Systematic review and meta-analysis of the growth and rupture rates of small abdominal aortic aneurysms: implications for surveillance intervals and their cost-effectiveness.

BACKGROUND: Small abdominal aortic aneurysms (AAAs; 3.0-5.4 cm in diameter) are usually asymptomatic and managed by regular ultrasound surveillance until they grow to a diameter threshold (commonly 5.5 cm) at which surgical intervention is considered. The choice of appropriate surveillance intervals is governed by the growth and rupture rates of small AAAs, as well as their relative cost-effectiveness. OBJECTIVES: The aim of this series of studies was to inform the evidence base for small AAA surveillance strategies. This was achieved by literature review, collation and analysis of individual patient data, a focus group and health economic modelling. DATA SOURCES: We undertook systematic literature reviews of growth rates and rupture rates of small AAAs. The databases MEDLINE, EMBASE on OvidSP, Cochrane Central Register of Controlled Trials 2009 Issue 4, ClinicalTrials.gov, and controlled-trials.com were searched from inception up until the end of 2009. We also obtained individual data on 15,475 patients from 18 surveillance studies. REVIEW METHODS: Systematic reviews of publications identified 15 studies providing small AAA growth rates, and 14 studies with small AAA rupture rates, up to December 2009 (later updated to September 2012). We developed statistical methods to analyse individual surveillance data, including the effects of patient characteristics, to inform the choice of surveillance intervals and provide inputs for health economic modelling. We updated an existing health economic model of AAA screening to address the cost-effectiveness of different surveillance intervals. RESULTS: In the literature reviews, the mean growth rate was 2.3 mm/year and the reported rupture rates varied between 0 and 1.6 ruptures per 100 person-years. Growth rates increased markedly with aneurysm diameter, but insufficient detail was available to guide surveillance intervals. Based on individual surveillance data, for each 0.5-cm increase in AAA diameter, growth rates increased by about 0.5 mm/year and rupture rates doubled. To control the risk of exceeding 5.5 cm to below 10% in men, on average a 7-year surveillance interval is sufficient for a 3.0-cm aneurysm, whereas an 8-month interval is necessary for a 5.0-cm aneurysm. To control the risk of rupture to below 1%, the corresponding estimated surveillance intervals are 9 years and 17 months. Average growth rates were higher in smokers (by 0.35 mm/year) and lower in patients with diabetes (by 0.51 mm/year). Rupture rates were almost fourfold higher in women than men, doubled in current smokers and increased with higher blood pressure. Increasing the surveillance interval from 1 to 2 years for the smallest aneurysms (3.0-4.4 cm) decreased costs and led to a positive net benefit. For the larger aneurysms (4.5-5.4 cm), increasing surveillance intervals from 3 to 6 months led to equivalent cost-effectiveness. LIMITATIONS: There were no clear reasons why the growth rates varied substantially between studies. Uniform diagnostic criteria for rupture were not available. The long-term cost-effectiveness results may be susceptible to the modelling assumptions made. CONCLUSIONS: Surveillance intervals of several years are clinically acceptable for men with AAAs in the range 3.0-4.0 cm. Intervals of around 1 year are suitable for 4.0-4.9-cm AAAs, whereas intervals of 6 months would be acceptable for 5.0-5.4-cm AAAs. These intervals are longer than those currently employed in the UK AAA screening programmes. Lengthening surveillance intervals for the smallest aneurysms was also shown to be cost-effective. Future work should focus on optimising surveillance intervals for women, studying whether or not the threshold for surgery should depend on patient characteristics, evaluating the usefulness of surveillance for those with aortic diameters of 2.5-2.9 cm, and developing interventions that may reduce the growth or rupture rates of small AAAs. FUNDING: The National Institute for Health Research Health Technology Assessment programme

β3-Adrenergic receptor-dependent modulation of the medium afterhyperpolarization in rat hippocampal CA1 pyramidal neurons.

