Association Between Ex Vivo Human Ulcerative Colitis Explant Protein Secretion Profiles and Disease Behaviour.

BACKGROUND: The clinical course of ulcerative colitis (UC) is variable. There is an unmet clinical need for biomarkers of UC disease behaviour. We aimed to evaluate the association between ex vivo human UC explant conditioned media (explant-CM) secreted protein profiles and UC disease behaviour. METHODS: UC patients undergoing endoscopy were prospectively recruited. Endoscopic biopsies were collected and explant-CM generated. Association between explant-CM protein secretion profiles and disease progression was evaluated. Disease progression was defined as the requirement for corticosteroid therapy, UC-related hospitalisation, UC-related surgery or the introduction of a new immunomodulatory agent. Association between explant-CM secreted protein profiles and anti-TNF failure status was also evaluated. p values < 0.05 were considered significant in analyses. RESULTS: Twenty-four UC patients were included (age [median, range]) 55 [21-72] years; 50% female. Disease progression during follow-up occurred in twelve (50%) patients. Multivariate analysis, including endoscopic remission status, demonstrated reduced IL-2 secretion to be independently associated with UC disease progression, p = 0.01. In univariate analysis, anti-TNF failure status was associated with significantly increased IL-17A/F (p = 0.015) and IL-12 / IL-23p40 (p = 0.044) concentrations. In multivariate analysis, there was a trend towards an association between IL-17A/F and anti-TNF failure status (p = 0.069); FLT-1 was demonstrated to be independently associated with anti-TNF failure status (p = 0.016). CONCLUSION: Reduced explant-CM secreted IL-2 is associated with UC disease progression. Increased secretion of IL-23 pathway-associated cytokines was observed in anti-TNF failure status consistent with previous reports. Ex vivo human UC explants, generated from endoscopic biopsies, have potential as precision medicine tools in inflammatory bowel disease.

Health literacy and the perception of risk in a breast cancer family history clinic.

BACKGROUND: Informed consent is an essential component of medical practice, and especially so in procedural based specialties which entail varying degrees of risk. Breast cancer is one of the most common cancers in women, and as such is the focus of extensive research and significant media attention. Despite this, considerable misperception exists regarding the risk of developing breast cancer. AIMS: This study aims to examine the accuracy of risk perception of women attending a breast cancer family history clinic, and to explore the relationship between risk perception accuracy and health literacy. METHODS: A cross-sectional study of women attending a breast cancer family history clinic (n = 86) was carried out, consisting of a patient survey and a validated health literacy assessment. Patients' perception of personal and population breast cancer risk was compared to actual risk as calculated by a validated risk assessment tool. RESULTS: Significant discordance between real and perceived risks was observed. The majority (83.7%) of women overestimated their personal lifetime risk of developing breast cancer, as well as that of other women of the same age (89.5%). Health literacy was considered potentially inadequate in 37.2% of patients; there was a correlation between low health literacy and increased risk perception inaccuracy across both personal ten-year (rs = 0.224, p = 0.039) and general ten-year population estimations. (rs = 0.267, p = 0.013). CONCLUSION: Inaccuracy in risk perception is highly prevalent in women attending a breast cancer family history clinic. Health literacy inadequacy is significantly associated with this inaccuracy.

Can an educational application increase risk perception accuracy amongst patients attending a high-risk breast cancer clinic?

OBJECTIVES: To design, develop and test the effect of an educational initiative to improve risk perception amongst patients attending a high-risk breast cancer clinic. This was achieved through three objectives - 1. identifying an optimal method of presenting risk data, 2. designing and building a risk application, and 3. testing the ability of the application to successfully modify patients perceived risk of cancer. MATERIALS AND METHODS: A mobile application was developed for this project using best practice methods for displaying risk information. Patients (n = 84) were randomly allocated into two groups - 'Control' or 'Treatment'. Both groups underwent standard risk counseling while the application was employed in the 'Treatment' group. The patients were surveyed before their session, immediately after and six weeks later. RESULTS: Increases in accuracy were seen in both groups with larger increases demonstrated in the 'Treatment' group with 'Personal 10 Year Risk' statistically significant ('Control' group increase from 21% to 48% vs the 'Treatment' group increase from 33% to 71% - p = 0.003). CONCLUSION: This project demonstrated trends towards improved risk perception, however mixed logistic regression was unable to show a 30% difference between groups. Numerical literacy and understanding of risk were identified as issues amongst the general population. Overestimating risk remains high amongst attendees. Using mobile applications to convey risk information to patients is a new and evolving area with a corresponding paucity of data. We have demonstrated its potential and emphasised the importance of designing how this information is communicated to patients in order to make it understandable and meaningful.

