The NeST (Neoadjuvant systemic therapy in breast cancer) study: National Practice Questionnaire of United Kingdom multi-disciplinary decision making.

BACKGROUND: Neoadjuvant systemic therapy (NST) is increasingly used in the treatment of breast cancer, yet it is clear that there is significant geographical variation in its use in the UK. This study aimed to examine stated practice across UK breast units, in terms of indications for use, radiological monitoring, pathological reporting of treatment response, and post-treatment surgical management. METHODS: Multidisciplinary teams (MDTs) from all UK breast units were invited to participate in the NeST study. A detailed questionnaire assessing current stated practice was distributed to all participating units in December 2017 and data collated securely usingREDCap. Descriptive statistics were calculated for each questionnaire item. RESULTS: Thirty-nine MDTs from a diverse range of hospitals responded. All MDTs routinely offered neoadjuvant chemotherapy (NACT) to a median of 10% (range 5-60%) of patients. Neoadjuvant endocrine therapy (NET) was offered to a median of 4% (range 0-25%) of patients by 66% of MDTs. The principal indication given for use of neoadjuvant therapy was for surgical downstaging. There was no consensus on methods of radiological monitoring of response, and a wide variety of pathological reporting systems were used to assess tumour response. Twenty-five percent of centres reported resecting the original tumour footprint, irrespective of clinical/radiological response. Radiologically negative axillae at diagnosis routinely had post-NACT or post-NET sentinel lymph node biopsy (SLNB) in 73.0 and 84% of centres respectively, whereas 16% performed SLNB pre-NACT. Positive axillae at diagnosis would receive axillary node clearance at 60% of centres, regardless of response to NACT. DISCUSSION: There is wide variation in the stated use of neoadjuvant systemic therapy across the UK, with general low usage of NET. Surgical downstaging remains the most common indication of the use of NAC, although not all centres leverage the benefits of NAC for de-escalating surgery to the breast and/or axilla. There is a need for agreed multidisciplinary guidance for optimising selection and management of patients for NST. These findings will be corroborated in phase II of the NeST study which is a national collaborative prospective audit of NST utilisation and clinical outcomes.

A Comparison of the Performance of SARS-CoV-2 Antibody Assays in Healthcare Workers with COVID-19.

Aims Since its emergence, significant interest surrounds the use of SARS-CoV-2 serological tests as an alternative or as an adjunct to molecular testing. However, given the speed of this pandemic, paralleled with the pressure to develop and provide serological tests in an expediated manner, not every assay has undergone the rigorous evaluation that is usually associated with medical diagnostic assays. We aimed to examine the performance of several commercially available SARS-CoV-2 IgG antibody assays among participants with confirmed COVID-19 disease and negative controls. Methods Serum taken between day 17 and day 40 post onset of symptoms from 41 healthcare workers with RT-PCR confirmed COVID-19 disease, and pre-pandemic serum from 20 negative controls, were tested for the presence of SARS-CoV-2 IgG using 7 different assays including point-of-care (POC) and laboratory-based assays. Results Assay performance varied. The lab-based Abbott diagnostics SARS-CoV-2 IgG assay proved to be the assay with the best positive and negative predictive value, and overall accuracy. The POC Nal von Minden GmbH and Biozek assays also performed well. Conclusion Our research demonstrates the variations in performance of several commercially available SARS-CoV-2 antibody assays. These findings identify the limitations of some serological tests for SARS-CoV-2. This information will help inform test selection and may have particular relevance to providers operating beyond accredited laboratories.

Transient receptor potential channels TRPC1/TRPC6 regulate lamina cribrosa cell extracellular matrix gene transcription and proliferation.

