Discrete Event Simulation for Decision Modeling in Health Care: Lessons from Abdominal Aortic Aneurysm Screening

Markov models are often used to evaluate the cost-effectiveness of new healthcare interventions but they are sometimes not flexible enough to allow accurate modeling or investigation of alternative scenarios and policies. A Markov model previously demonstrated that a one-off invitation to screening for abdominal aortic aneurysm (AAA) for men aged 65 y in the UK and subsequent follow-up of identified AAAs was likely to be highly cost-effective at thresholds commonly adopted in the UK (£20,000 to £30,000 per quality adjusted life-year). However, new evidence has emerged and the decision problem has evolved to include exploration of the circumstances under which AAA screening may be cost-effective, which the Markov model is not easily able to address. A new model to handle this more complex decision problem was needed, and the case of AAA screening thus provides an illustration of the relative merits of Markov models and discrete event simulation (DES) models. An individual-level DES model was built using the R programming language to reflect possible events and pathways of individuals invited to screening v. those not invited. The model was validated against key events and cost-effectiveness, as observed in a large, randomized trial. Different screening protocol scenarios were investigated to demonstrate the flexibility of the DES. The case of AAA screening highlights the benefits of DES, particularly in the context of screening studies

Investigating hyper-vigilance for social threat of lonely children

The hypothesis that lonely children show hypervigilance for social threat was examined in a series of three studies that employed different methods including advanced eye-tracking technology. Hypervigilance for social threat was operationalized as hostility to ambiguously motivated social exclusion in a variation of the hostile attribution paradigm (Study 1), scores on the Children’s Rejection-Sensitivity Questionnaire (Study 2), and visual attention to socially rejecting stimuli (Study 3). The participants were 185 children (11 years-7 months to 12 years-6 months), 248 children (9 years-4 months to 11 years-8 months) and 140 children (8 years-10 months to 12 years-10 months) in the three studies, respectively. Regression analyses showed that, with depressive symptoms covaried, there were quadratic relations between loneliness and these different measures of hypervigilance to social threat. As hypothesized, only children in the upper range of loneliness demonstrated elevated hostility to ambiguously motivated social exclusion, higher scores on the rejection sensitivity questionnaire, and disengagement difficulties when viewing socially rejecting stimuli. We found that very lonely children are hypersensitive to social threat

The Generation of Successive Unmarked Mutations and Chromosomal Insertion of Heterologous Genes in Actinobacillus pleuropneumoniae Using Natural Transformation

We have developed a simple method of generating scarless, unmarked mutations in Actinobacillus pleuropneumoniae by exploiting the ability of this bacterium to undergo natural transformation, and with no need to introduce plasmids encoding recombinases or resolvases. This method involves two successive rounds of natural transformation using linear DNA: the first introduces a cassette carrying cat (which allows selection by chloramphenicol) and sacB (which allows counter-selection using sucrose) flanked by sequences to either side of the target gene; the second transformation utilises the flanking sequences ligated directly to each other in order to remove the cat-sacB cassette. In order to ensure efficient uptake of the target DNA during transformation, A. pleuropneumoniae uptake sequences are added into the constructs used in both rounds of transformation. This method can be used to generate multiple successive deletions and can also be used to introduce targeted point mutations or insertions of heterologous genes into the A. pleuropneumoniae chromosome for development of live attenuated vaccine strains. So far, we have applied this method to highly transformable isolates of serovars 8 (MIDG2331), which is the most prevalent in the UK, and 15 (HS143). By screening clinical isolates of other serovars, it should be possible to identify other amenable strains

Cost-Effectiveness Findings from the Agewell Pilot Study of Behaviour Change to Promote Health and Wellbeing in Later Life.

