Chronic activation of anti-oxidant pathways and iron accumulation in epileptogenic malformations.

AIMS: Oxidative stress is evident in resected epileptogenic brain tissue of patients with developmental brain malformations related to mammalian target of rapamycin activation: tuberous sclerosis complex (TSC) and focal cortical dysplasia type IIb (FCD IIb). Whether chronic activation of anti-oxidant pathways is beneficial or contributes to pathology is not clear. METHODS: We investigated oxidative stress markers, including haem oxygenase 1, ferritin and the inflammation associated microRNA-155 in surgically resected epileptogenic brain tissue of TSC (n = 10) and FCD IIb (n = 8) patients and in a TSC model (Tsc1GFAP-/- mice) using immunohistochemistry, in situ hybridization, real-time quantitative PCR and immunoblotting. Using human foetal astrocytes we performed an in vitro characterization of the anti-oxidant response to acute and chronic oxidative stress and evaluated overexpression of the disease-relevant pro-inflammatory microRNA-155. RESULTS: Resected TSC or FCD IIb tissue displayed higher expression of oxidative stress markers and microRNA-155. Tsc1GFAP-/- mice expressed more microRNA-155 and haem oxygenase 1 in the brain compared to wild-type, preceding the typical development of spontaneous seizures in these animals. In vitro, chronic microRNA-155 overexpression induced haem oxygenase 1, iron regulatory elements and increased susceptibility to oxidative stress. Overexpression of iron regulatory genes was also detected in patients with TSC, FCD IIb and Tsc1GFAP-/- mice. CONCLUSION: Our results demonstrate that early and sustained activation of anti-oxidant signalling and dysregulation of iron metabolism are a pathological hallmark of FCD IIb and TSC. Our findings suggest novel therapeutic strategies aimed at controlling the pathological link between both processes.

Unilateral vestibular schwannoma and meningiomas in a patient with PIK3CA-related segmental overgrowth: Co-occurrence of mosaicism for 2 rare disorders.

A 28-year-old female with PIK3CA-related segmental overgrowth presented with headaches. She also had a unilateral vestibular schwannoma (VS), as well as 3 small (<2 cm) meningiomas, which according to the Manchester consensus diagnostic criteria for neurofibromatosis 2 (NF2) is sufficient for a clinical diagnosis. Analysis of blood revealed a mosaic PIK3CA c.2740G>A (p.Gly914Arg) mutation, confirming the diagnosis of PIK3CA-related overgrowth, but no mutations in NF2 were detected. Although VS has not previously been reported in PIK3CA-related segmental overgrowth, meningiomas have, raising the question of whether this patient's VS and meningiomas represent coincidental NF2 or phenotypic extension of her overgrowth syndrome. Genetic analysis of the VS revealed a heterozygous NF2 mutation c.784C>T (p.Arg262Ter) and loss of a portion of 22q, including NF2, SMARCB1, and LZTR1 genes. These results suggest that the patient has 2 different mosaic disorders, NF2 and PIK3CA-related overgrowth. The PIK3CA mutation was also present in the VS. Confirmation of the clinical diagnosis of mosaic NF2 in this patient has implications for monitoring and highlights the possibility of co-occurrence of mosaicism for multiple rare disorders in a single patient.

Delayed conception in women with low-urinary iodine concentrations: a population-based prospective cohort study.

STUDY QUESTION: Is iodine deficiency associated with decreased fecundability? SUMMARY ANSWER: Moderate to severe iodine deficiency is associated with a 46% decrease in fecundability. WHAT IS KNOWN ALREADY: Iodine deficiency is common in women of childbearing age but its effect on fecundability has not been investigated. STUDY DESIGN, SIZE, DURATION: The LIFE Study, a population-based prospective cohort study, enrolled 501 women who had discontinued contraception within 2 months to become pregnant between 2005 and 2009. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women reported on risk factors for infertility by interview then kept daily journals of relevant information. Women used fertility monitors to time intercourse relative to ovulation then used home digital pregnancy tests to identify pregnancies on the day of expected menstruation. Urine samples for iodine analysis were collected on enrollment. MAIN RESULTS AND THE ROLE OF CHANCE: Samples were in the deficiency range in 44.3% of participants. The group whose iodine-creatinine ratios were below 50 µg/g (moderate to severe deficiency) had a 46% reduction in fecundity (P = 0.028) compared with the group whose iodine-creatinine ratios were in the adequate range: adjusted fecundability odds ratio of becoming pregnant per cycle, 0.54 (95% confidence interval 0.31-0.94). LIMITATIONS, REASONS FOR CAUTION: Iodine concentrations vary within individuals over time, so the data must be interpreted by group as we have done; residual confounding is possible. WIDER IMPLICATIONS OF THE FINDINGS: Significant delays in becoming pregnant occur at iodine concentrations that are common in women in the USA and parts of Europe. Replicating these findings will be important to determine whether improving iodine status could be beneficial in improving fecundability. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, USA. Contracts N01-HD-3-3355; N01-HD-3-3356; N01-HD-3-3358 and HHSN275201100001l/HHSN27500007. None of the authors has any conflict of interest to declare.