The lamina cribrosa (LC) in glaucoma is with augmented production of extracellular matrix proteins (ECM) and connective tissue fibrosis. Fundamental pathological mechanisms for this fibrosis comprise fibrotic growth factors and oxidative stress. Transient receptor potential canonical channels (TRPC) channels play a key role in ECM fibrosis. Here, we study TRPC expression in glaucomatous LC cells, and investigate the role of TRPC in oxidative stress induced-profibrotic ECM gene transcription and cell proliferation in normal LC cells. Age-matched human LC cells (normal, n = 3 donors; glaucoma, n = 3 donors) were used. Hydrogen peroxide (H2O2, 100 µM), was used to induce oxidative stress in LC cells in the presence or absence of the pan TRPC inhibitor SKF96365 (10 µM) or knockdown of TRPC1/6 with siRNA. After treatments, ECM gene transcription, LC cell viability and proliferation and the phosphorylation of the transcription factor NFATc3, were measured using real time RT-PCR, colorimetric cell counting with the methyl-thiazolyl tetrazolium salt (MTS) assay, and Western immunoblotting, respectively. Results showed that TRPC1/C6 transcript and protein expression levels were significantly (p < 0.05) enhanced in glaucoma LC cells. Both SKF96365 and siRNA-TRPC1/C6 treatments significantly reduced the oxidative stress induced-ECM gene expression (transforming growth factor-ß1 (TGFß1), alpha smooth muscle actin (α-SMA), and collagen type 1A1 (Col1A1)), and cell proliferation in normal and glaucoma LC cells. Also, SKF96365 treatment inhibited the H2O2-induced NFATc3 protein dephosphorylation in LC cells. In conclusion, TRPC1/C6 expression is enhanced in glaucoma LC cells. These channels may contribute to oxidative stress-induced ECM gene transcription and cell proliferation in normal and glaucoma LC cells through Ca2+-NFATc3 signaling pathway mechanism. TRPC1 and TRPC6 channels could be important therapeutic targets to prevent ECM remodeling and fibrosis development in glaucoma optic neuropathy.

Congenital anomalies following antenatal exposure to dolutegravir: a Canadian surveillance study.

OBJECTIVE: Dolutegravir is recommended worldwide as a first-line antiretroviral therapy (ART) for individuals living with HIV. A recent study reported increased rates of neural tube defects in infants of dolutegravir-treated women. This study examined rates of congenital anomalies in infants born to women living with HIV (WLWH) in Canada. DESIGN: The Canadian Perinatal HIV Surveillance Programme captures surveillance data on pregnant WLWH and their babies and was analysed to examine the incidence of congenital anomalies. SETTING: Paediatric HIV clinics. POPULATION: Live-born infants born in Canada to WLWH between 2007 and 2017. METHODS: Data on mother-infant pairs, including maternal ART use at conception and during pregnancy, are collected by participating sites. MAIN OUTCOME MEASURES: Congenital anomalies. RESULTS: Of the 2423 WLWH, 85 (3.5%, 95% CI 2.85-4.36%) had non-chromosomal congenital anomalies. There was no evidence of a significant difference in rates of congenital anomalies between women who were on ART in their first trimester (3.9%, CI 1.7-7.6%) or later in the pregnancy (3.9%, 95% CI 2.6-5.6%). Four of the 80 (5.0%, 95% CI 1.4-12.3%) neonates born to WLWH on dolutegravir during the first trimester had congenital anomalies, none were neural tube defects (95% CI 0.00-3.10%). CONCLUSION: Despite recent evidence raising a safety concern, this analysis found no signal for increased congenital anomalies. TWEETABLE ABSTRACT: Five percent of the infants of Canadian women living with HIV on dolutegravir at conception had congenital anomalies; none had neural tube defects.

The Role of Interventional Radiology in the Management of Obstetric and Gynaecological Haemorrhage

Aim We will review our experience of emergent arterial embolization used to treat haemodynamically unstable patients with obstetric and gynaecological haemorrhage. Methods This is a retrospective study of patients with haemodynamically unstable obstetric and gynaecological haemorrhage treated with emergent arterial embolization from 2010 to 2015. Results 22 patients (average age 41 (SD +/-9) years) had emergent arterial embolization. 63% had post-partum haemorrhage (PPH). 82% of cases were performed with conscious sedation and local anaesthesia. Embolization was technically successful in all cases. Embolization was clinically successful in 95% (21/22). In one case of PPH the patient represented six days later with recurrent bleeding and was treated with surgical suturing of the cervix. There were no complications or deaths. Conclusion Arterial embolization is a highly successful treatment of obstetric and gynaecological haemorrhage in unstable patients.

