Screening for Popliteal Aneurysms Should not be a Routine Part of a Community-Based Aneurysm Screening Program

Martin Claridge1, Simon Hobbs1, Clive Quick2, Donald Adam1, Andrew Bradbury1, Teun Wilmink11University Department of Vascular Surgery, Birmingham Heartlands Hospital, Birmingham, UK; 2Department of Surgery, Hinchingbrooke Hospital, Huntingdon, UKIntroduction: Several studies have found an increased incidence of peripheral aneurysms in patients with an abdominal aortic aneurysm (AAA). The aim of this study was to determine whether screening for popliteal aneurysms should be part of an AAA screening programme.Setting: A community-based AAA screening programmeMethods: The diameters of the internal abdominal aorta and both popliteal arteries were assessed by B-Mode ultrasound in a subgroup of the screened population. An AAA was defined as an infrarenal aortic diameter >29 mm. A popliteal aneurysm was defined as a popliteal diameter >19 mm.Results: Information was available for 283 subjects, 112 subjects with a small AAA, and 171 subjects with a normal aorta. No popliteal aneurysms were found in the subjects with a normal aorta. Three popliteal aneurysms were found in patients with a small AAA. Scanning both popliteal arteries took an experienced sonographer on average three times as long as scanning for an AAA (5 vs 15 minutes).Conclusion: Popliteal artery aneurysms are seen in less than 3% of men with a small AAA and not at all in men with a normal aortic diameter. It is therefore not cost effective to include screening for popliteal aneurysms in population screening for AAA.Keywords: popliteal aneurysm, screening progra

Nonsteroidal Antiinflammatory Drugs are Associated with Increased Aortic Stiffness

Martin Claridge1, Simon Hobbs1, Clive Quick2, Nick Day3, Andrew Bradbury1, Teun Wilmink11Department of Vascular Surgery, University of Birmingham, Birmingham Heartlands Hospital Birmingham, UK; 2Department of Surgery, Hinchingbrooke Hospital, Huntingdon, UK; 3Department of Epidemiology and Biostatistics, University of Cambridge, Cambridge, UKObjectives: Nonsteroidal antiinflammatory drugs (NSAIDS) have been shown to retard aneurysm growth in animal models. In vitro studies have shown an inhibitory effect of NSAIDS on matrix metalloproteinase-9, interleukin-1β, and IL-6 mediated arterial wall elastolysis. The aim of this study was to investigate the effects of NSAIDs on arterial stiffness, a surrogate marker of elastolysis.Methods: 447 subjects enrolled in a community-based abdominal aortic aneurysm (AAA) screening program were assessed for age, blood pressure, smoking status, and drug history. Aortic diameter and stiffness were measured by M-Mode ultrasound. The concentration of the amino-terminal propeptide of type III procollagen was used as a proxy measurement of type III collagen turnover.Results: NSAID ingestion was significantly (p = 0.006) associated with increased aortic wall stiffness after adjusting for age, aortic diameter, blood pressure, and smoking status. No such effect was seen for β-blockers, calcium channel antagonists, nitrates, angiotensin-converting enzyme inhibitors, diuretics, or antiplatelet agents.Discussion: These novel data show that NSAIDS are associated with increased aortic stiffness, possibly through the effects of cytokine mediated elastolysis. This in turn may prevent aortic expansion and the development of AAA.Keywords: nonsteroidal antiinflammatory drugs, abdominal aortic aneurysm, aortic stiffness, elastolysi

Recreational ketamine-related deaths notified to the National Programme on Substance Abuse Deaths, England, 1997-2019

© 2021 The Authors. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Background: Ketamine is a phencyclidine derivative with dissociative anaesthetic properties. Increasing numbers of individuals in England take ketamine recreationally. Information on deaths arising from such use in England is presented. Methods: Cases were extracted on 31 January 2020 from the National Programme on Substance Abuse Deaths database, based on text searches of the cause of death, coroner’s verdict and positive toxicology results for the terms ‘ketamine’ or ‘norketamine’. Findings: During 1997–2005, there were <5 deaths p.a. in which ketamine was implicated. Numbers increased until 2009 (21), plateauing until 2016; thereafter, deaths have risen to about 30 p.a. Decedents’ characteristics (N = 283): male 84.1%, mean age 31.2 (SD 10.0) years, employed 56.5%, drug use history 79.6% and living with others 60.3%. Ketamine was detected with other substances in most cases. Main (74.6%) underlying cause of death was accidental poisoning. Ketamine may have impaired judgement in other cases. Conclusions: Although controlled, recreational ketamine use and related fatalities continue to increase. Consumers need to be more aware of the potentially fatal risks they face.Peer reviewedFinal Published versio