An isotope dilution model for partitioning of phenylalanine and tyrosine uptake by the liver of lactating dairy cows.

An isotope dilution model to describe the partitioning of phenylalanine and tyrosine in the bovine liver was developed. The model comprises four intracellular and six extracellular pools and various flows connecting these pools and external blood. Conservation of mass principles were applied to generate the fundamental equations describing the behaviour of the system in the steady state. The model was applied to datasets from multi-catheterised dairy cattle during a constant infusion of [1-13C]phenylalanine and [2,3,5,6-2H]tyrosine tracers. Model solutions described the extraction of phenylalanine and tyrosine from the liver via the portal vein and hepatic artery. In addition, the exchange of free phenylalanine and tyrosine between extracellular and intracellular pools was explained and the hydroxylation of phenylalanine to tyrosine was estimated. The model was effective in providing information about the fates of phenylalanine and tyrosine in the liver and could be used as part of a more complex system describing amino acid metabolism in the whole animal.

The effect of transportation and lairage on faecal shedding and carcass contamination with Escherichia coli O157 and O26 in very young calves in New Zealand.

The effect of transportation and lairage on the faecal shedding and post-slaughter contamination of carcasses with Escherichia coli O157 and O26 in young calves (4-7-day-old) was assessed in a cohort study at a regional calf-processing plant in the North Island of New Zealand, following 60 calves as cohorts from six dairy farms to slaughter. Multiple samples from each animal at pre-slaughter (recto-anal mucosal swab) and carcass at post-slaughter (sponge swab) were collected and screened using real-time PCR and culture isolation methods for the presence of E. coli O157 and O26 (Shiga toxin-producing E. coli (STEC) and non-STEC). Genotype analysis of E. coli O157 and O26 isolates provided little evidence of faecal-oral transmission of infection between calves during transportation and lairage. Increased cross-contamination of hides and carcasses with E. coli O157 and O26 between co-transported calves was confirmed at pre-hide removal and post-evisceration stages but not at pre-boning (at the end of dressing prior to chilling), indicating that good hygiene practices and application of an approved intervention effectively controlled carcass contamination. This study was the first of its kind to assess the impact of transportation and lairage on the faecal carriage and post-harvest contamination of carcasses with E. coli O157 and O26 in very young calves.

Farm and abattoir sources of Carnobacterium species and implications for lamb meat spoilage.

AIMS: To investigate the transmission route of Carnobacterium from the farm environment to the meat-manufacturing plant and potential risk for meat spoilage. METHODS AND RESULTS: A sheep farm-level survey of Carnobacterium, consisting of 150 environmental and animal (no 100) associated samples, was carried out on two farms. A further 20 lamb carcass samples were taken from an abattoir servicing one of the farms. The majority of Carnobacterium maltaromaticum isolates were associated with fleece followed by hard sheep contact surfaces, rectal-anal mucosal swabs and carcasses. Enterobacterial repetitive intergenic consenus PCR (ERIC-PCR) profiling revealed four distinct ERIC types. Each ERIC type was found on both farms, three of which were also found on lamb carcasses. CONCLUSIONS: Enterobacterial repetitive intergenic consenus PCR was effective at demonstrating within-species variability in C. maltaromaticum. This study provides initial information showing that farm sources maybe an important transmission route of Carnobacterium for contamination of lamb carcasses and subsequently the meat processing environment. SIGNIFICANCE AND IMPACT OF THE STUDY: Data on distribution, diversity, sources and transmission routes for meat product contamination is limited for spoilage bacteria. This study highlights the importance of good hygienic slaughter practices and cleaning routines to remove accumulated detritus from the handling of animals that may lead to cross-contamination.

The profile of diabetes healthcare professionals in Indonesia: a scoping review.

