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Repeated administration of high doses of propofol to patients with treatment-resistant depression (TRD) has been shown to produce antidepressant effects in small clinical trials. These effects can be elicited when the patient's EEG burst-suppression ratio (BSR) is maintained at 70-90% for 15 min in repeated treatments. This deep anesthesia domain lies beyond the range of current propofol pharmacokinetic/pharmacodynamic (PK/PD) models. In this study, we adapt the Eleveld model for use at deep anesthesia levels with a BSR endpoint, with the goal of aiding the estimation of the dosage of propofol needed to achieve 70-90% BSR for 15 min. We test the ability of the adapted model to predict BSR for these treatments. Twenty participants underwent 6-9 treatments of high doses of propofol (5-9 of which were included in this analysis) for a total of 115 treatments. To adapt the Eleveld model for this endpoint, we optimized the model parameters Ke0, γ and Ce50. These parameters were then used in the adapted model to estimate second-by-second BSR for each treatment. Estimated BSR was compared with observed BSR for each treatment of each participant. Median absolute performance error (MdAPE) between the estimated and observed BSR (25th-75th percentile) was 6.63 (3.79-12.96) % points and 8.51 (4.32-16.74) % between the estimated and observed treatment duration. This predictive performance is statistically significantly better at predicting BSR compared with the standard Eleveld model at deep anesthesia levels. Our adapted Eleveld model provides a useful tool to aid dosing propofol for high-dose anesthetic treatments for depression.

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BACKGROUND: Personalized music programs have been proposed as an adjunct therapy for patients with Alzheimer disease related dementia, and multicenter trials have now demonstrated improvements in agitation, anxiety, and behavioral symptoms. Underlying neurophysiological mechanisms for these effects remain unclear. METHODS: We examined 17 individuals with a clinical diagnosis of Alzheimer disease related dementia using functional MRI following a training period in a personalized music listening program. RESULTS: We find that participants listening to preferred music show specific activation of the supplementary motor area, a region that has been associated with memory for familiar music that is typically spared in early Alzheimer disease. We also find widespread increases in functional connectivity in corticocortical and corticocerebellar networks following presentation of preferred musical stimuli, suggesting a transient effect on brain function. CONCLUSIONS: Findings support a mechanism whereby attentional network activation in the brain's salience network may lead to improvements in brain network synchronization.

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OBJECTIVE: To estimate the prevalence of painful sex among women in Britain, and to explore associated sexual, relationship and health factors that should be considered in assessment. DESIGN: Multi-stage, clustered and stratified population probability sample survey, using computer-assisted self-interview. Sample frame was the British Postcode Address File. SETTING: Participants interviewed at home between 2010 and 2012. SAMPLE: A total of 15 162 adults aged 16-74 years (8869 women). Data reported from 6669 sexually active women. METHODS: Age-adjusted logistic regressions to examine associations between painful sex and indicators of sexual, relational, mental and physical health. MAIN OUTCOME MEASURE: Physical pain as a result of sex for ≥3 months in the past year, plus measures of symptom severity. RESULTS: Painful sex was reported by 7.5% (95% CI 6.7-8.3) of sexually active women, of whom one-quarter experienced symptoms very often or always, for ≥6 months, and causing distress. Reporting painful sex was strongly associated with other sexual function problems, notably vaginal dryness (age adjusted odds ratio 7.9; 6.17-10.12), anxiety about sex (6.34; 4.76-8.46) and lacking enjoyment in sex (6.12; 4.81-7.79). It was associated with sexual relationship factors [such as not sharing same level of interest in sex (2.56; 1.97-3.33)], as well as with adverse experiences such as non-volitional sex (2.17; 1.68-2.80). Associations were also found with measures of psychological and physical health, including depressive symptoms (1.68; 1.28-2.21). CONCLUSION: Painful sex is reported by a sizeable minority of women in Britain. Health professionals should be supported to undertake holistic assessment and treatment which takes account of the sexual, relationship and health context of symptoms. TWEETABLE ABSTRACT: Painful sex-reported by 7.5% of women in Britain-is linked to poorer sexual, physical, relational and mental health.