Effect of ramipril on renal function in patients with intermittent claudication

Simon D Hobbs1, Martin W Claridge1, Antonius BM Wilmink1, Donald J Adam1, Mark E Thomas2, Andrew W Bradbury11University Department of Vascular Surgery and 2Department of Nephrology, Heart of England NHS Trust (Teaching), Birmingham, UKBackground: The Heart Outcomes Prevention Study (HOPE) demonstrated that ramipril resulted in a blood-pressure-independent 25% reduction in cardiovascular events in patients with peripheral arterial disease (PAD). Despite this, general practitioners and vascular surgeons remain reluctant to prescribe ACE inhibitors in this group of patients because of concerns about renal artery stenosis (RAS). We aimed to define the effect of ramipril on renal function in patients with intermittent claudication (IC).Methods and Results: Of 132 unselected patients with IC entering the study 78 (59%) were excluded due to: current ACE inhibitor use (38%), renal impairment (serum creatinine above normal range) (15%), known severe RAS (1%) or unwillingness to participate (5%). The remaining 54 patients were titrated to 10 mg ramipril and renal function was monitored at 1, 5, and 12 weeks. Treatment was discontinued during titration in 5 patients due to symptoms (3) or lack of compliance (2). In the remainder, median [IQR] serum creatinine increased (94 [85.8&amp;ndash;103.3] to 98 [88.0&amp;ndash;106.5] &amp;micro;mol/L, p &amp;le; 0.001) and median [IQR] GFR decreased (71.5 [64.6&amp;ndash;82.3] to 68.7 [59.8&amp;ndash;74.7] mL/min per 1.73 m2, p &amp;le; 0.001) between baseline and 5 weeks. These changes were not considered clinically significant. By 12 weeks these values had returned almost to baseline (Cr 95.5 [88.0&amp;ndash;103.25] &amp;micro;mol/L, GFR 71.8 [65.3&amp;ndash;77.4] mL/min). No patient had a serum creatinine rise &amp;gt;30%.Conclusion: Most of patients with IC and a normal serum creatinine can be safely commenced on ramipril provided they are screened, titrated and monitored as described above. Studies in patients with borderline renal impairment (serum creatinine up to 30% above baseline) are on-going.Keywords: peripheral arterial disease, ramipril, renal function, intermittent claudicatio

Autonomic modulation in patients with heart failure increases beat-to-beat variability of ventricular action potential duration

Background: Exaggerated beat-to-beat variability of ventricular action potential duration (APD) is linked to arrhythmogenesis. Sympathetic stimulation has been shown to increase QT interval variability, but its effect on ventricular APD in humans has not been determined.Methods and Results: Eleven heart failure patients with implanted bi-ventricular pacing devices had activation–recovery intervals (ARI, surrogate for APD) recorded from LV epicardial electrodes under constant RV pacing. Sympathetic activity was increased using a standard autonomic challenge (Valsalva) and baroreceptor indices were applied to determine changes in sympathetic stimulation. Two Valsalvas were performed for each study and were repeated, both off and on bisoprolol. In addition sympathetic nerve activity (SNA) was measured from skin electrodes on the thorax using a novel validated method. Autonomic modulation significantly increased mean short-term variability in ARI; off bisoprolol mean STV increased from 3.73 ± 1.3 to 5.27 ± 1.04 ms (p = 0.01), on bisoprolol mean STV of ARI increased from 4.15 ± 1.14 to 4.62 ± 1 ms (p = 0.14). Adrenergic indices of the Valsalva demonstrated significantly reduced beta-adrenergic function when on bisoprolol (Δ pressure recovery time, p = 0.04; Δ systolic overshoot in Phase IV, p = 0.05). Corresponding increases in SNA from rest both off (1.4 uV, p &lt; 0.01) and on (0.7 uV, p &lt; 0.01) bisoprolol were also seen.Conclusions: Beat-to-beat variability of ventricular APD increases during brief periods of increased sympathetic activity in patients with heart failure. Bisoprolol reduces, but does not eliminate, these effects. This may be important in the genesis of ventricular arrhythmias in heart failure patients

Distal Repair After Total Aortic Arch Replacement With Frozen Elephant Trunk in Patients With Chronic Multilevel Thoracic Aortic Disease.