AIM: To explore and synthesize evidence of the literature about healthcare professionals involved in the provision of diabetes management within an Indonesian context. BACKGROUND: Indonesia is challenged to control the major burden of diabetes prevalence rate that requires a multidimensional approach with the aim to optimize existing health services by involving healthcare professionals who can promote access and provide diabetes management. METHODS: This literature review, which is integrated with a scoping study framework, used the electronic databases including CINAHL, PubMed, Scopus and Web of Science to locate papers particular to the Indonesian context. From the total of 568 papers found, 20 papers were selected. RESULTS: The literature review identified physicians, nurses, pharmacists, dieticians and diabetes educators as the providers of diabetes care and management in Indonesia. Collaborative management involving either interdisciplinary or intradisciplinary teams was mentioned in several papers. Internal challenges included limited skills and knowledge. External challenges included high patient volumes; a shortage of healthcare professionals and reduced funding. CONCLUSIONS: Overcoming the challenges cannot be undertaken with a workforce dominated by any one single healthcare professional. Coordinating with the government to improve the implementation of different roles in diabetes management will improve patient outcomes and thus reduce the burden of diabetes. IMPLICATION FOR NURSING AND HEALTH POLICY: Health policy reform should support nurses and other healthcare professionals in their professional development at all levels of health care. Policy makers can use the review findings to modify the current healthcare system to address key issues in workforce development; funding for services and medications; and fostering multidisciplinary care for diabetes management.

A dermatological questionnaire for general practitioners in England with a focus on melanoma; misdiagnosis in black patients compared to white patients.

BACKGROUND: Malignant melanoma presents a significant health burden in the UK in terms of mortality and financial cost. This aggressive and often fatal disease is under-diagnosed among patients with darker skin tones (type 5 and 6) such as Afro-Caribbean patients. A lack of both patient and practitioner awareness leads to a later diagnosis in patients with black compared to white skin. There is currently a paucity of literature looking at the diagnosis rates of melanoma between patients of different ethnicities in the UK and the reasons behind these differences. OBJECTIVE: The primary aim was to obtain data on the diagnosis rate of melanoma in the primary care setting, with particular attention to white vs. black skin types. METHODS: An online questionnaire was sent to 2975 general practitioner (GP) practices in England and 287 responses were received. The questionnaire contained 20 high-quality picture questions of differing common skin conditions. The participants were asked to choose their diagnosis from 20 potential diagnoses. Only 4/20 questions were melanomas, two on white and two on black skin. No accompanying histories were provided. RESULTS: The mean score for the questionnaire was 11.6/20 (58%) with a range from 5% to 100%. Of the two black skin melanoma pictures, 177/287 (62%) and 90/287 (31%) responses were incorrectly identified, compared to 37/287 (13%) and 19/287 (7%) in the white skin melanoma pictures. CONCLUSION: The questionnaire results show a clear increased misdiagnosis of melanoma in black patients in primary care vs. white. The results suggest that vigilance is needed when diagnosing possible melanoma in black patients and better quality melanoma teaching is required in GP training concentrating on pigmented skin. This pilot study should encourage more research into ethnic skin inequalities in the UK.

A mechanistic model of small intestinal starch digestion and glucose uptake in the cow.

The high contribution of postruminal starch digestion (up to 50%) to total-tract starch digestion on energy-dense, starch-rich diets demands that limitations to small intestinal starch digestion be identified. A mechanistic model of the small intestine was described and evaluated with regard to its ability to simulate observations from abomasal carbohydrate infusions in the dairy cow. The 7 state variables represent starch, oligosaccharide, glucose, and pancreatic amylase in the intestinal lumen, oligosaccharide and glucose in the unstirred water layer at the intestinal wall, and intracellular glucose of the enterocyte. Enzymatic hydrolysis of starch was modeled as a 2-stage process involving the activity of pancreatic amylase in the lumen and of oligosaccharidase at the brush border of the enterocyte confined within the unstirred water layer. The Na+-dependent glucose transport into the enterocyte was represented along with a facilitative glucose transporter 2 transport system on the basolateral membrane. The small intestine is subdivided into 3 main sections, representing the duodenum, jejunum, and ileum for parameterization. Further subsections are defined between which continual digesta flow is represented. The model predicted nonstructural carbohydrate disappearance in the small intestine for cattle unadapted to duodenal infusion with a coefficient of determination of 0.92 and a root mean square prediction error of 25.4%. Simulation of glucose disappearance for mature Holstein heifers adapted to various levels of duodenal glucose infusion yielded a coefficient of determination of 0.81 and a root mean square prediction error of 38.6%. Analysis of model behavior identified limitations to the efficiency of small intestinal starch digestion with high levels of duodenal starch flow. Limitations to individual processes, particularly starch digestion in the proximal section of the intestine, can create asynchrony between starch hydrolysis and glucose uptake capacity.

EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis.

In this article, the 2009 European League Against Rheumatism (EULAR) recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have been updated. The 2009 recommendations were on the management of primary small and medium vessel vasculitis. The 2015 update has been developed by an international task force representing EULAR, the European Renal Association and the European Vasculitis Society (EUVAS). The recommendations are based upon evidence from systematic literature reviews, as well as expert opinion where appropriate. The evidence presented was discussed and summarised by the experts in the course of a consensus-finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) determined. In addition to the voting by the task force members, the relevance of the recommendations was assessed by an online voting survey among members of EUVAS. Fifteen recommendations were developed, covering general aspects, such as attaining remission and the need for shared decision making between clinicians and patients. More specific items relate to starting immunosuppressive therapy in combination with glucocorticoids to induce remission, followed by a period of remission maintenance; for remission induction in life-threatening or organ-threatening AAV, cyclophosphamide and rituximab are considered to have similar efficacy; plasma exchange which is recommended, where licensed, in the setting of rapidly progressive renal failure or severe diffuse pulmonary haemorrhage. These recommendations are intended for use by healthcare professionals, doctors in specialist training, medical students, pharmaceutical industries and drug regulatory organisations.

Anomalously Large Chiral Sensitivity in the Dissociative Electron Attachment of 10-Iodocamphor.

We have studied dissociative electron attachment (DEA) between low energy (≤0.6 eV) longitudinally polarized electrons and gas-phase chiral targets of 3-bromocamphor (C_{10}H_{15}BrO), 3-iodocamphor (C_{10}H_{15}IO), and 10-iodocamphor. The DEA rate depends on the sign of the incident electron helicity for a given target handedness, and it varies with both the atomic number (Z) and location of the heaviest atom in the molecule. While simple dynamic mechanisms can account for the asymmetry dependence on Z, they fail to explain the large asymmetry variation with the heavy atom location.

Performance of prognostic markers in the prediction of wound healing or amputation among patients with foot ulcers in diabetes: a systematic review.

Prediction of wound healing and major amputation in patients with diabetic foot ulceration is clinically important to stratify risk and target interventions for limb salvage. No consensus exists as to which measure of peripheral artery disease (PAD) can best predict outcomes. To evaluate the prognostic utility of index PAD measures for the prediction of healing and/or major amputation among patients with active diabetic foot ulceration, two reviewers independently screened potential studies for inclusion. Two further reviewers independently extracted study data and performed an assessment of methodological quality using the Quality in Prognostic Studies instrument. Of 9476 citations reviewed, 11 studies reporting on 9 markers of PAD met the inclusion criteria. Annualized healing rates varied from 18% to 61%; corresponding major amputation rates varied from 3% to 19%. Among 10 studies, skin perfusion pressure ≥ 40 mmHg, toe pressure ≥ 30 mmHg (and ≥ 45 mmHg) and transcutaneous pressure of oxygen (TcPO2 ) ≥ 25 mmHg were associated with at least a 25% higher chance of healing. Four studies evaluated PAD measures for predicting major amputation. Ankle pressure < 70 mmHg and fluorescein toe slope < 18 units each increased the likelihood of major amputation by around 25%. The combined test of ankle pressure < 50 mmHg or an ankle brachial index (ABI) < 0.5 increased the likelihood of major amputation by approximately 40%. Among patients with diabetic foot ulceration, the measurement of skin perfusion pressures, toe pressures and TcPO2 appear to be more useful in predicting ulcer healing than ankle pressures or the ABI. Conversely, an ankle pressure of < 50 mmHg or an ABI < 0.5 is associated with a significant increase in the incidence of major amputation.

Effectiveness of bedside investigations to diagnose peripheral artery disease among people with diabetes mellitus: a systematic review.