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BACKGROUND: Partnership type is a determinant of STI risk; yet, it is poorly and inconsistently recorded in clinical practice and research. We identify a novel, empirical-based categorisation of partnership type, and examine whether reporting STI diagnoses varies by the resulting typologies. METHODS: Analyses of probability survey data collected from 15 162 people aged 16-74 who participated in Britain's third National Survey of Sexual Attitudes and Lifestyles were undertaken during 2010-2012. Computer-assisted self-interviews asked about participants' ≤3 most recent partners (N=14 322 partners/past year). Analysis of variance and regression tested for differences in partnership duration and perceived likelihood of sex again across 21 'partnership progression types' (PPTs) derived from relationship status at first and most recent sex. Multivariable regression examined the association between reporting STI diagnoses and partnership type(s) net of age and reported partner numbers (all past year). RESULTS: The 21 PPTs were grouped into four summary types: 'cohabiting', 'now steady', 'casual' and 'ex-steady' according to the average duration and likelihood of sex again. 11 combinations of these summary types accounted for 94.5% of all men; 13 combinations accounted for 96.9% of all women. Reporting STI diagnoses varied by partnership-type combination, including after adjusting for age and partner numbers, for example, adjusted OR: 6.03 (95% CI 2.01 to 18.1) for men with two 'casual' and one 'now steady' partners versus men with one 'cohabiting' partner. CONCLUSIONS: This typology provides an objective method for measuring partnership type and demonstrates its importance in understanding STI risk, net of partner numbers. Epidemiological research and clinical practice should use these methods and results to maximise individual and public health benefit.

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BACKGROUND: Health risk behaviours are prominent in late adolescence and young adulthood, yet UK population-level research examining the relationship between drug or alcohol use and sexual health and behaviour among young people is scarce, despite public health calls for an integrated approach to health improvement. Our objective was to further our understanding of the scale of and nature of any such relationship, using contemporary data from Britain's third National Survey of Sexual Attitudes and Lifestyles (Natsal-3). METHODS: Analyses of data from Natsal-3, a stratified probability survey of 15 162 men and women (3869 aged 16-24 years), undertaken in 2010-2012, using computer-assisted personal interviewing, were carried out. Logistic regression was used to explore associations between reporting (1) frequent binge drinking (≥weekly), (2) recent drug use (within past 4 weeks) or (3) multiple (both types of) substance use, and key sexual risk behaviours and adverse sexual health outcomes. We then examined the sociodemographic profile, health behaviours and attitudes reported by 'risky' young people, defined as those reporting ≥1 type of substance use plus non-condom use at first sex with ≥1 new partner(s), last year. RESULTS: Men and women reporting frequent binge drinking or recent drug use were more likely to report: unprotected first sex with ≥1 new partner(s), last year; first sex with their last partner after only recently meeting; emergency contraception use (last year) and sexually transmitted infection diagnosis/es (past 5 years). Associations with sexual risk were frequently stronger for those reporting multiple substance use, particularly among men. The profile of 'risky' young people differed from that of other 16-24 years old. CONCLUSIONS: In this nationally representative study, substance use was strongly associated with sexual risk and adverse sexual health outcomes among young people. Qualitative or event-level research is needed to examine the context and motivations behind these associations to inform joined-up interventions to address these inter-related behaviours.

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STUDY QUESTION: What is the prevalence of infertility and of help seeking among women and men in Britain? SUMMARY ANSWER: One in eight women and one in ten men aged 16-74 years had experienced infertility, defined by unsuccessfully attempting pregnancy for a year or longer, and little more than half of these people sought medical or professional help. WHAT IS KNOWN ALREADY: Estimates of infertility and help seeking in Britain vary widely and are not easily comparable because of different definitions and study populations. STUDY DESIGN, SIZE, DURATION: A cross-sectional population survey was conducted between 2010 and 2012 with a sample of 15 162 women and men aged 16-74 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants completed the Natsal-3 questionnaire, using computer-assisted personal interviewing (CAPI) and computer-assisted self-interview (CASI). MAIN RESULTS AND THE ROLE OF CHANCE: The reported prevalence of infertility was 12.5% (CI 95% 11.7-13.3) among women and 10.1% (CI 95% 9.2-11.1) among men. Increased prevalence was associated with later cohabitation with a partner, higher socio-economic status and, for those who had a child, becoming parents at older ages. The reported prevalence of help seeking was 57.3% (CI 95% 53.6-61.0) among women and 53.2% (CI 95% 48.1-58.1) among men. Help seekers were more likely to be better educated and in higher status occupations and, among those who had a child, to have become parents later in life. LIMITATIONS, REASONS FOR CAUTION: These data are cross-sectional so it is not possible to establish temporality or infer causality. Self-reported data may be subject to recall bias. WIDER IMPLICATIONS OF THE FINDINGS: The study provides estimates of infertility and help seeking in Britain and the results indicate that the prevalence of infertility is higher among those delaying parenthood. Those with higher educational qualifications and occupational status are more likely to consult with medical professionals for fertility problems than others and these inequalities in help seeking should be considered by clinical practice and public health. STUDY FUNDING/COMPETING INTERESTS: Funding was provided by grants from the Medical Research Council and the Wellcome Trust, with support from the Economic and Social Research Council and the Department of Health. AMJ is a Governor of the Wellcome Trust. Other authors have no competing interests.