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordAction potential firing in hippocampal pyramidal neurons is regulated by generation of an afterhyperpolarization (AHP). Three phases of AHP are recognised, with the fast AHP regulating action potential firing at the onset of a burst, and the medium and slow AHPs supressing action potential firing over 100s of milliseconds and seconds respectively. Activation of β-adrenergic receptors suppresses the slow AHP by a protein kinase A-dependent pathway. However, little is known regarding modulation of the medium AHP. Application of the selective β-adrenergic receptor agonist isoproterenol suppressed both the medium and slow AHPs evoked in rat CA1 hippocampal pyramidal neurons recorded from slices maintained in organotypic culture. Suppression of the slow AHP was mimicked by intracellular application of cAMP, with the suppression of the medium AHP by isoproterenol still being evident in cAMP-dialysed cells. Suppression of both the medium and slow AHPs was antagonised by the β-adrenergic receptor antagonist propranolol. The effect of isoproterenol to suppress the medium AHP was mimicked by two β3-adrenergic receptor agonists: BRL37344 and SR58611A. The medium AHP was mediated by activation of SK and deactivation of H channels at the resting membrane potential. Suppression of the medium AHP by isoproterenol was reduced by pre-treating cells with the H-channel blocker ZD7288. These data suggest that activation of β3-adrenergic receptors inhibits H-channels, which suppresses the medium AHP in CA1 hippocampal neurons by utilising a pathway that is independent of a rise of intracellular cAMP. This finding highlights a potential new target in modulating H-channel activity, and thereby neuronal excitability

In vitro characterisation of cell-level neurophysiological diversity in the rostral nucleus reuniens of adult mice

PublishedThis is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.The nucleus reuniens (Re) is the largest of the midline thalamic nuclei. We have performed a detailed neurophysiological characterization of neurons in the rostral Re of brain slices prepared from adult male mice. At resting potential (−63.7 ± 0.6 mV), circa 90% of Re neurons fired action potentials, typically continuously at ∼8 Hz. Although Re neurons experience a significant spontaneous barrage of fast, amino-acid-mediate synaptic transmission, this was not predominantly responsible for spontaneous spiking as firing persisted in the presence of glutamate and GABA receptor antagonists. With resting potential preset to −80 mV −20 pA current injections revealed a mean input resistance of 615 MΩ and mean time constant of 38 ms. Following cessation of this stimulus a significant rebound potential was seen that was sometimes large enough to trigger a short burst of very high frequency (100–300 Hz) firing. In most cells short (2 ms), strong (2 nA) current injections elicited a single spike followed by a large afterdepolarizing potential (ADP) which, when suprathreshold, generated high frequency spiking. Similarly, in the majority of cells preset at −80 mV, 500 ms depolarizing current injections to cells led to a brief initial burst of very high frequency firing, although this was lost when cells were preset at −72 mV. Biophysical and pharmacological experiments indicate a prominent role for T-type Ca2+ channels in the high-frequency bursting of Re neurons. Finally, we describe a novel form of activity-dependent intrinsic plasticity that persistently eliminates the burst firing potential of Re neurons

Keyed Non-Parametric Hypothesis Tests

The recent popularity of machine learning calls for a deeper understanding of AI security. Amongst the numerous AI threats published so far, poisoning attacks currently attract considerable attention. In a poisoning attack the opponent partially tampers the dataset used for learning to mislead the classifier during the testing phase. This paper proposes a new protection strategy against poisoning attacks. The technique relies on a new primitive called keyed non-parametric hypothesis tests allowing to evaluate under adversarial conditions the training input's conformance with a previously learned distribution $\mathfrak{D}$. To do so we use a secret key $\kappa$ unknown to the opponent. Keyed non-parametric hypothesis tests differs from classical tests in that the secrecy of $\kappa$ prevents the opponent from misleading the keyed test into concluding that a (significantly) tampered dataset belongs to $\mathfrak{D}$.Comment: Paper published in NSS 201

Voltage- and Temperature-Dependent Allosteric Modulation of α7 Nicotinic Receptors by PNU120596