Non-invasive tests for the detection of peripheral artery disease (PAD) among individuals with diabetes mellitus are important to estimate the risk of amputation, ulceration, wound healing and the presence of cardiovascular disease, yet there are no consensus recommendations to support a particular diagnostic modality over another and to evaluate the performance of index non-invasive diagnostic tests against reference standard imaging techniques (magnetic resonance angiography, computed tomography angiography, digital subtraction angiography and colour duplex ultrasound) for the detection of PAD among patients with diabetes. Two reviewers independently screened potential studies for inclusion and extracted study data. Eligible studies evaluated an index test for PAD against a reference test. An assessment of methodological quality was performed using the quality assessment for diagnostic accuracy studies instrument. Of the 6629 studies identified, ten met the criteria for inclusion. In these studies, the patients had a median age of 60-74 years and a median duration of diabetes of 9-24 years. Two studies reported exclusively on patients with symptomatic (ulcerated/infected) feet, two on patients with asymptomatic (intact) feet only, and the remaining six on patients both with and without foot ulceration. Ankle brachial index (ABI) was the most widely assessed index test. Overall, the positive likelihood ratio and negative likelihood ratio (NLR) of an ABI threshold <0.9 ranged from 2 to 25 (median 8) and <0.1 to 0.7 (median 0.3), respectively. In patients with neuropathy, the NLR of the ABI was generally higher (two out of three studies), indicating poorer performance, and ranged between 0.3 and 0.5. A toe brachial index <0.75 was associated with a median positive likelihood ratio and NLRs of 3 and ≤ 0.1, respectively, and was less affected by neuropathy in one study. Also, in two separate studies, pulse oximetry used to measure the oxygen saturation of peripheral blood and Doppler wave form analyses had NLRs of 0.2 and <0.1. The reported performance of ABI for the diagnosis of PAD in patients with diabetes mellitus is variable and is adversely affected by the presence of neuropathy. Limited evidence suggests that toe brachial index, pulse oximetry and wave form analysis may be superior to ABI for diagnosing PAD in patients with neuropathy with and without foot ulcers. There were insufficient data to support the adoption of one particular diagnostic modality over another and no comparisons existed with clinical examination. The quality of studies evaluating diagnostic techniques for the detection of PAD in individuals with diabetes is poor. Improved compliance with guidelines for methodological quality is needed in future studies.

Effectiveness of revascularization of the ulcerated foot in patients with diabetes and peripheral artery disease: a systematic review.

Symptoms or signs of peripheral artery disease (PAD) can be observed in up to 50% of the patients with a diabetic foot ulcer and is a risk factor for poor healing and amputation. In 2012, a multidisciplinary working group of the International Working Group on the Diabetic Foot published a systematic review on the effectiveness of revascularization of the ulcerated foot in patients with diabetes and PAD. This publication is an update of this review and now includes the results of a systematic search for therapies to revascularize the ulcerated foot in patients with diabetes and PAD from 1980 to June 2014. Only clinically relevant outcomes were assessed. The research conformed to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, and Scottish Intercollegiate Guidelines Network methodological scores were assigned. A total of 56 articles were eligible for full-text review. There were no randomized controlled trials, but there were four nonrandomized studies with a control group. The major outcomes following endovascular or open bypass surgery were broadly similar among the studies. Following open surgery, the 1-year limb salvage rates were a median of 85% (interquartile range of 80-90%), and following endovascular revascularization, these rates were 78% (70-89%). At 1-year follow-up, 60% or more of ulcers had healed following revascularization with either open bypass surgery or endovascular techniques. Studies appeared to demonstrate improved rates of limb salvage associated with revascularization compared with the results of conservatively treated patients in the literature. There were insufficient data to recommend one method of revascularization over another. There is a real need for standardized reporting of baseline demographic data, severity of disease and outcome reporting in this group of patients.

Psychological processes underlying the association between childhood trauma and psychosis in daily life: an experience sampling study.

BACKGROUND: Evidence has accumulated that implicates childhood trauma in the aetiology of psychosis, but our understanding of the putative psychological processes and mechanisms through which childhood trauma impacts on individuals and contributes to the development of psychosis remains limited. We aimed to investigate whether stress sensitivity and threat anticipation underlie the association between childhood abuse and psychosis. METHOD: We used the Experience Sampling Method to measure stress, threat anticipation, negative affect, and psychotic experiences in 50 first-episode psychosis (FEP) patients, 44 At-Risk Mental State (ARMS) participants, and 52 controls. Childhood abuse was assessed using the Childhood Trauma Questionnaire. RESULTS: Associations of minor socio-environmental stress in daily life with negative affect and psychotic experiences were modified by sexual abuse and group (all p FWE < 0.05). While there was strong evidence that these associations were greater in FEP exposed to high levels of sexual abuse, and some evidence of greater associations in ARMS exposed to high levels of sexual abuse, controls exposed to high levels of sexual abuse were more resilient and reported less intense negative emotional reactions to socio-environmental stress. A similar pattern was evident for threat anticipation. CONCLUSIONS: Elevated sensitivity and lack of resilience to socio-environmental stress and enhanced threat anticipation in daily life may be important psychological processes underlying the association between childhood sexual abuse and psychosis.

