Ultrasound-guided breast-sparing surgery to improve cosmetic outcomes and quality of life. A prospective multicentre randomised controlled clinical trial comparing ultrasound-guided surgery to traditional palpation-guided surgery (COBALT trial)

<p>Abstract</p> <p>Background</p> <p>Breast-conserving surgery for breast cancer was developed as a method to preserve healthy breast tissue, thereby improving cosmetic outcomes. Thus far, the primary aim of breast-conserving surgery has been the achievement of tumour-free resection margins and prevention of local recurrence, whereas the cosmetic outcome has been considered less important. Large studies have reported poor cosmetic outcomes in 20-40% of patients after breast-conserving surgery, with the volume of the resected breast tissue being the major determinant. There is clear evidence for the efficacy of ultrasonography in the resection of nonpalpable tumours. Surgical resection of palpable breast cancer is performed with guidance by intra-operative palpation. These palpation-guided excisions often result in an unnecessarily wide resection of adjacent healthy breast tissue, while the rate of tumour-involved resection margins is still high. It is hypothesised that the use of intra-operative ultrasonography in the excision of palpable breast cancer will improve the ability to spare healthy breast tissue while maintaining or even improving the oncological margin status. The aim of this study is to compare ultrasound-guided surgery for palpable tumours with the standard palpation-guided surgery in terms of the extent of healthy breast tissue resection, the percentage of tumour-free margins, cosmetic outcomes and quality of life.</p> <p>Methods/design</p> <p>In this prospective multicentre randomised controlled clinical trial, 120 women who have been diagnosed with palpable early-stage (T1-2N0-1) primary invasive breast cancer and deemed suitable for breast-conserving surgery will be randomised between ultrasound-guided surgery and palpation-guided surgery. With this sample size, an expected 20% reduction of resected breast tissue and an 18% difference in tumour-free margins can be detected with a power of 80%. Secondary endpoints include cosmetic outcomes and quality of life. The rationale, study design and planned analyses are described.</p> <p>Conclusion</p> <p>The COBALT trial is a prospective, multicentre, randomised controlled study to assess the efficacy of ultrasound-guided breast-conserving surgery in patients with palpable early-stage primary invasive breast cancer in terms of the sparing of breast tissue, oncological margin status, cosmetic outcomes and quality of life.</p> <p>Trial Registration Number</p> <p>Netherlands Trial Register (NTR): <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2579">NTR2579</a></p

Drug-gene interactions of antihypertensive medications and risk of incident cardiovascular disease: a pharmacogenomics study from the CHARGE consortium

Background Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals. Methods Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases). Results Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction &gt; 5.0×10−8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD

The CRCbiome study : a large prospective cohort study examining the role of lifestyle and the gut microbiome in colorectal cancer screening participants

Background: Colorectal cancer (CRC) screening reduces CRC incidence and mortality. However, current screening methods are either hampered by invasiveness or suboptimal performance, limiting their effectiveness as primary screening methods. To aid in the development of a non-invasive screening test with improved sensitivity and specificity, we have initiated a prospective biomarker study (CRCbiome), nested within a large randomized CRC screening trial in Norway. We aim to develop a microbiome-based classification algorithm to identify advanced colorectal lesions in screening participants testing positive for an immunochemical fecal occult blood test (FIT). We will also examine interactions with host factors, diet, lifestyle and prescription drugs. The prospective nature of the study also enables the analysis of changes in the gut microbiome following the removal of precancerous lesions. Methods: The CRCbiome study recruits participants enrolled in the Bowel Cancer Screening in Norway (BCSN) study, a randomized trial initiated in 2012 comparing once-only sigmoidoscopy to repeated biennial FIT, where women and men aged 50-74 years at study entry are invited to participate. Since 2017, participants randomized to FIT screening with a positive test result have been invited to join the CRCbiome study. Self-reported diet, lifestyle and demographic data are collected prior to colonoscopy after the positive FIT-test (baseline). Screening data, including colonoscopy findings are obtained from the BCSN database. Fecal samples for gut microbiome analyses are collected both before and 2 and 12 months after colonoscopy. Samples are analyzed using metagenome sequencing, with taxonomy profiles, and gene and pathway content as primary measures. CRCbiome data will also be linked to national registries to obtain information on prescription histories and cancer relevant outcomes occurring during the 10 year follow-up period. Discussion: The CRCbiome study will increase our understanding of how the gut microbiome, in combination with lifestyle and environmental factors, influences the early stages of colorectal carcinogenesis. This knowledge will be crucial to develop microbiome-based screening tools for CRC. By evaluating biomarker performance in a screening setting, using samples from the target population, the generalizability of the findings to future screening cohorts is likely to be high.Peer reviewe

The twilight of the Liberal Social Contract? On the Reception of Rawlsian Political Liberalism