Children with facial morphoea managing everyday life: a qualitative study.

BACKGROUND: Facial morphoea is a chronic inflammatory skin disorder, typically presenting in childhood and adolescence, which can be disfiguring, and which has been suggested to cause mild-to-moderate impairment in quality of life. OBJECTIVES: To explore the everyday experiences of children with facial morphoea by examining the psychosocial impact of living with facial morphoea and how children and their families manage its impact. METHODS: We used a qualitative, social constructionist approach involving focus groups, in-depth interviews and drawing activities with 10 children with facial morphoea aged 8-17 years and 13 parents. Interpretive thematic analysis was utilized to examine the data. RESULTS: Children and parents reported on the stress of living with facial morphoea, which was related to the lack of knowledge about facial morphoea and the extent to which they perceived themselves as different from others. Self-perceptions were based on the visibility of the lesion, different phases of life transitions and the reactions of others (e.g. intrusive questioning and bullying). Medication routines, and side-effects such as weight gain, added to the stress experienced by the participants. To manage the impact of facial morphoea, children and their parents used strategies to normalize the experience by hiding physical signs of the illness, constructing explanations about what 'it' is, and by connecting with their peers. CONCLUSIONS: Understanding what it is like to live with facial morphoea from the perspectives of children and parents is important for devising ways to help children with the disorder achieve a better quality of life. Healthcare providers can help families access resources to manage anxiety, deal with bullying and construct adequate explanations of facial morphoea, in addition to providing opportunities for peer support.

Peripherally Inserted Central Catheters (PICCs) and Potential Cost Savings and Shortened Bed Stays In an Acute Hospital Setting.

Peripheral inserted central catheters (PICCs) have increasingly become the mainstay of patients requiring prolonged treatment with antibiotics, transfusions, oncologic IV therapy and total parental nutrition. They may also be used in delivering a number of other medications to patients. In recent years, bed occupancy rates have become hugely pressurized in many hospitals and any potential solutions to free up beds is welcome. Recent introductions of doctor or nurse led intravenous (IV) outpatient based treatment teams has been having a direct effect on early discharge of patients and in some cases avoiding admission completely. The ability to deliver outpatient intravenous treatment is facilitated by the placement of PICCs allowing safe and targeted treatment of patients over a prolonged period of time. We carried out a retrospective study of 2,404 patients referred for PICCs from 2009 to 2015 in a university teaching hospital. There was an exponential increase in the number of PICCs requested from 2011 to 2015 with a 64% increase from 2012 to 2013. The clear increase in demand for PICCs in our institution is directly linked to the advent of outpatient intravenous antibiotic services. In this paper, we assess the impact that the use of PICCs combined with intravenous outpatient treatment may have on cost and hospital bed demand. We advocate that a more widespread implementation of this service throughout Ireland may result in significant cost savings as well as decreasing the number of patients on hospital trollies.

Somatic mutation, copy number and transcriptomic profiles of primary and matched metastatic estrogen receptor-positive breast cancers.

BACKGROUND: Estrogen receptor-positive (ER+) breast cancers (BCs) constitute the most frequent BC subtype. The molecular landscape of ER+ relapsed disease is not well characterized. In this study, we aimed to describe the genomic evolution between primary (P) and matched metastatic (M) ER+ BCs after failure of adjuvant therapy. MATERIALS AND METHODS: A total of 182 ER+ metastatic BC patients with long-term follow-up were identified from a single institution. P tumor tissue was available for all patients, with 88 having matched M material. According to the availability of tumor material, samples were characterized using a 120 mutational hotspot qPCR, a 29 gene copy number aberrations (CNA) and a 400 gene expression panels. ESR1 mutations were assayed by droplet digital PCR. Molecular alterations were correlated with overall survival (OS) using the Cox proportional hazards regression models. RESULTS: The median follow-up was 6.4 years (range 0.5-26.6 years). Genomic analysis of P tumors revealed somatic mutations in PIK3CA, KRAS, AKT1, FGFR3, HRAS and BRAF at frequencies of 41%, 6%, 5%, 2%, 1% and 2%, respectively, and CN amplification of CCND1, ZNF703, FGFR1, RSF1 and PAK1 at 23%, 19%, 17%, 12% and 11%, respectively. Mutations and CN amplifications were largely concordant between P and matched M (>84%). ESR1 mutations were found in 10.8% of the M but none of the P. Thirteen genes, among which ESR1, FOXA1, and HIF1A, showed significant differential expression between P and M. In P, the differential expression of 18 genes, among which IDO1, was significantly associated with OS (FDR < 0.1). CONCLUSIONS: Despite the large concordance between P and matched M for the evaluated molecular alterations, potential actionable targets such as ESR1 mutations were found only in M. This supports the importance of characterizing the M disease. Other targets we identified, such as HIF1A and IDO1, warrant further investigation in this patient population.