Background: Participation in cognitive and physical activities may help to maintain health and wellbeing in older people. The Agewell study explored the feasibility of increasing cognitive and physical activity in older people through a goal-setting approach. This paper describes the findings of the cost-effectiveness analysis. Method: Individuals over the age of 50 and attending an Agewell centre in North Wales were randomised to one of three conditions: control (IC), goal-setting (GS), or goal-setting with mentoring (GM). We undertook a cost-effectiveness analysis comparing GS vs. IC, GM vs. IC and GM vs. GS. The primary outcome measure for this analysis was the QALY, calculated using the EQ-5D. Participants’ health and social care contacts were recorded and costed using national unit costs. Results: Seventy participants were followed-up at 12 months. Intervention set up and delivery costs were £252 per participant in the GS arm and £269 per participant in the GM arm. Mean health and social care costs over 12 months were £1,240 (s.d. £3,496) per participant in the IC arm, £1,259 (s.d. £3,826) per participant in the GS arm and £1,164 (s.d. £2,312) per participant in the GM arm. At a willingness to pay threshold of £20,000 per QALY there was a 65% probability that GS was cost-effective compared to IC (ICER of £1,070). However, there was only a 41% probability that GM was cost-effective compared to IC (ICER of £2,830) at a threshold of £20,000 per QALY. Conclusion: Setting up and running the community based intervention was feasible. Due to the small sample size it is not possible to draw a firm conclusion about cost-effectiveness; however, our preliminary results suggest that goal- setting is likely to be cost-effective compared to the control condition of no goal-setting, the addition of mentoring was effective but not cost-effective.Lifelong Health and Well-being Programme through the Medical Research Counci

In Vitro Functional Analyses of Infrequent Nucleotide Variants in the Lactase Enhancer Reveal Different Molecular Routes to Increased Lactase Promoter Activity and Lactase Persistence

The genetic trait that allows intestinal lactase to persist into adulthood in some 35% of humans worldwide operates at the level of transcription, the effect being caused by cis-acting nucleotide changes upstream of the lactase gene (LCT). A single nucleotide substitution, -13910 C>T, the first causal variant to be identified, accounts for lactase persistence over most of Europe. Located in a region shown to have enhancer function in vitro, it causes increased activity of the LCT promoter in Caco-2 cells, and altered transcription factor binding. Three other variants in close proximity, -13907 C>G, -13915 T>C and -14010 G>C, were later shown to behave in a similar manner. Here, we study four further candidate functional variants. Two, -14009 T>G and -14011 C>T, adjacent to the well-studied -14010 G>C variant, also have a clear effect on promoter activity upregulation as assessed by transfection assays, but notably are involved in different molecular interactions. The results for the two other variants (-14028 T>C, -13779 G>C) were suggestive of function, -14028*C showing a clear change in transcription factor binding, but no obvious effect in transfections, while -13779*G showed greater effect in transfections but less on transcription factor binding. Each of the four variants arose on independent haplotypic backgrounds with different geographic distribution

Disrupted hippocampal sharp-wave ripple-associated spike dynamics in a transgenic mouse model of dementia.

This is the peer reviewed version of the article, which has been published in final form at DOI: 10.1113/jphysiol.2014.282889. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.Neurons within the CA1 region of the hippocampus are co-activated during high frequency (100-250 Hz) sharp wave ripple (SWR) activity in a manner that likely drives synaptic plasticity and promotes memory consolidation. In this study we have used a transgenic mouse model of dementia (rTg4510 mice) which overexpresses a mutant form of tau protein, to examine the effects of tauopathy on hippocampal SWRs and associated neuronal firing. Tetrodes were used to record simultaneous extracellular action potentials and local field potentials from the dorsal CA1 pyramidal cell layer of 7-8 month old wild-type and rTg4510 mice at rest in their home cage. At this age point these mice exhibit neurofibrillary tangles, neurodegeneration and cognitive deficits. Epochs of sleep or quiet restfulness were characterised by minimal locomotor activity and a low theta/delta ratio in the local field potential power spectrum. SWRs detected off-line were significantly lower in amplitude and had an altered temporal structure in rTg4510 mice. Nevertheless, the average frequency profile and duration of the SWRs were relatively unaltered. Putative interneurons displayed significantly less temporal and phase locking to SWRs in rTg4510 mice, whilst putative pyramidal neurons showed increased temporal and phase locking to SWRs. These findings indicate there is reduced inhibitory control of hippocampal network events and points to a novel mechanism which may contribute to impairments in memory consolidation in this model of dementia. This article is protected by copyright. All rights reserved.Alzheimer’s Research UKMedical Research Counci

Cold-Water Mediates Greater Reductions in Limb Blood Flow than Whole Body Cryotherapy.