This is the final version of the article. Available from Frontiers Media via the DOI in this record.Alpha7 nicotinic acetylcholine receptors (α7 nAChR) are widely distributed throughout the central nervous system and are found at particularly high levels in the hippocampus and cortex. Several lines of evidence indicate that pharmacological enhancement of α7 nAChRs function could be a potential therapeutic route to alleviate disease-related cognitive deficits. A recent pharmacological approach adopted to increase α7 nAChR activity has been to identify selective positive allosteric modulators (PAMs). α7 nAChR PAMs have been divided into two classes: type I PAMs increase agonist potency with only subtle effects on kinetics, whereas type II agents produce additional dramatic effects on desensitization and deactivation kinetics. Here we report novel observations concerning the pharmacology of the canonical type II PAM, PNU120596. Using patch clamp analysis of acetylcholine (ACh)-mediated currents through recombinant rat α7 nAChR we show that positive allosteric modulation measured in two different ways is greatly attenuated when the temperature is raised to near physiological levels. Furthermore, PNU120596 largely removes the strong inward rectification usually exhibited by α7 nAChR-mediated responses

Disrupted in schizophrenia 1 and synaptic function in the mammalian central nervous system

This is the final version of the article. Available from the publisher via the DOI in this record.The disrupted in schizophrenia 1 (DISC1) gene is found at the breakpoint of an inherited chromosomal translocation, and segregates with major mental illnesses. Its potential role in central nervous system (CNS) malfunction has triggered intensive investigation of the biological roles played by DISC1, with the hope that this may shed new light on the pathobiology of psychiatric disease. Such work has ranged from investigations of animal behavior to detailed molecular-level analysis of the assemblies that DISC1 forms with other proteins. Here, we discuss the evidence for a role of DISC1 in synaptic function in the mammalian CNS.M. Kurihara was supported by a Medical Research Council Industrial collaborative studentship in collaboration with Pfizer, who also supported aspects of DISC1-related work in A. D. Randall’s laborator

I wish he'd listen: Client-centered interviewing approaches are associated with higher compliance with behavioral modification advice in pet dog owners

In the UK, over 40,000 dogs are given up annually to shelters or euthanized due to problem behaviors. It may be possible to reduce these numbers through behavior counseling and development of a behavior modification plan (BMP) by a canine professional (CP). However, if the client does not or cannot adhere to the BMP the dog's prospects may be compromised. This study explored the experience of the initial behavior consultation and possible reasons for adhering to (or not) the BMP from the client's perspective. An online survey solicited the opinions of canine behavior clients who had sought professional help in the UK for their dog's unwanted behavior within the last 2 years. Principal Component Analysis of Likert scale statements revealed one significant PC (P < 0.001) that explained 57% of the variation in the data and was significantly correlated with BMP compliance (r = 0.567, P < 0.001). Specifically, believing the plan was right for their dog and having CP support throughout to achieve behavior improvement through the implementation of a mutually agreed BMP were important. Qualitative thematic analysis of free text responses regarding motivation for future client BMP compliance echoed these factors. Conversely, a negative consultation experience was created by CPs adopting an authoritarian or ‘telling’ approach with their clients for example, making them feel judged. This was associated with a lack of BMP compliance. Essentially, CPs who involved their clients in BMP development were perceived as creating a positive experience of the initial behavior consultation and as a result were able to promote client BMP adherence and improvement in unwanted behavior improvement. This CP approach, which adopts a nurturing rather than an authoritarian strategy, has been termed Client-Centered Interviewing (CCI). The main thing about CCI is the client is an equal partner in the process. The core conditions are as per Rogers and Egan of empathy, congruence and unconditional positive regard. CCI builds on empathy with the client, avoids inappropriately challenging client beliefs by gently exploring options without being judgemental, clearly explains the likely cause of the behavior and the plan to resolve it, and provides a BMP that is bespoke and flexible. Future research is required to validate the findings, for example through a prospective comparison of Client-Centered Interviewing versus an instructional (authoritarian) approach. Crucially, the impact of Client-Centered Interviewing on canine welfare must also be evaluated

Will artificial intelligence eventually replace psychiatrists?