ObjectiveTo examine the management of distal aortic disease after total arch replacement with the frozen elephant trunk (TAR + FET) in patients with chronic thoracic aortic disease.MethodsTwo centre retrospective study of consecutive patients treated between January 2010 and December 2019. Primary endpoint was 30 day/in hospital mortality. Secondary end point was mid-term survival. Data are presented as median (IQR). Chi squared or Fisher's exact test was used as appropriate. Estimated survival (standard error) was assessed by the calculating Kaplan-Meier product limit estimator with right censoring of survival data. A p value of ResultsA total of 158 patients (72 men; median age 70, IQR 64, 75; median distal aortic diameter 58 mm (46, 68; 127 aneurysmal disease, 31 chronic dissection) underwent TAR + FET. Peri-operative mortality was 10.1% (9/107 elective, 7/51 non-elective). Of 74 (46.8%) patients with a primary distal seal, seven (9.5%) died peri-operatively, distal seal was maintained during follow up in 51, nine underwent late distal repair (two planned, seven unplanned; one open, eight endovascular; one peri-operative death) with a median interval to unplanned repair of 777 days (462, 1480), and seven with loss of seal had no intervention. Distal seal failed in 2/28 (7%) patients with a distal seal length > 30 mm and device oversizing > 10%, compared with 12/39 (31%) patients who did not meet these criteria (p = .031). In 84 patients without primary distal seal, nine (10.7%) died peri-operatively, the distal aorta remained below the size threshold for repair during follow up in 12 patients, 44 had distal repair (median aortic diameter 64 mm, 60, 75; eight open, one hybrid, 35 endovascular repairs; no mortality) at a median of 256 days (135, 740), and 19 did not have distal repair at the end of the follow up period: six died before planned repair at a median interval of 115 days (85, 120); eight were considered unfit; one was assessed as fit but declined; and four patients were awaiting assessment). Median follow up was 46 months (26, 75): no patients were lost to follow up. Estimated ± standard error five year survival was 61.5 ± 4.1%: elective 70.6 ± 4.7%, non-elective 43.2 ± 7.2%.ConclusionTAR + FET achieved primary distal seal in 47% of patients, but late failure occurred in 21% of patients. Distal repair was ultimately indicated in 84% of survivors without primary distal seal and of these 70% underwent repair, almost 10% died before planned repair, and 13% were considered unfit. Earlier distal endovascular repair and better assessment of patient fitness may improve mid-term outcomes

A Pair of Dopamine Neurons Target the D1-Like Dopamine Receptor DopR in the Central Complex to Promote Ethanol-Stimulated Locomotion in Drosophila

Dopamine is a mediator of the stimulant properties of drugs of abuse, including ethanol, in mammals and in the fruit fly Drosophila. The neural substrates for the stimulant actions of ethanol in flies are not known. We show that a subset of dopamine neurons and their targets, through the action of the D1-like dopamine receptor DopR, promote locomotor activation in response to acute ethanol exposure. A bilateral pair of dopaminergic neurons in the fly brain mediates the enhanced locomotor activity induced by ethanol exposure, and promotes locomotion when directly activated. These neurons project to the central complex ellipsoid body, a structure implicated in regulating motor behaviors. Ellipsoid body neurons are required for ethanol-induced locomotor activity and they express DopR. Elimination of DopR blunts the locomotor activating effects of ethanol, and this behavior can be restored by selective expression of DopR in the ellipsoid body. These data tie the activity of defined dopamine neurons to D1-like DopR-expressing neurons to form a neural circuit that governs acute responding to ethanol

Dopamine Modulates the Rest Period Length without Perturbation of Its Power Law Distribution in Drosophila melanogaster

