p53 and P-glycoprotein are often co-expressed and are associated with poor prognosis in breast cancer.

Expression of both P-glycoprotein (P-gp) and mutant p53 have recently been reported to be associated with poor prognosis of breast cancer. The expression of P-gp is associated in vitro and in vivo with cross-resistance to several anti-cancer drugs. p53 plays a regulatory role in apoptosis, and mutant p53 has been suggested to be involved in drug resistance. Interestingly, in vitro experiments have shown that mutant p53 can activate the promoter of the MDR1 gene, which encodes P-gp. We investigated whether p53 and P-gp are simultaneously expressed in primary breast cancer cells and analysed the impact of the co-expression on patients prognosis. Immunohistochemistry was used to investigate P-gp expression (JSB-1, C219) and nuclear p53 accumulation (DO-7) in 20 operable chemotherapy untreated and 30 locally advanced breast cancers undergoing neoadjuvant chemotherapy with doxorubicin and cyclophosphamide. Double immunostaining showed that P-gp expression and nuclear p53 accumulation often occur concomitantly in the same tumour cells. A correlation between p53 and P-gp expression was found in all 50 breast cancers (P = 0.003; Fisher's exact test). P-gp expression, nuclear p53 accumulation, and co-expression of p53 and P-gp were more frequently observed in locally advanced breast cancers than in operable breast cancers (P = 0.0004, P = 0.048; P = 0.002 respectively. Fisher's exact test). Co-expression of p53 and P-gp was the strongest prognostic factor for shorter survival by multivariate analysis (P = 0.004) in the group of locally advanced breast cancers (univariate analysis: P = 0.0007). Only 3 out of 13 samples sequentially taken before and after chemotherapy displayed a change in P-gp or p53 staining. In conclusion, nuclear p53 accumulation is often associated with P-gp expression in primary breast cancer, and simultaneous expression of p53 and P-gp is associated with shorter survival in locally advanced breast cancer patients. Co-expression of P-gp and mutant p53 belong to a series of molecular events resulting in a more aggressive phenotype, drug resistance and poor prognosis

MyAirCoach: the use of home-monitoring and mHealth systems to predict deterioration in asthma control and the occurrence of asthma exacerbations; study protocol of an observational study.

INTRODUCTION: Asthma is a variable lung condition whereby patients experience periods of controlled and uncontrolled asthma symptoms. Patients who experience prolonged periods of uncontrolled asthma have a higher incidence of exacerbations and increased morbidity and mortality rates. The ability to determine and to predict levels of asthma control and the occurrence of exacerbations is crucial in asthma management. Therefore, we aimed to determine to what extent physiological, behavioural and environmental data, obtained by mobile healthcare (mHealth) and home-monitoring sensors, as well as patient characteristics, can be used to predict episodes of uncontrolled asthma and the onset of asthma exacerbations. METHODS AND ANALYSIS: In an 1-year observational study, patients will be provided with mHealth and home-monitoring systems to record daily measurements for the first-month (phase I) and weekly measurements during a follow-up period of 11 months (phase II). Our study population consists of 150 patients, aged ≥18 years, with a clinician's diagnosis of asthma, currently on controller medication, with uncontrolled asthma and/or minimally one exacerbation in the past 12 months. They will be enrolled over three participating centres, including Leiden, London and Manchester. Our main outcomes are the association between physiological, behavioural and environmental data and (1) the loss of asthma control and (2) the occurrence of asthma exacerbations. ETHICS: This study was approved by the Medical Ethics Committee of the Leiden University Medical Center in the Netherlands and by the NHS ethics service in the UK. TRIAL REGISTRATION NUMBER: NCT02774772

Femorodistal venous bypass evaluated with intravascular ultrasound

Objective:To evaluate the feasibility of intravascular ultrasound imaging during femorodistal venous bypass procedures to assess qualitative and quantitative parameters of the greater saphenous vein and to detect potential causes for (re)stenosis and/or occlusion.Methods:Intravascular ultrasound data obtained from 15 patients were reviewed and compared with angiographic data.Results:Intravascular ultrasound enabled differentiation between normal and thickened vein wall. Venous side-branches could be located. Intact valves could be differentiated from valves disrupted by valve cutting. Patent anastomoses could be distinguished from anastomoses with some degree of obstruction. Intravascular ultrasound imaging of the inflow and outflow tracts revealed obstructive lesions, not evidenced angiographically. Quantitative analysis revealed that the median normal vein wall thickness (tunica intima and tunica media) was 0.25 mm (range 0.17–0.40 mm). The distinct vein wall thickening encountered in three patients measured 0.82, 0.95 and 1.06 mm, respectively, and was associated with narrowing in two patients. In five of 15 patients intravascular ultrasound findings altered surgical management.Conclusion:Intravascular ultrasound is able to assess qualitative and quantitative parameters of the venous bypass and has the potential to influence surgical management based on morphologic and quantitative data

Sustained response and HBsAg loss after nucleo(s)tide analogue discontinuation in chronic hepatitis B patients:the prospective SNAP study