When pathological and radiological correlation is achieved, excision of fibroadenoma with lobular neoplasia on core biopsy is not warranted.

BACKGROUND: The diagnosis and management of lobular neoplasia (LN) including lobular carcinoma in situ (LCIS) and atypical lobular hyperplasia (ALH) remains controversial. Current management options after a core needle biopsy (CNB) with lobular neoplasia (LN) incorporating both ALH and LCIS include excision biopsy or careful clinical and radiologic follow up. METHODS: A retrospective analysis of the surgical database at Cork University Hospital was performed to identify all core needle biopsies from January 1st 2010 to 31st December 2013 with a diagnosis of FA who subsequently underwent surgical excision biopsy. All cases with associated LN including ALH and classical LCIS were selected. We excluded cases with coexistent ductal carcinoma in situ (DCIS), invasive carcinoma, LN associated with necrosis, pleomorphic lobular carcinoma in situ (PLCIS) or lesions which would require excision in their own right (papilloma, radial scar, atypical ductal hyperplasia (ADH) or flat epithelial atypia (FEA)). Cases in which the radiologic targeted mass was discordant with a diagnosis of FA were also excluded. RESULTS: 2878 consecutive CNB with a diagnosis of FA were identified. 25 cases had a diagnosis of concomitant ALH or classical LCIS. Our study cohort consisted of 21 women with a mean age 53 years (age range 41-70 years). The core biopsy diagnosis was of LCIS and FA in 16 cases and ALH and FA in 5 cases. On excision biopsy, a FA was confirmed in all 21 cases. In addition to the FA, residual LCIS was present in 14 cases with residual ALH in 2 cases. One of the twenty-one cases (4.8%) was upgraded to invasive ductal carcinoma on excision.

Topographical Differences of Infant Mortality in Nepal.

Background Infant mortality is a major problem in Nepal, particularly in the mountainous region of the country. Objective To identify factors that contributes to the high rate of infant mortality in the mountain zone in Nepal. Method Data were derived from the 2011 Nepal Demographic and Health Survey (NDHS). Infant mortality was analyzed across three ecological zones in a sample of 5,306 live births in the five years preceding the survey. The contribution of risk factors to the excess infant mortality was assessed using multiple logistic regression. Result Infant mortality rate (deaths per 1000 live births) in the ecological zones were 59 (95% CI: 36, 81), 44 (35, 53), and 40 (33, 47) for the mountain, hill and terai zones, respectively. Women living in the mountain zone were more likely to report that distance to care was a "big problem" and had a greater risk of infant mortality compared to the terai zone (OR=1.42, 95% CI: 1.01, 2.02, p=0.04). This increased risk was observed only among births to mothers who perceived distance to the nearest health facility as a "big problem" (aOR=1.57, 95% CI: 1.01, 2.40, p=0.04) controlling for other risk factors. Conclusion These findings suggest that the higher Infant mortality rate (IMR) in the mountain zone was among the women who perceived distance to health facilities as a big problem. Improved accessibility to health services, particularly in this zone, is an essential strategy for reducing infant mortality in Nepal.

The classification and diagnostic algorithm for primary lymphatic dysplasia: an update from 2010 to include molecular findings.

Historically, primary lymphoedema was classified into just three categories depending on the age of onset of swelling; congenital, praecox and tarda. Developments in clinical phenotyping and identification of the genetic cause of some of these conditions have demonstrated that primary lymphoedema is highly heterogenous. In 2010, we introduced a new classification and diagnostic pathway as a clinical and research tool. This algorithm has been used to delineate specific primary lymphoedema phenotypes, facilitating the discovery of new causative genes. This article reviews the latest molecular findings and provides an updated version of the classification and diagnostic pathway based on this new knowledge.

Surgical resection for non-small cell lung cancer: clinical features and outcomes for a consecutive series at an Irish tertiary referral centre.

BACKGROUND: Few patients diagnosed with lung cancer are still alive 5 years after diagnosis. The aim of the current study was to conduct a 10-year review of a consecutive series of patients undergoing curative-intent surgical resection at the largest tertiary referral centre to identify prognostic factors. METHODS: Case records of all patients operated on for lung cancer between 1998 and 2008 were reviewed. The clinical features and outcomes of all patients with non-small cell lung cancer (NSCLC) stage I-IV were recorded. RESULTS: A total of 654 patients underwent surgical resection with curative intent during the study period. Median overall survival for the entire cohort was 37 months. The median age at operation was 66 years, with males accounting for 62.7 %. Squamous cell type was the most common histological subtype, and lobectomies were performed in 76.5 % of surgical resections. Pneumonectomy rates decreased significantly in the latter half of the study (25 vs. 16.3 %), while sub-anatomical resection more than doubled (2 vs. 5 %) (p < 0.005). Clinico-pathological characteristics associated with improved survival by univariate analysis include younger age, female sex, smaller tumour size, smoking status, lobectomy, lower T and N status and less advanced pathological stage. Age, gender, smoking status and tumour size, as well as T and N descriptors have emerged as independent prognostic factors by multivariate analysis. CONCLUSION: We identified several factors that predicted outcome for NSCLC patients undergoing curative-intent surgical resection. Survival rates in our series are comparable to those reported from other thoracic surgery centres.