Supports and modified nano-particles for designing model catalysts.

In order to design catalytic materials, we need to understand the essential causes for material properties resulting from its composite nature. In this paper we discuss two, at first sight, diverse aspects: (a) the effect of the oxide-metal interface on metal nanoparticle properties and (b) the consequences of metal particle modification after activation on the selectivity of hydrogenation reactions. However, these two aspects are intimately linked. The metal nanoparticle's electronic structure changes at the interface as a catalyst is brought to different reaction temperatures due to morphological modifications in the metal and, as we will discuss, these changes in the chemistry lead to changes in the reaction path. As the morphology of the particle varies, facets of different orientations and sizes are exposed, which may lead to a change in the surface chemistry as well. We use two specific reactions to address these issues in some detail. To the best of our knowledge, the present paper reports the first observations of this kind for well-defined model systems. The changes in the electronic structure of Au nanoparticles due to their size and interaction with a supporting oxide are revealed as a function of temperature using CO2 activation as a probe. The presence of spectator species (oxopropyl), formed during an activation step of acrolein hydrogenation, strongly controls the selectivity of the reaction towards hydrogenation of the unsaturated C[double bond, length as m-dash]O bond vs. the C[double bond, length as m-dash]C bond on Pd(111) when compared with oxide-supported Pd nanoparticles.

Temporal changes in bile acid levels and 12α-hydroxylation after Roux-en-Y gastric bypass surgery in type 2 diabetes.

INTRODUCTION: Gastric bypass surgery (GBP) leads to sustained weight loss and significant improvement in type 2 diabetes (T2DM). Bile acids (BAs), signaling molecules which influence glucose metabolism, are a potential mediator for the improvement in T2DM after GBP. This study sought to investigate the effect of GBP on BA levels and composition in individuals with T2DM. METHODS: Plasma BA levels and composition and fibroblast growth factor (FGF)-19 levels were measured during fasting and in response to an oral glucose load before and at 1 month and 2 years post GBP in 13 severely obese women with T2DM. RESULTS: A striking temporal change in BA levels and composition was observed after GBP. During the fasted state, BA concentrations were generally reduced at 1 month, but increased 2 years post GBP. Postprandial BA levels were unchanged 1 month post GBP, but an exaggerated postprandial peak was observed 2 years after the surgery. A significant increase in the 12α-hydroxylated/non12α-hydroxylated BA ratio during fasting and postprandially at 2 years, but not 1 month, post GBP was observed. Significant correlations between BAs vs FGF-19, body weight, the incretin effect and peptide YY (PYY) were also found. CONCLUSIONS: This study provides evidence that GBP temporally modifies the concentration and composition of circulating BAs in individuals with T2DM, and suggests that BAs may be linked to the improvement in T2DM after GBP.

Cardiovascular risk factors and metabolic syndrome in people with established psychotic illnesses: baseline data from the IMPaCT RCT study--Corrigendum.

The author regrets to announce that affiliation 8, in the above article (Gardner-Sood et al. 2015), contained an error in the author affiliation address and author surname, which were published in the approved article. The correct surname and affiliation address are given below. J. Eberhard, Clinical Psychiatric Research Center, Lund University, Skåne, Sweden

Cardiovascular risk factors and metabolic syndrome in people with established psychotic illnesses: baseline data from the IMPaCT randomized controlled trial.