PURPOSE: Cold-water immersion (CWI) and whole body cryotherapy (WBC) are widely used recovery methods in an attempt to limit exercise-induced muscle damage, soreness and functional deficits after strenuous exercise. The aim of this study was to compare the effects of ecologically-valid CWI and WBC protocols on post-exercise lower limb thermoregulatory, femoral artery and cutaneous blood flow responses. METHODS: Ten males completed a continuous cycle exercise protocol at 70% maximal oxygen uptake until a rectal temperature of 38°C was attained. Participants were then exposed to lower-body CWI (8°C) for 10 min, or WBC (-110°C) for 2 min, in a randomized cross-over design. Rectal and thigh skin, deep and superficial muscle temperatures, thigh and calf skin blood flow (laser Doppler flowmetry), superficial femoral artery blood flow (duplex ultrasound) and arterial blood pressure were measured prior to, and for 40 min post, cooling interventions. RESULTS: Greater reductions in thigh skin (CWI, -5.9±1.8°C; WBC, 0.2±0.5°C; P < 0.001) and superficial (CWI, -4.4±1.3°C; WBC, -1.8±1.1°C; P < 0.001) and deep (CWI, -2.9±0.8°C; WBC, -1.3±0.6°C; P < 0.001) muscle temperatures occurred immediately after CWI. Decreases in femoral artery conductance were greater after CWI (CWI, -84±11%; WBC, -59±21%, P < 0.02) and thigh (CWI, -80±5%; WBC, -59±14%, P < 0.001) and calf (CWI, -73±13%; WBC, -45±17%, P < 0.001) cutaneous vasoconstriction was greater following CWI. Reductions in rectal temperature were similar between conditions after cooling (CWI, -0.6±0.4°C; WBC, -0.6±0.3°C; P = 0.98). CONCLUSION: Greater reductions in blood flow and tissue temperature were observed after CWI in comparison to WBC. These novel findings have practical and clinical implications for the use of cooling in the recovery from exercise and injury

Stress and visual function in infantile nystagmus syndrome.

PURPOSE: Infantile nystagmus syndrome (INS) is an involuntary oscillation of the eyes that has been reported to impair vision and worsen under stress. This investigation aimed to measure visual function in terms of visual acuity (VA) and response time (RT), when INS subjects are placed under stress. METHODS: A total of 23 subjects with INS and 20 control subjects performed a 2-alternative forced choice (2AFC) staircase procedure identifying the gap in a Landolt C, under 4 experimental conditions: initial acclimatization (A); task demand (TD), during which subjects received a small electrical shock for every incorrect answer; anticipatory anxiety (AA), during which subjects received a small shock at random intervals; and relaxed (R). Arousal was monitored with galvanic skin conductance (SkC). In addition to VA and eye movements, RTs were recorded. RESULTS: The SkC was higher in the TD and AA periods and lower during A and R. Shock significantly increased nystagmus amplitude (P < 0.01) and intensity (P < 0.007), and reduced foveation periods (FPs, P < 0.022). In both groups, VA was not reduced, but showed a slight improvement. However, shock increased RT (P < 0.009), and INS subjects were slower than controls (P < 0.0005). CONCLUSIONS: Increased arousal ("stress") provoked more intense nystagmus eye movements. As seen in other studies, stress did not reduce VA despite the shorter FPs. Although VA and FP can correlate across subjects, there would appear to be little correlation, if any, within a subject. However, RTs did increase with stress and shorter FPs, which may have an adverse impact on the visual performance of those with INS

Potentiation of sensory responses in ventrobasal thalamus in vivo via selective modulation of mGlu1 receptors with a positive allosteric modulator.

Metabotropic glutamate subtype 1 (mGlu1) receptor is thought to play a role in synaptic responses in thalamic relay nuclei. The aim of this study was to evaluate the positive allosteric modulator (PAM) Ro67-4853 as a tool to modulate thalamic mGlu1 receptors on single thalamic neurones in vivo. Ro67-4853, applied by iontophoresis onto ventrobasal thalamus neurones of urethane-anaesthetised rats, selectively enhanced responses to the agonist (S)-3,5-dihydroxy-phenylglycine (DHPG), an effect consistent with mGlu1 potentiation. The PAM was also able to enhance maintained responses to 10 Hz trains of sensory stimulation of the vibrissae, but had little effect on responses to single sensory stimuli. Thus Ro67-4853 appears to be a highly selective tool that can be useful in investigating how mGlu1 receptor potentiation can alter neural processing in vivo. Our results show the importance of mGlu1 in sensory processing and attention mechanisms at the thalamic level and suggest that positive modulation of mGlu1 receptors might be a useful mechanism for enhancing cognitive and attentional processes