types. Furthermore, key species interactions that can enhance heterogeneity, such as facilitation cascades of foundation species, have been largely overlooked in general biodiversity models. Here, we performed 22 geographically distributed experiments in different ecosystems and biogeographical regions to assess the extent to which variation in biodiversity is explained by three axes of habitat heterogeneity: the amount of habitat, its morphological complexity, and capacity to provide ecological resources (e.g. food) within and between co-occurring foundation species. We show that positive and additive effects across the three axes of heterogeneity are common, providing a compelling mechanistic insight into the universal importance of habitat heterogeneity in promoting biodiversity via cascades of facilitative interactions. Because many aspects of habitat heterogeneity can be controlled through restoration and management interventions, our findings are directly relevant to biodiversity conservation.

Modelling the impact of changes to abdominal aortic aneurysm screening and treatment services in England during the COVID-19 pandemic.

BACKGROUND: The National Health Service (NHS) abdominal aortic aneurysm (AAA) screening programme (NAAASP) in England screens 65-year-old men. The programme monitors those with an aneurysm, and early intervention for large aneurysms reduces ruptures and AAA-related mortality. AAA screening services have been disrupted following COVID-19 but it is not known how this may impact AAA-related mortality, or where efforts should be focussed as services resume. METHODS: We repurposed a previously validated discrete event simulation model to investigate the impact of COVID-19-related service disruption on key outcomes. This model was used to explore the impact of delayed invitation and reduced attendance in men invited to screening. Additionally, we investigated the impact of temporarily suspending scans, increasing the threshold for elective surgery to 7cm and increasing drop-out in the AAA cohort under surveillance, using data from NAAASP to inform the population. FINDINGS: Delaying invitation to primary screening up to two years had little impact on key outcomes whereas a 10% reduction in attendance could lead to a 2% lifetime increase in AAA-related deaths. In surveillance patients, a 1-year suspension of surveillance or increase in the elective threshold resulted in a 0.4% increase in excess AAA-related deaths (8% in those 5-5.4cm at the start). Longer suspensions or a doubling of drop-out from surveillance would have a pronounced impact on outcomes. INTERPRETATION: Efforts should be directed towards encouraging men to attend AAA screening service appointments post-COVID-19. Those with AAAs on surveillance should be prioritised as the screening programme resumes, as changes to these services beyond one year are likely to have a larger impact on surgical burden and AAA-related mortality.

Comparative analysis of Microcystis buoyancy in western Lake Erie and Saginaw Bay of Lake Huron.

Microcystis is the predominant genus of harmful cyanobacterium in both Lake Erie and Saginaw Bay of Lake Huron and has the capacity to regulate the buoyancy of its colonies, sinking under certain conditions while floating towards the surface in others. Understanding the factors that control buoyancy is critical for interpretation of remote sensing data, modeling and forecasting harmful algal blooms within these two systems. To determine if Microcystis colony buoyancy in the two lakes responds similarly to diurnal light cycles, colony buoyant velocity (floating/sinking terminal velocity in a quiescent water column) and size were measured after manipulating the intensity of sunlight. Overall, there were more positively buoyant (floating) colonies in Lake Erie while most of the colonies in Saginaw Bay were negatively buoyant (sinking). In Lake Erie the colonies became less buoyant at increased light intensities and were less buoyant in the afternoon than in the morning. In both lakes, apparent colony density was more variable among small colonies (< 200 µm), whereas larger colonies showed a diminished response of density to light intensity and duration. These findings suggest that colony density becomes less plastic as colonies increase in size, leading to a weak relationship between size and velocity. These relationships may ultimately affect how the bloom is transported throughout each system and will help explain observed differences in vertical distribution and movement of Microcystis in the two lakes.

Interleukin-6 Receptor Signaling and Abdominal Aortic Aneurysm Growth Rates.