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OBJECTIVE: Endoscopic vein harvesting (EVH) for arterial bypass surgery may be associated with lower wound complication rates than open vein harvesting (OVH), but other long-term outcomes remain controversial, and there are concerns that graft patency may be poorer after EVH compared with OVH. We conducted a systematic review of all available evidence for EVH in lower extremity arterial bypass (LEAB). METHODS: A literature search of Medline, Embase, Ovid and Cochrane databases between 1996 and 2013 was performed using the terms "endoscopic vein harvesting", "minimally invasive vein harvest", "peripheral bypass surgery", and "lower extremity bypass surgery", and detailed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Primary outcomes were graft patency and overall wound complication rates. Secondary outcomes were wound infection, length of hospital stay, and cost-effectiveness. Summary estimates were calculated by random effects meta-analysis if sufficient data were available. RESULTS: We identified 18 cohort studies and case series, with considerable clinical heterogeneity, including 2,343 patients. Meta-analysis of six studies revealed a significantly reduced rate of primary patency after EVH (hazard ratio 1.29, 95% confidence interval [CI] 1.03-1.63), with no significant difference between EVH and OVH with respect to wound infection in 12 studies (odds ratio 0.81, 95% CI 0.61-1.08). There was a lack of strong evidence to support the secondary outcomes of EVH. CONCLUSION: EVH reduces primary patency rates after LEAB, but does not demonstrate an advantage with respect to postoperative wound complications. However, the available data are heterogeneous, and uncertainty is introduced by both evolution in technology and increasing technical experience. EVH should be used with caution and in the context of formal research.

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Diabetes-related foot disease is a major health problem leading to significant morbidity and cost. If high-risk populations could be identified and treated before they develop complications, a significant reduction in the burden of foot disease and number of amputations might be expected. We examined the evidence to support population-based screening programs. MEDLINE and EMBASE databases were searched from January 1970 to February 2012 to identify studies assessing the impact of screening on lower limb complications in diabetes. Foot screening was defined as combined risk stratification and intervention to prevent foot complications in a population of people with diabetes mellitus. Articles reporting singularly on stratification of risk factors to predict subsequent complications but not reporting effect on minor, major and/or combined major and minor (total) amputation were excluded. Two randomized control trials were identified. These demonstrated patient benefit from screening in the setting of a general secondary care diabetes clinic and renal dialysis unit. Four before and after studies suggested benefit from primary care or regional screening. One study tried to address confounding from general improvements in the provision of diabetes foot care separately from screening. All the observational studies were prone to confounding. The evidence base for formal national primary care-based foot screening of all patients with diabetes is weak. Focused research is needed to confirm that general population-based screening in the community is effective and cost-effective. Limited evidence suggests that screening of high-risk populations of patients may be justified.

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OBJECTIVES: Wounds of the lower limb in patients with diabetes are frequently difficult to heal. Some wounds fail to heal despite optimal medical and surgical care. This review examines the evidence for whether free tissue transfer techniques may reduce the requirement of amputation in these patients. DESIGN: A systematic review. MATERIALS & METHODS: Pubmed, Embase, AMED, SCOPUS and CINAHL and Cochrane Library were searched for all articles on free tissue transfer in lower limb wounds in patients with diabetes (September 2010). Current experience, indications and outcomes were analysed. RESULTS: 528 patients from 18 studies were included in the systematic review. 66% of patients had concomitant revascularisation with bypass surgery. 63% of flaps were muscle based, 35% fasciocutaneous and 1.7% omental. Pooled in-hospital mortality rate was 4.4%, flap survival was 92% and limb salvage rate of 83.4% over a 28 months average follow-up time. CONCLUSIONS: In conclusion free tissue transfer achieves successful wound healing in selected patients with diabetes and difficult to heal wounds that would have required amputation. Pre-operative optimisation of vascular supply and eradication of infection is key to success. Objective wound assessment scores and a clear multidisciplinary team (MDT) approach would improve patient care.