This chapter discusses the Rawlsian project of public reason, or public justification-based 'political' liberalism, and its reception. After a brief philosophical rather than philological reconstruction of the project, the chapter revolves around a distinction between idealist and realist responses to it. Focusing on political liberalism’s critical reception illuminates an overarching question: was Rawls’s revival of a contractualist approach to liberal legitimacy a fruitful move for liberalism and/or the social contract tradition? The last section contains a largely negative answer to that question. Nonetheless the chapter's conclusion shows that the research programme of political liberalism provided and continues to provide illuminating insights into the limitations of liberal contractualism, especially under conditions of persistent and radical diversity. The programme is, however, less receptive to challenges to do with the relative decline of the power of modern states

Constitutivism

A brief explanation and overview of constitutivism

Cancellations of (helicopter-transported) mobile medical team dispatches in the Netherlands

The trauma centre of the Trauma Center Region North-West Netherlands (TRNWN) has consensus criteria for Mobile Medical Team (MMT) scene dispatch. The MMT can be dispatched by the EMS-dispatch centre or by the on-scene ambulance crew and is transported by helicopter or ground transport. Although much attention has been paid to improve the dispatch criteria, the MMT is often cancelled after being dispatched. The aim of this study was to assess the cancellation rate and the noncompliant dispatches of our MMT and to identify factors associated with this form of primary overtriage. By retrospective analysis of all MMT dispatches in the period from 1 July 2006 till 31 December 2006 using chart review, we conducted a consecutive case review of 605 dispatches. Four hundred and sixty seven of these were included for our study, collecting data related to prehospital triage, patient's condition on-scene and hospital course. Average age was 35.9 years; the majority of the patients were male (65.3%). Four hundred and thirty patients were victims of trauma, sustaining injuries in most cases from blunt trauma (89.3%). After being dispatched, the MMT was cancelled 203 times (43.5%). Statistically significant differences between assists and cancellations were found for overall mortality, mean RTS, GCS and ISS, mean hospitalization, length and amount of ICU admissions (p < 0.001). All dispatches were evaluated by using the MMT-dispatch criteria and mission appropriateness criteria. Almost 26% of all dispatches were neither appropriate, nor met the dispatch criteria. Fourteen missions were appropriate, but did not meet the dispatch criteria. The remaining 318 dispatches had met the dispatch criteria, of which 135 (30.3%) were also appropriate. The calculated additional costs of the cancelled dispatches summed up to a total of a,not sign 34,448, amounting to 2.2% of the total MMT costs during the study period. In our trauma system, the MMT dispatches are involved with high rates of overtriage. After being dispatched, the MMT is cancelled in almost 50% of all cases. We found an undertriage rate of 4%, which we think is acceptable. All cancellations were justified. The additional costs of the cancelled missions were within an acceptable range. According to this study, it seems to be possible to reduce the overtriage rate of the MMT dispatches, without increasing the undertriage rate to non-acceptable level

The Herschel-Heterodyne Instrument for the Far-Infrared (HIFI): instrument and pre-launch testing

This paper describes the Heterodyne Instrument for the Far-Infrared (HIFI), to be launched onboard of ESA's Herschel Space Observatory, by 2008. It includes the first results from the instrument level tests. The instrument is designed to be electronically tuneable over a wide and continuous frequency range in the Far Infrared, with velocity resolutions better than 0.1 km/s with a high sensitivity. This will enable detailed investigations of a wide variety of astronomical sources, ranging from solar system objects, star formation regions to nuclei of galaxies. The instrument comprises 5 frequency bands covering 480-1150 GHz with SIS mixers and a sixth dual frequency band, for the 1410-1910 GHz range, with Hot Electron Bolometer Mixers (HEB). The Local Oscillator (LO) subsystem consists of a dedicated Ka-band synthesizer followed by 7 times 2 chains of frequency multipliers, 2 chains for each frequency band. A pair of Auto-Correlators and a pair of Acousto-Optic spectrometers process the two IF signals from the dual-polarization front-ends to provide instantaneous frequency coverage of 4 GHz, with a set of resolutions (140 kHz to 1 MHz), better than < 0.1 km/s. After a successful qualification program, the flight instrument was delivered and entered the testing phase at satellite level. We will also report on the pre-flight test and calibration results together with the expected in-flight performance

Establishing Zebrafish as a Novel Exercise Model: Swimming Economy, Swimming-Enhanced Growth and Muscle Growth Marker Gene Expression

Zebrafish has been largely accepted as a vertebrate multidisciplinary model but its usefulness as a model for exercise physiology has been hampered by the scarce knowledge on its swimming economy, optimal swimming speeds and cost of transport. Therefore, we have performed individual and group-wise swimming experiments to quantify swimming economy and to demonstrate the exercise effects on growth in adult zebrafish