Successful treatment of a disseminated infection with extensively drug-resistant Klebsiella pneumoniae in a liver transplant recipient with a fosfomycin-based multidrug regimen.

Donor-derived infections with multidrug-resistant gram-negative bacteria are associated with poor outcomes, in part because of limited treatment options. Here, we describe a case of donor-derived, disseminated infection with colistin-resistant, carbapenemase-producing Klebsiella pneumoniae in a liver transplant recipient that was cured with addition of intravenous fosfomycin to a multidrug regimen, in conjunction with aggressive surgical source control. Intravenous fosfomycin represents a promising adjunctive agent for use in treatment of extensively drug-resistant infections in immunocompromised hosts.

Management of agricultural soils for greenhouse gas mitigation: Learning from a case study in NE Spain.

A portfolio of agricultural practices is now available that can contribute to reaching European mitigation targets. Among them, the management of agricultural soils has a large potential for reducing GHG emissions or sequestering carbon. Many of the practices are based on well tested agronomic and technical know-how, with proven benefits for farmers and the environment. A suite of practices has to be used since none of the practices can provide a unique solution. However, there are limitations in the process of policy development: (a) agricultural activities are based on biological processes and thus, these practices are location specific and climate, soils and crops determine their agronomic potential; (b) since agriculture sustains rural communities, the costs and potential for implementation have also to be regionally evaluated and (c) the aggregated regional potential of the combination of practices has to be defined in order to inform abatement targets. We believe that, when implementing mitigation practices, three questions are important: Are they cost-effective for farmers? Do they reduce GHG emissions? What policies favour their implementation? This study addressed these questions in three sequential steps. First, mapping the use of representative soil management practices in the European regions to provide a spatial context to upscale the local results. Second, using a Marginal Abatement Cost Curve (MACC) in a Mediterranean case study (NE Spain) for ranking soil management practices in terms of their cost-effectiveness. Finally, using a wedge approach of the practices as a complementary tool to link science to mitigation policy. A set of soil management practices was found to be financially attractive for Mediterranean farmers, which in turn could achieve significant abatements (e.g., 1.34 MtCO2e in the case study region). The quantitative analysis was completed by a discussion of potential farming and policy choices to shape realistic mitigation policy at European regional level.

Learning from the QUEST multicentre feasibility randomization trials in breast reconstruction after mastectomy.

BACKGROUND: Breast reconstruction aims to improve health-related quality of life after mastectomy. However, evidence guiding patients and surgeons in shared decision-making concerning the optimal type or timing of surgery is lacking. METHODS: QUEST comprised two parallel feasibility phase III randomized multicentre trials to assess the impact of the type and timing of latissimus dorsi breast reconstruction on health-related quality of life when postmastectomy radiotherapy is unlikely (QUEST A) or highly probable (QUEST B). The primary endpoint for the feasibility phase was the proportion of women who accepted randomization, and it would be considered feasible if patient acceptability rates exceeded 25 per cent of women approached. A companion QUEST Perspectives Study (QPS) of patients (both accepting and declining trial participation) and healthcare professionals assessed trial acceptability. RESULTS: The QUEST trials opened in 15 UK centres. After 18 months of recruitment, 17 patients were randomized to QUEST A and eight to QUEST B, with overall acceptance rates of 19 per cent (17 of 88) and 22 per cent (8 of 36) respectively. The QPS recruited 56 patients and 51 healthcare professionals. Patient preference was the predominant reason for declining trial entry, given by 47 (53 per cent) of the 88 patients approached for QUEST A and 22 (61 per cent) of the 36 approached for QUEST B. Both trials closed to recruitment in December 2012, acknowledging the challenges of achieving satisfactory patient accrual. CONCLUSION: Despite extensive efforts to overcome recruitment barriers, it was not feasible to reach timely recruitment targets within a feasibility study. Patient preferences for breast reconstruction types and timings were common, rendering patients unwilling to enter the trial.