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AIMS: Foot ulcers are a common and important complication of diabetes. Variation in the clinical presentation of this disease has resulted in a paucity of evidence from comparable studies to guide optimal clinical management. A validated scoring system might help clinicians and researchers in everyday assessment and management of patients or the development and assessment of new therapies. The aim of the present review was to critically appraise the published literature of wound scoring systems for diabetic foot ulcers. METHODS: An electronic search was performed using the EMBASE and MEDLINE databases from 1966 until 2009 for scoring systems for diabetic foot ulcers. The literature review conformed to PRISMA statement standards. RESULTS: The literature search identified 197 articles, of which 180 were excluded. Eleven scoring systems and six validation or comparative studies are described. CONCLUSIONS: Many scoring systems exist for classification of the diabetic foot, few of which have been validated. Detailed scoring systems offer a valuable method for the comparison of data from different diabetic foot centres. Simplistic scoring systems may be used in clinical practice and the choice of scoring system should be determined by the population under study.

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BACKGROUND: : The aim was to investigate whether a relationship existed between case volume and outcome for lower limb vascular surgical procedures. METHODS: : PubMed, Embase, the Cochrane Library and Google Scholar were searched for all articles on population-based studies on the volume-outcome relationship for lower limb vascular surgery at hospital level. Outcomes were mortality and subsequent amputation after lower limb vascular surgery. The data were subjected to meta-analysis by outcome. RESULTS: : Some 452 093 patients from ten studies were included in the systematic review and five studies were included in meta-analyses. Seven of these articles found a significant positive hospital-volume outcome relationship. The pooled effect estimate for mortality was odds ratio (OR) 0.81 (95 per cent confidence interval 0.71 to 0.91) and that for amputation was OR 0.88 (0.79 to 0.98), with better results being found after surgery at higher-volume hospitals. Significant heterogeneity was seen in the data. CONCLUSION: : Higher-volume hospitals were associated with reduced amputation and mortality rates after lower limb vascular surgery. These data were not as conclusive as those for other vascular surgical procedures owing to significant heterogeneity.

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AIM: Recent studies have shown that percutaneous transluminal angioplasty (PTA) can be safely performed as a day-case procedure. Many centers consider diabetes mellitus as a contraindication to day-case PTA. In this study, the safety and efficacy of 95 day-case PTA in 66 diabetic patients with critical leg ischemia (CLI) were evaluated. METHODS: Diabetic patients with CLI were assessed in a one-stop multidisciplinary outpatient clinic. Sixty-six outpatients with CLI deemed suitable for radiological intervention by non-invasive imaging (ultrasound angiology or magnetic resonance angiography) were scheduled for day-case PTA. RESULTS: PTA was initially successful in 63 out of 66 patients (95%). In 3 patients (5%), PTA was not possible because the lesion could not be balloon dilated or crossed with a guide wire. Clinically suspected first, second and third re-stenosis confirmed by non-invasive studies occurred in 20 out of 63 (31%), 7 out of 20 (35%) and 2 out of 7 (28%) patients, respectively. Following PTA, debridement was performed in 11 patients (17%), minor amputation in 8 (13%) and major amputation in 3 (5%). Relief of the primary symptom of rest pain or healing of ulcers was achieved in 23 out of 32 (72%) and 25 out of 27 (92.5%) patients, respectively. No peri-interventional morbidity or mortality was encountered. CONCLUSION: PTA is feasible and safe as a day-case procedure in diabetic patients with CLI. Re-stenosis can be managed by repeat day-case PTA.

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Abdominal aortic aneurysm (AAA) is a common degenerative condition affecting the elderly population. Rupture carries a high overall mortality. Elective endovascular stent graft repair is well described. We describe a patient with ruptured AAA and co-morbid conditions making him unfit for surgery and general or epidural anaesthesia, who was successfully treated by endovascular stent graft under local anaesthesia.

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PURPOSE: To report the benefit of endoluminal repair of mycotic aortic aneurysms and highlight the need for a registry. METHODS: Nine patients (five female) were identified over 5 years (1998-2003) as having presumed mycotic aortic aneurysms (12 in total) suitable for endoluminal grafting. A total of nine thoracic and three abdominal were grafted and followed up for a median of 36 months. RESULTS: Six of the aneurysms have resolved and one was converted to an open repair. There was one early death from rupture of a second undiagnosed aneurysm and two late deaths from rupture due to persistent inflammation. Long-term antibiotics have not been mandatory to ensure survival. CONCLUSIONS: Mycotic aortic aneurysms of the thoracic and abdominal aorta do benefit from endoluminal repair, particularly when arising in previously normal aortic tissue. Endoluminal grafting also has a role in the palliation of secondarily infected aortas and so to prove its efficacy in the treatment of all these rare cases a registry is required.