BACKGROUND: The aims of the study were to determine the prevalence of cardiometabolic risk factors and establish the proportion of people with psychosis meeting criteria for the metabolic syndrome (MetS). The study also aimed to identify the key lifestyle behaviours associated with increased risk of the MetS and to investigate whether the MetS is associated with illness severity and degree of functional impairment. METHOD: Baseline data were collected as part of a large randomized controlled trial (IMPaCT RCT). The study took place within community mental health teams in five Mental Health NHS Trusts in urban and rural locations across England. A total of 450 randomly selected out-patients, aged 18-65 years, with an established psychotic illness were recruited. We ascertained the prevalence rates of cardiometabolic risk factors, illness severity and functional impairment and calculated rates of the MetS, using International Diabetes Federation (IDF) and National Cholesterol Education Program Third Adult Treatment Panel criteria. RESULTS: High rates of cardiometabolic risk factors were found. Nearly all women and most men had waist circumference exceeding the IDF threshold for central obesity. Half the sample was obese (body mass index ≥ 30 kg/m2) and a fifth met the criteria for type 2 diabetes mellitus. Females were more likely to be obese than males (61% v. 42%, p < 0.001). Of the 308 patients with complete laboratory measures, 57% (n = 175) met the IDF criteria for the MetS. CONCLUSIONS: In the UK, the prevalence of cardiometabolic risk factors in individuals with psychotic illnesses is much higher than that observed in national general population studies as well as in most international studies of patients with psychosis.

De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability.

Schizophrenia is a serious psychiatric disorder with a broadly undiscovered genetic etiology. Recent studies of de novo mutations (DNMs) in schizophrenia and autism have reinforced the hypothesis that rare genetic variation contributes to risk. We carried out exome sequencing on 57 trios with sporadic or familial schizophrenia. In sporadic trios, we observed a ~3.5-fold increase in the proportion of nonsense DNMs (0.101 vs 0.031, empirical P=0.01, Benjamini-Hochberg-corrected P=0.044). These mutations were significantly more likely to occur in genes with highly ranked probabilities of haploinsufficiency (P=0.0029, corrected P=0.006). DNMs of potential functional consequence were also found to occur in genes predicted to be less tolerant to rare variation (P=2.01 × 10(-)(5), corrected P=2.1 × 10(-)(3)). Genes with DNMs overlapped with genes implicated in autism (for example, AUTS2, CHD8 and MECP2) and intellectual disability (for example, HUWE1 and TRAPPC9), supporting a shared genetic etiology between these disorders. Functionally CHD8, MECP2 and HUWE1 converge on epigenetic regulation of transcription suggesting that this may be an important risk mechanism. Our results were consistent in an analysis of additional exome-based sequencing studies of other neurodevelopmental disorders. These findings suggest that perturbations in genes, which function in the epigenetic regulation of brain development and cognition, could have a central role in the susceptibility to, pathogenesis and treatment of mental disorders.

Validation and Assessment of a Technology Familiarity Score in Patients Attending a Symptomatic Breast Clinic.

INTRODUCTION: New media technologies (computers, mobile phones and the internet) have the potential to transform the healthcare information needs of patients with breast disease (Ferlay et al. in Eur J Cancer 49:1374-1403, 2013). However, patients' current level of use and their willingness to accept new media for education and communication remain unknown. METHODS: This was a single-centre clinic-based prospective cross-sectional study. A previously developed instrument was modified, validated and tested on patients attending a symptomatic breast clinic. RESULTS: The instrument was evaluated on 200 symptomatic breast patients. The commonest outlets for education were staff (95 %), leaflets (69 %) and websites (59 %). Websites are more likely to be consulted by younger patients (<47 years), and patients who were working, students or homemakers (p < 0.05). Patients rated usefulness of information media in this order: (1) print, (2) phone, (3) website, (4) email, (5) text and (6) apps. Patients who were new to the clinic were more likely to find text messaging and emailing useful (n < 0.05). Younger patients (<47 years) are more likely to find text messages, apps, websites and email useful (p < 0.05). Urban patients are more likely to find websites and email useful (p < 0.05). Patients with higher education were more likely to favour apps, websites and email (p < 0.05). Smartphone owners were significantly more likely to rate text messaging, apps, websites and email as useful media (p < 0.05). CONCLUSION: This study demonstrates that new media technology use among breast patients is expanding as expected along generational trends. As such its' further integration into healthcare systems can potentially ameliorate patient education and communication.