We analyzed the effects of dopamine signaling on the temporal organization of rest and activity in Drosophila melanogaster. Locomotor behaviors were recorded using a video-monitoring system, and the amounts of movements were quantified by using an image processing program. We, first, confirmed that rest bout durations followed long-tailed (i.e., power-law) distributions, whereas activity bout durations did not with a strict method described by Clauset et al. We also studied the effects of circadian rhythm and ambient temperature on rest bouts and activity bouts. The fraction of activity significantly increased during subjective day and at high temperature, but the power-law exponent of the rest bout distribution was not affected. The reduction in rest was realized by reduction in long rest bouts. The distribution of activity bouts did not change drastically under the above mentioned conditions. We then assessed the effects of dopamine. The distribution of rest bouts became less long-tailed and the time spent in activity significantly increased after the augmentation of dopamine signaling. Administration of a dopamine biosynthesis inhibitor yielded the opposite effects. However, the distribution of activity bouts did not contribute to the changes. These results suggest that the modulation of locomotor behavior by dopamine is predominantly controlled by changing the duration of rest bouts, rather than the duration of activity bouts

Targeted kinase inhibition relieves slowness and tremor in a Drosophila model of LRRK2 Parkinson’s disease

Disease models: A reflex reaction A simple reflex in flies can be used to test the effectiveness of therapies that slow neurodegeneration in Parkinson’s disease (PD). Christopher Elliott and colleagues at the University of York in the United Kingdom investigated the contraction of the proboscis muscle which mediates a taste behavior response and is regulated by a single dopaminergic neuron. Flies bearing particular mutations in the PD-associated gene leucine-rich repeat kinase 2 (LRRK2) in dopaminergic neurons lost their ability to feed on a sweet solution. This was due to the movement of the proboscis muscle becoming slower and stiffer, hallmark features of PD. The authors rescued the impaired reflex reaction by feeding the flies l-DOPA or LRRK2 inhibitors. These findings highlight the proboscis extension response as a useful tool to identify other PD-associated mutations and test potential therapeutic compounds

Biogeography in the deep : hierarchical population genomic structure of two beaked whale species

Funding for this research was provided by the Office of Naval Research, Award numbers N000141613017 and N000142112712. ABO was supported by a partial studentship from the University of St Andrews, School of Biology; OEG by the Marine Alliance for Science and Technology for Scotland (Scottish Funding Council grant HR09011); ELC by a Rutherford Discovery Fellowship from the Royal Society of New Zealand Te Aparangi; NAS by a Ramon y Cajal Fellowship from the Spanish Ministry of Innovation; MLM by the European Union’s Horizon 2020 Research and Innovation Programme (Marie Skłodowska-Curie grant 801199); CR by the Marine Institute (Cetaceans on the Frontier) and the Irish Research Council; and MTO by the Hartmann Foundation.The deep sea is the largest ecosystem on Earth, yet little is known about the processes driving patterns of genetic diversity in its inhabitants. Here, we investigated the macro- and microevolutionary processes shaping genomic population structure and diversity in two poorly understood, globally distributed, deep-sea predators: Cuvier’s beaked whale (Ziphius cavirostris) and Blainville’s beaked whale (Mesoplodon densirostris). We used double-digest restriction associated DNA (ddRAD) and whole mitochondrial genome (mitogenome) sequencing to characterise genetic patterns using phylogenetic trees, cluster analysis, isolation-by-distance, genetic diversity and differentiation statistics. Single nucleotide polymorphisms (SNPs; Blainville’s n = 43 samples, SNPs=13988; Cuvier’s n = 123, SNPs= 30479) and mitogenomes (Blainville’s n = 27; Cuvier’s n = 35) revealed substantial hierarchical structure at a global scale. Both species display significant genetic structure between the Atlantic, Indo-Pacific and in Cuvier’s, the Mediterranean Sea. Within major ocean basins, clear differentiation is found between genetic clusters on the east and west sides of the North Atlantic, and some distinct patterns of structure in the Indo-Pacific and Southern Hemisphere. We infer that macroevolutionary processes shaping patterns of genetic diversity include biogeographical barriers, highlighting the importance of such barriers even to highly mobile, deep-diving taxa. The barriers likely differ between the species due to their thermal tolerances and evolutionary histories. On a microevolutionary scale, it seems likely that the balance between resident populations displaying site fidelity, and transient individuals facilitating gene flow, shapes patterns of connectivity and genetic drift in beaked whales. Based on these results, we propose management units to facilitate improved conservation measures for these elusive species.Publisher PDFPeer reviewe