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BACKGROUND: The elastinolytic cysteine proteases, including cathepsins S and K, are overexpressed at sites of arterial elastin damage. Cystatin C, an inhibitor of these enzymes, is expressed in arterial smooth muscle cells; an imbalance in cystatin C has been implicated in the aortic wall degeneration observed in abdominal aortic aneurysms (AAAs). The aim of the study was to investigate the impact of a polymorphism in the signal peptide of the cystatin C gene on the growth of small AAAs. METHODS: Some 424 patients with a small AAA (4.0-5.5 cm) were monitored for AAA growth by ultrasonography and provided a DNA sample for analysis of the + 148 G > A polymorphism in the cystatin C signal peptide and the-82 G > C polymorphism in the gene promoter. The median length of follow-up was 2.8 years and AAA growth rates were calculated by linear regression analysis. RESULTS: For patients of + 148 GG (n = 263), GA (n = 147) and AA (n = 20) genotypes, the mean(s.d.) AAA growth rates were 0.37(0.29), 0.37(0.23) and 0.30(0.26) cm, and initial diameters were 4.58(0.35), 4.58(0.35) and 4.62(0.36) cm, respectively. Patients of + 148 AA genotype had a slower aneurysm growth rate (unadjusted P = 0.058; after adjustment for age, sex, initial AAA diameter and smoking, P = 0.027). There also was a trend for the rare homozygotes of the-82 C allele to have slower AAA growth (adjusted P = 0.055). Smoking history had a stronger association with aneurysm growth (P = 0.003). CONCLUSION: There was a weak association between variation in the cystatin C gene and AAA growth. Medical strategies to limit AAA growth might include the inhibition of cysteine proteases.

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BACKGROUND: Prostaglandin (PG) E(2) (PGE(2)) appears to have a role in stimulating production of interleukin-6 (IL-6) and apoptosis of smooth muscle cells in diseased aortic tissue. These actions are mediated by cellular receptors for PGE(2) EP receptors. OBJECTIVE: This study was undertaken to identify EP receptors associated with production of IL-6 by aortic explants. METHODS: Biopsy specimens of abdominal aortic aneurysm were used for explant culture and preparation of messenger RNA. The presence of EP1, EP2, EP3, and EP4 receptors in tissue and cells was investigated with reverse-transcriptase polymerase chain reaction. IL-6 and cyclic adenosine monophosphate were measured with an enzyme-linked immunosorbent assay. RESULTS: PGE(2) or 11-deoxy-PGE(1) (EP 2/3/4 agonist) reversed partially the indomethacin suppression of IL-6 secretion from explant cultures, whereas butaprost (EP2 receptor agonist) and sulprostone (EP 1/3 receptor agonist) had no effect. Aortic biopsy specimens expressed EP2, EP3-III, and EP4 receptors. Aortic smooth muscle cells expressed EP2 receptor and four variants of EP3 receptor, ie, EP3-Ib, EP3-II, EP3-III, and EP3-IV, but PGE(2) did not stimulate secretion of IL-6. In contrast, PGE(2) or 11-deoxy-PGE(1) stimulated secretion of IL-6 from aortic macrophages. CONCLUSIONS: In aortic explants, PGE(2) stimulates IL-6 secretion by activation of EP4 receptors, present in macrophages.

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Abdominal aortic aneurysm is a smoking-related disorder. Cadmium, inhaled from cigarettes, may accumulate in the aorta and facilitate weakening of the aorta through adverse effects on smooth muscle cell metabolism. Cadmium was measured by atomic absorption spectrometry in infrarenal aortas from 13 patients with abdominal aortic aneurysm and from 17 age- and sex-matched patients with normal-diameter abdominal aorta. Total cadmium content was associated with smoking, assessed as pack-years (r=0.54, P=0.004), but was similar in aneurysmal and undilated aortas. The cadmium content (mean+/-SE) was higher in the media (3.25+/-0.53 ng/mg dry wt, 7+/-1.2 micromol/L) than in the intima or adventitia (1.14+/-0.24 and 1.87+/-0.38 ng/mg dry wt, respectively; ANOVA, P<0.005). There was a strong correlation between medial cadmium content and pack-years of smoking (r=0.87, P<0.001). In aortic smooth muscle cells cultured on fibrillar collagen, cadmium inhibited DNA synthesis and collagen synthesis and diminished cell numbers (IC(50) 2 micromol/L, 6 micromol/L, and 6 micromol/L, respectively), but higher concentrations of cadmium were required for upregulation of metallothionein (EC(50) 23 micromol/L). The cadmium content of the aorta increases in direct proportion to the pack-years of cigarettes smoked, with selective accumulation in the medial layer. However, the cadmium content of aneurysmal aortas was not higher than that of nondilated aortas for patients with matched smoking history. In smokers, the level of cadmium accumulation is probably sufficient to impair the viability of cultured smooth muscle cells. Similar mechanisms could underlie the development of degenerative aortic disease in smokers.

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