BACKGROUND: The Asp358Ala variant (rs2228145; A>C) in the IL (interleukin)-6 receptor ( IL6R) gene has been implicated in the development of abdominal aortic aneurysms (AAAs), but its effect on AAA growth over time is not known. We aimed to investigate the clinical association between the IL6R-Asp358Ala variant and AAA growth and to assess the effect of blocking the IL-6 signaling pathway in mouse models of aortic aneurysm rupture or dissection. METHODS: Using data from 2863 participants with AAA from 9 prospective cohorts, age- and sex-adjusted mixed-effects linear regression models were used to estimate the association between the IL6R-Asp358Ala variant and annual change in AAA diameter (mm/y). In a series of complementary randomized trials in mice, the effect of blocking the IL-6 signaling pathways was assessed on plasma biomarkers, systolic blood pressure, aneurysm diameter, and time to aortic rupture and death. RESULTS: After adjusting for age and sex, baseline aneurysm size was 0.55 mm (95% CI, 0.13-0.98 mm) smaller per copy of the minor allele [C] of the Asp358Ala variant. Change in AAA growth was -0.06 mm per year (-0.18 to 0.06) per copy of the minor allele; a result that was not statistically significant. Although all available worldwide data were used, the genetic analyses were not powered for an effect size as small as that observed. In 2 mouse models of AAA, selective blockage of the IL-6 trans-signaling pathway, but not combined blockage of both, the classical and trans-signaling pathways, was associated with improved survival ( P<0.05). CONCLUSIONS: Our proof-of-principle data are compatible with the concept that IL-6 trans-signaling is relevant to AAA growth, encouraging larger-scale evaluation of this hypothesis.

Genetic Association of Lipids and Lipid Drug Targets With Abdominal Aortic Aneurysm: A Meta-analysis.

Importance: Risk factors for abdominal aortic aneurysm (AAA) are largely unknown, which has hampered the development of nonsurgical treatments to alter the natural history of disease. Objective: To investigate the association between lipid-associated single-nucleotide polymorphisms (SNPs) and AAA risk. Design, Setting, and Participants: Genetic risk scores, composed of lipid trait-associated SNPs, were constructed and tested for their association with AAA using conventional (inverse-variance weighted) mendelian randomization (MR) and data from international AAA genome-wide association studies. Sensitivity analyses to account for potential genetic pleiotropy included MR-Egger and weighted median MR, and multivariable MR method was used to test the independent association of lipids with AAA risk. The association between AAA and SNPs in loci that can act as proxies for drug targets was also assessed. Data collection took place between January 9, 2015, and January 4, 2016. Data analysis was conducted between January 4, 2015, and December 31, 2016. Exposures: Genetic elevation of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). Main Outcomes and Measures: The association between genetic risk scores of lipid-associated SNPs and AAA risk, as well as the association between SNPs in lipid drug targets (HMGCR, CETP, and PCSK9) and AAA risk. Results: Up to 4914 cases and 48 002 controls were included in our analysis. A 1-SD genetic elevation of LDL-C was associated with increased AAA risk (odds ratio [OR], 1.66; 95% CI, 1.41-1.96; P = 1.1 × 10-9). For HDL-C, a 1-SD increase was associated with reduced AAA risk (OR, 0.67; 95% CI, 0.55-0.82; P = 8.3 × 10-5), whereas a 1-SD increase in triglycerides was associated with increased AAA risk (OR, 1.69; 95% CI, 1.38-2.07; P = 5.2 × 10-7). In multivariable MR analysis and both MR-Egger and weighted median MR methods, the association of each lipid fraction with AAA risk remained largely unchanged. The LDL-C-reducing allele of rs12916 in HMGCR was associated with AAA risk (OR, 0.93; 95% CI, 0.89-0.98; P = .009). The HDL-C-raising allele of rs3764261 in CETP was associated with lower AAA risk (OR, 0.89; 95% CI, 0.85-0.94; P = 3.7 × 10-7). Finally, the LDL-C-lowering allele of rs11206510 in PCSK9 was weakly associated with a lower AAA risk (OR, 0.94; 95% CI, 0.88-1.00; P = .04), but a second independent LDL-C-lowering variant in PCSK9 (rs2479409) was not associated with AAA risk (OR, 0.97; 95% CI, 0.92-1.02; P = .28). Conclusions and Relevance: The MR analyses in this study lend support to the hypothesis that lipids play an important role in the etiology of AAA. Analyses of individual genetic variants used as proxies for drug targets support LDL-C lowering as a potential effective treatment strategy for preventing and managing AAA.