The COMET (Comparison of Operative versus Monitoring and Endocrine Therapy) trial: a phase III randomised controlled clinical trial for low-risk ductal carcinoma in situ (DCIS)

Introduction Ductal carcinoma in situ (DCIS) is a noninvasive non-obligate precursor of invasive breast cancer. With guideline concordant care (GCC), DCIS outcomes are at least as favourable as some other early stage cancer types such as prostate cancer, for which active surveillance (AS) is a standard of care option. However, AS has not yet been tested in relation to DCIS. The goal of the COMET (Comparison of Operative versus Monitoring and Endocrine Therapy) trial for low-risk DCIS is to gather evidence to help future patients consider the range of treatment choices for low-risk DCIS, from standard therapies to AS. The trial will determine whether there may be some women who do not substantially benefit from current GCC and who could thus be safely managed with AS. This protocol is version 5 (11 July 2018). Any future protocol amendments will be submitted to Quorum Centralised Institutional Review Board/local institutional review boards for approval via the sponsor of the study (Alliance Foundation Trials). Methods and analysis COMET is a phase III, randomised controlled clinical trial for patients with low-risk DCIS. The primary outcome is ipsilateral invasive breast cancer rate in women undergoing GCC compared with AS. Secondary objectives will be to compare surgical, oncological and patient-reported outcomes. Patients randomised to the GCC group will undergo surgery as well as radiotherapy when appropriate; those in the AS group will be monitored closely with surgery only on identification of invasive breast cancer. Patients in both the GCC and AS groups will have the option of endocrine therapy. The total planned accrual goal is 1200 patients. Ethics and dissemination The COMET trial will be subject to biannual formal review at the Alliance Foundation Data Safety Monitoring Board meetings. Interim analyses for futility/safety will be completed annually, with reporting following Consolidated Standards of Reporting Trials (CONSORT) guidelines for noninferiority trials

Variation in Vector Competence for Dengue Viruses Does Not Depend on Mosquito Midgut Binding Affinity

Several factors, such as mosquito and virus genetics and environmental variables, determine the ability of mosquitoes to transmit dengue viruses. In this report, we describe new and important information that in some ways contradicts what is in the literature. Midgut infection barriers have been described as important determinants of virus transmission in mosquitoes but we found that virus binding to these midgut cells does not vary. When we compared binding of 8 different, low passage dengue viruses to mosquito midguts that were dissected out of Aedes aegypti mosquitoes (the main vectors of dengue) from Mexico and Texas, we found that there were no differences. Previously, we (and others) had shown that these same viruses differed significantly in replication and dissemination throughout the rest of the mosquito body, including the salivary glands, and therefore they differed greatly in their potential to be transmitted to humans. Thus, the data presented here are important considerations for future studies of vector competence and in determining strategies for control of dengue viruses in the vector

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

cgMLST characterisation of invasive Neisseria meningitidis serogroup C and W strains associated with increasing disease incidence in the Republic of Ireland.