The cost of the inpatient management of febrile neutropenia in cancer patients--a micro-costing study in the Irish healthcare setting.

The objective was to evaluate the resource use and cost of hospitalisation for febrile neutropenia (FN) from the health-payer's perspective. This was a single centre study. Adults undergoing chemotherapy, who were admitted for FN, were identified prospectively. Patient medical records were reviewed retrospectively. Demographics and resource utilisation data were obtained from a cohort of 32 patients (69% female, mean age = 58.8 years). Twenty-five per cent of patients had more than one FN episode. In total, 42 FN episodes were captured; 60% of episodes had occurred within the first two cycles of chemotherapy. The bootstrap estimation was used to determine mean hospital length of stay (LOS) with standard deviation (±SD) and mean costs ± SD. The mean LOS was 7.3 ± 0.5 days. The mean cost per FN episode was €8915 ± 718. The major cost driver was hospital bed-stay (mean cost of €6851 ± 549). Other cost drivers included antibacterial treatment at €760 ± 156, laboratory investigations at €538 ± 47 and the requirement for blood bank products at €525 ± 189. To our knowledge, this is the first investigation of the cost of chemotherapy induced FN within the context of the Irish healthcare setting.

Changes in the levels of Cryspovirus during in vitro development of Cryptosporidium parvum.

The purpose of this study was to develop and utilize semi-quantitative RT-PCR and PCR assays for measuring the level of Cryspovirus, the viral symbiont of Cryptosporidium parvum, during in vitro development of the protozoan. Cultures of human carcinoma cells (HCT-8) were inoculated with excysting C. parvum sporozoites, followed by harvest of cells and culture medium at 2-, 24-, 48-, and 72-h post-infection. Changes in viral RNA levels were detected by RT-PCR using primers specific for RNA encoding the 40-kDa capsid protein (CP) or RNA-dependent RNA polymerase (RdRp). Parasite or host DNA was quantified by PCR specific for C. parvum or human glyceraldehyde-3-phosphate dehydrogenase (HuGAPDH). An internal standard (competitor) was incorporated into all assays as a control for PCR inhibition. Intracellular levels of C. parvum DNA increased between 2- and 48-h post-infection, and then decreased at 72 h. Culture medium overlying these C. parvum-infected cells displayed a similar increase in CP and RdRp signal, reaching peak levels at 48 h. However, the CP and RdRp levels in cellular RNA displayed only a modest increase between 2 and 48 h, and exhibited no change (CP) or decreased (RdRp) at 72 h. These data suggest that during the first 48 h of C. parvum in vitro development, Cryspovirus is released into the media overlying cells but remains at fairly constant levels within infected cells.

Epidermal growth factor receptor (EGFR) mutation testing, from bench to practice: a single institute experience.

Epidermal growth factor receptor (EGFR) gene mutations determine the treatment and prognosis in lung adenocarcinoma. Exon 19 and exon 21 (L858R) deletions represent the most common recognised mutations detected. To date, no figures regarding the prevalence of EGFR mutations in the Irish population have been published. The prevalence of EGFR mutations was retrospectively analysed for all patient samples tested since the introduction of EGFR testing routinely (Mar to Dec 2012) in a single Irish institute. The presence of 41 known treatment linked EGFR mutations in exons 18, 19, 20 and 21 of the EGFR gene was tested in 209 Irish patients. Resection, core biopsy or FNA samples were analysed using a commercially available CE-IVD marked multiplex real-time PCR assay. Samples were included from patients of curative and palliative treatment intent likely to harbour an EGFR mutation.