SUMMARY: The dystopian scenario of an 'artificial intelligence takeover' imagines artificial intelligence (AI) becoming the dominant form of intelligence on Earth, rendering humans redundant. As a society we have become increasingly familiar with AI and robots replacing humans in many tasks, certain jobs and even some areas of medicine, but surely this is not the fate of psychiatry?Here a computational neuroscientist (Janaina Mourão-Miranda) and psychiatrist (Justin Taylor Baker) suggest that psychiatry as a profession is relatively safe, whereas psychiatrists Christian Brown and Giles William Story predict that robots will be taking over the asylum

Muscarinic receptor-dependent long term depression in the perirhinal cortex and recognition memory are impaired in the rTg4510 mouse model of tauopathy.

This is the final version of the article. Available from the publisher via the DOI in this record.Neurodegenerative diseases affecting cognitive dysfunction, such as Alzheimer's disease and fronto-temporal dementia, are often associated impairments in the visual recognition memory system. Recent evidence suggests that synaptic plasticity, in particular long term depression (LTD), in the perirhinal cortex (PRh) is a critical cellular mechanism underlying recognition memory. In this study, we have examined novel object recognition and PRh LTD in rTg4510 mice, which transgenically overexpress tauP301L. We found that 8-9 month old rTg4510 mice had significant deficits in long- but not short-term novel object recognition memory. Furthermore, we also established that PRh slices prepared from rTg4510 mice, unlike those prepared from wildtype littermates, could not support a muscarinic acetylcholine receptor-dependent form of LTD, induced by a 5 Hz stimulation protocol. In contrast, bath application of the muscarinic agonist carbachol induced a form of chemical LTD in both WT and rTg4510 slices. Finally, when rTg4510 slices were preincubated with the acetylcholinesterase inhibitor donepezil, the 5 Hz stimulation protocol was capable of inducing significant levels of LTD. These data suggest that dysfunctional cholinergic innervation of the PRh of rTg4510 mice, results in deficits in synaptic LTD which may contribute to aberrant recognition memory in this rodent model of tauopathy.SES was supported by a Medical Research Council studentship. JTB was an Alzheimer’s Research UK Senior Research Fellow. Eli Lilly & Co supplied the rTg4510 mice

Initiation and slow propagation of epileptiform activity from ventral to dorsal medial entorhinal cortex is constrained by an inhibitory gradient.

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.The medial entorhinal cortex (mEC) has an important role in the generation and propagation of seizure activity. The organisation of the mEC is such that a number of dorso-ventral relationships exist in neurophysiological properties of neurons. These range from intrinsic and synaptic properties to density of inhibitory connectivity. We examined the influence of these gradients on generation and propagation of epileptiform activity in the mEC. Using a 16-shank silicon probe array to record along the dorso-ventral axis of the mEC in vitro, we found 4-aminopyridine (4-AP) application produces ictal-like activity originating predominantly in ventral areas. This activity spreads to dorsal mEC at a surprisingly slow velocity (138 μm.s-1), while cross-site interictal-like activity appeared relatively synchronous. We propose that ictal propagation is constrained by differential levels of GABAergic control since increasing (diazepam) or decreasing (Ro19-4603) GABAAreceptor activation, respectively, reduced or increased the slope of ictal initiation. The observation that ictal activity is predominately generated in ventral mEC was replicated using a separate 0-Mg2+model of epileptiform activity in vitro. By using a distinct disinhibition model (co-application of kainate and picrotoxin) we show that additional physiological features (for example intrinsic properties of mEC neurons) still produce a prevalence for interictal-like initiation in ventral mEC. These findings suggest that the ventral mEC is more likely to initiate hyperexcitable discharges than dorsal, and that seizure propagation is highly dependent on levels of GABAergic expression across the mEC. This article is protected by copyright. All rights reserved.This work was supported by a University of Exeter and Eli Lilly studentship (T.R). P.M 513 was supported by an MRC Proximity to Discovery award in partnership with 514 AstraZeneca. K.G.P was an employee of Eli Lilly. A.D.R was part funded by a Royal 515 Society Industrial Fellowship. J.T.B was an Alzheimer’s Research UK Senior Research 516 Fellow (ARUK-SRF2012-6)