Introduction and aimsSince 2013 MenC and MenW disease incidence and associated mortality rates have increased in the Republic of Ireland. From 2002/2003 to 2012/2013, the average annual MenC incidence was 0.08/100,000, which increased to 0.34/100,000 during 2013/2014 to 2017/18, peaking in 2016/17 (0.72/100,000) with an associated case fatality rate (CFR) of 14.7%. MenW disease incidence has increased each year from 0.02/100,000 in 2013/2014, to 0.29/100,000 in 2017/18, with an associated CFR of 28.6%. We aimed to characterise and relate recent MenC isolates to the previously prevalent MenC:cc11 ET-15 clones, and also characterise and relate recent MenW isolates to the novel 'Hajj' clones.MethodsUsing WGS we characterised invasive (n = 74, 1997/98 to 2016/17) and carried (n = 16, 2016/17) MenC isolates, and invasive (n = 18, 2010/11 to 2016/17) and carried (n = 15, 2016/17) MenW isolates. Genomes were assembled using VelvethOptimiser and stored on the PubMLST Neisseria Bacterial Isolate Genome Sequence Database. Isolates were compared using the cgMLST approach.ResultsMost MenC and MenW isolates identified were cc11. A single MenC:cc11 sub-lineage contained the majority (68%, n = 19/28) of recent MenC:cc11 disease isolates and all carried MenC:cc11 isolates, which were interspersed and distinct from the historically significant ET-15 clones. MenW:cc11 study isolates clustered among international examples of both the original UK 2009 MenW:cc11, and novel 2013 MenW:cc11clones.ConclusionsWe have shown that the majority of recent MenC disease incidence was caused by strain types distinct from the MenC:cc11 ET-15 clone of the late 1990s, which still circulate but have caused only sporadic disease in recent years. We have identified that the same aggressive MenW clone now established in several other European countries, is endemic in the RoI and responsible for the recent MenW incidence increases. This data informed the National immunisation Advisory Committee, who are currently deliberating a vaccine policy change to protect teenagers

Higher C6 Enzyme Immunoassay Index Values Correlate with a Diagnosis of Noncutaneous Lyme Disease

The correlation between the Food and Drug Administration-cleared C6 enzyme immunoassay (EIA) C6 index values and a diagnosis of Lyme disease has not been examined. We used pooled patient-level data from 5 studies of adults and children with Lyme disease and control subjects who were tested with the C6 EIA. We constructed a receiver operating characteristic curve using regression clustered by study and measured the area under the curve (AUC) to examine the accuracy of the C6 index values in differentiating between patients with noncutaneous Lyme disease and control subjects. In the 4821 included patients, the C6 index value had excellent ability to distinguish between patients with noncutaneous Lyme disease and control subjects [AUC 0.99; 95% confidence interval (CI) 0.99-1.00]. An index value cut point of \u3e/=3.0 had a sensitivity of 90.9% (95% CI, 87.8-93.3) and specificity of 99.0% (95% CI, 98.6-99.2%) for Lyme disease

Target gene sequencing to characterize the penicillin G susceptibility of Neisseria meningitidis

Clinical isolates of Neisseria meningitidis with reduced susceptibility to penicillin G (intermediate isolates, Pen(I)) harbor alterations in the penA gene encoding the penicillin binding protein 2 (PBP2). A 402-bp DNA fragment in the 3’ half of penA was sequenced from a collection of 1,670 meningococcal clinical isolates from 22 countries that spanned 60 years. Phenotyping, genotyping, and the determination of MICs of penicillin G were also performed. A total of 139 different pen,4 alleles were detected with 38 alleles that were highly related, clustered together in maximum-likelihood analysis and corresponded to the penicillin G-susceptible isolates. The remaining 101 penA alleles were highly diverse, corresponded to different genotypes or phenotypes, and accounted for 38% of isolates, but no clonal expansion was detected. Analysis of the altered alleles that were represented by at least five isolates showed high correlation with the Pen(I) phenotype. The deduced amino acid sequence of the corresponding PBP2 comprised five amino acid residues that were always altered. This correlation was not complete for rare alleles, suggesting that other mechanisms may also be involved in conferring reduced susceptibility to penicillin. Evidence of mosaic structures through events of interspecies recombination was also detected in altered alleles. A new website was created based on the data from this work (http://neisseria.org/nm/typing/penA). These data argue for the use of penA sequencing to identify isolates with reduced susceptibility to penicillin G and as a tool to improve typing of meningococcal isolates, as well as to analyze DNA exchange among Neisseria species

Excessive daytime sleepiness is associated with poor medication adherence in adults with heart failure

A relationship between excessive daytime sleepiness (EDS) and poor treatment adherence has been suspected but not confirmed. We hypothesized that medication adherence would be poorer in adults with heart failure (HF) and EDS and that cognitive status would be the mechanism of effect