Background &amp; Aim(s): Current guidelines suggest that nucleos(t)ide analogues (NA) can be discontinued before HBsAg loss in a selected group of chronic hepatitis B (CHB) patients. We aimed to study the safety and off-treatment response after NA cessation. Methods: This is a prospective, multicentre, cohort study in which eligible patients discontinued NA therapy. Adult patients, with a CHB mono-infection, HBeAg-negative, without a (history of) liver cirrhosis, who had achieved long-term viral suppression were eligible. Follow-up visits were planned at week 2-4-8-12-24-36-48-72-96. Re-treatment criteria included severe hepatitis (ALT &gt;10x ULN), signs of imminent liver failure (bilirubin &gt;1.5x ULN or INR &gt;1.5), or at the physician's own discretion. Results: In total, 33 patients were enrolled. Patients were predominantly Caucasian (45.5%) and had genotype A/B/C/D/unknown in 3/4/6/10/10 (9.1/12.1/18.2/30.3/30.3%). At week 48, 15 patients (45.5%) achieved a sustained response (HBV DNA &lt;2,000 IU/mL). At week 96, 13 patients (39.4%) achieved a sustained response, 4 (12.1%) achieved HBsAg loss, and 12 (36.4%) were re-treated. Severe hepatitis was the main reason for re-treatment (n=7, 21.2%). One patient with severe hepatitis developed jaundice, without signs of hepatic decompensation. Re-treatment was successful in all patients.Conclusion: NA therapy can be ceased in a highly selected group of CHB patients if close follow-up can be guaranteed. Treatment cessation may increase the chance of HBsAg loss in selected patients, which is counterbalanced by a significant risk of severe hepatitis.</p

Nuclear power and coastal birds: predicting the ecological consequences of warm-water outflows

Local alteration of species abundance in natural communities due to anthropogenic impacts may have secondary, cascading effects on species at higher trophic levels. Such effects are typically hard to single out due to their ubiquitous nature and, therefore, may render impact assessment exercises difficult to undertake. Here we describe how we used empirical knowledge together with modelling tools to predict the indirect trophic effects of a future warm-water outflow on populations of shorebirds and wildfowl. Of the main potential benthic prey used by the birds in this instance, the clam Macoma balthica was the only species suspected to be adversely affected by a future increase of temperature. Various scenarios of decreases in prey energy content, simulating various degrees of temperature increase, were tested using an individual-based model, MORPH, in order to assess the effects on birds. The survival and body condition of eight of the 10 bird species modelled, dunlin, ringed plover, turnstone, redshank, grey plover, black-tailed godwit, oystercatcher and shelduck were shown to be not influenced even by the most conservative prey reduction scenarios. Most of these species are known to feed primarily on polychaete worms. For the few bivalve-feeding species, the larger size-classes of polychaete worms were predicted to be a sufficient alternative food. Only knot was predicted to have a lower survival under the two worst case scenario of decreased M. balthica energy content. We believe that this is the first time such predicted cascade effects from a future warm-water outflow have been shown

Efficacy and safety of an intravenous monoclonal anti-HBs in chronic hepatitis B patients

Background Aims: In this study the safety and efficacy of a monoclonal anti-HBs, Tuvirumab (Mab), were investigated. Tuvirumab is a human monoclonal antibody recognizing the stable 'a'-determinant of the HBsAg. Methods: We included ten chronic hepatitis B patients: four received monotherapy, and six combination therapy with interferon alpha 2b. Results: Because the development of insoluble [HBsAg-HBsAb] complexes led to adverse events, the Mab dose had to be reduced in seven patients. In nine patients treatment was stopped prematurely because of lack of efficacy, i.e. neutralization of HBsAg in serum. However, temporary HBsAg levels were reduced by at least 50% in all patients; in three patients receiving combination therapy, background levels of HBsAg in serum were reached. A loss of serum HBV-DNA was seen in three patients in the combination group, followed by HBeAg seroconversion in two patients. Conclusions: We conclude that Mab was not effective in achieving primary efficacy as assessed by neutralization of circulating HBsAg. Whether a combination of Mab with an antiviral agent that reduces the HBsAg load - and therefore minimizes the risk of adverse events - may result in clinical efficacy should be investigated

SERIES: eHealth in primary care. Part 5: a critical appraisal of five widely used eHealth applications for primary care - opportunities and challenges

Background Given the pressure on modern healthcare systems, eHealth can offer valuable opportunities. However, understanding the potential and challenges of eHealth in daily practice can be challenging for many general practitioners (GPs) and their staff. Objectives To critically appraise five widely used eHealth applications, in relation to safe, evidence-based and high-quality eHealth. Using these applications as examples, we aim to increase understanding of eHealth among GPs and highlight the opportunities and challenges presented by eHealth. Discussion eHealth applications can support patients while increasing efficiency for GPs. A three-way division (inform, monitor, track; interaction; data utilisation) characterises many eHealth applications, with an increasing degree of complexity depending on the domain. All applications provide information and some have extra functionalities that promote interaction, while data analysis and artificial intelligence may be applied to support or (fully) automate care processes. Applications in the inform domain are relatively easy to use and implement but their impact on clinical outcomes may be limited. More demanding applications, in terms of privacy and ethical aspects, are found in the data utilisation domain and may potentially have a more significant impact on care processes and patient outcomes. When selecting and implementing eHealth applications, we recommend that GPs remain critical regarding preconditions on safe, evidence-based and high-quality eHealth, particularly in the case of more complex applications in the data utilisation domain.Prevention, Population and Disease management (PrePoD)Public Health and primary car