IRF6 Screening of Syndromic and a priori Non-Syndromic Cleft Lip and Palate Patients: Identification of a New Type of Minor VWS Sign.

Van der Woude syndrome (VWS), caused by dominant IRF6 mutation, is the most common cleft syndrome. In 15% of the patients, lip pits are absent and the phenotype mimics isolated clefts. Therefore, we hypothesized that some of the families classified as having non-syndromic inherited cleft lip and palate could have an IRF6 mutation. We screened in total 170 patients with cleft lip with or without cleft palate (CL/P): 75 were syndromic and 95 were a priori part of multiplex non-syndromic families. A mutation was identified in 62.7 and 3.3% of the patients, respectively. In one of the 95 a priori non-syndromic families with an autosomal dominant inheritance (family B), new insights into the family history revealed the presence, at birth, of lower lip pits in two members and the diagnosis was revised as VWS. A novel lower lip sign was observed in one individual in this family. Interestingly, a similar lower lip sign was also observed in one individual from a 2nd family (family A). This consists of 2 nodules below the lower lip on the external side. In a 3rd multiplex family (family C), a de novo mutation was identified in an a priori non-syndromic CL/P patient. Re-examination after mutation screening revealed the presence of a tiny pit-looking lesion on the inner side of the lower lip leading to a revised diagnosis of VWS. On the basis of this data, we conclude that IRF6 should be screened when any doubt rises about the normality of the lower lip and also if a non-syndromic cleft lip patient (with or without cleft palate) has a family history suggestive of autosomal dominant inheritance.

A new classification system for primary lymphatic dysplasias based on phenotype.

Traditional classification systems for lymphoedema are of limited use for the diagnosis of specific forms of primary lymphoedema. The understanding of primary lymphoedema has been impeded by confusing terminology and a tendency to simply divide patients into three categories based on the age of onset: lymphoedema congenita manifests at or shortly after birth, lymphoedema praecox is apparent before the age of 35 years and lymphoedema tarda manifests thereafter. The clinical presentation in the spectrum of primary lymphoedema disorders is very variable; the phenotypes of primary lymphoedema conditions vary in the age of onset, site of the oedema, inheritance patterns, associated features and genetic causes. Different inheritance patterns are recognised and there are numerous associated anomalies. Some subgroups, such as Milroy disease and Lymphoedema distichiasis, are well characterised, but others are not. A new clinical classification for primary lymphoedema has been developed as a diagnostic algorithm. Its use is demonstrated on 333 probands referred to our lymphoedema clinic. Grouping patients by accurate phenotyping facilitates molecular investigations, understanding of inheritance patterns, and the natural history of different types of primary lymphoedema. Descriptions of the diagnostic categories, some of which have not been previously clearly defined as distinct clinical entities, are illustrated by clinical cases.

Analysis of the coding regions of VEGFR3 and VEGFC in Milroy disease and other primary lymphoedemas.

Milroy disease (hereditary lymphoedema type I, MIM 153100) is a congenital onset primary lymphoedema with autosomal dominant inheritance. Mutations in the gene, vascular endothelial growth factor receptor 3, VEGFR3 (FLT4), are known to cause Milroy disease, but there is uncertainty about the prevalence of VEGFR3 mutations in patients with primary lymphoedema and more specifically in those with a phenotype that resembles Milroy disease. This study aims to address this issue and thereby delineate the Milroy disease phenotype. Fifty-two patients with primary lymphoedema were analysed for mutations in the coding regions of VEGFR3. Patients were divided into four groups: Typical Milroy disease with family history (group I), typical Milroy disease with no family history (group II), atypical Milroy disease (group III), and complex primary lymphoedema (group IV). Results demonstrated that with rigorous phenotyping the likelihood of detecting VEGFR3 mutations is optimised. Mutation prevalence is 75% in typical Milroy patients with a family history (group I) and 68% if positive family history is not a diagnostic criterion. A positive family history is not essential in Milroy disease. The likelihood of detecting VEGFR3 mutations in patients who have a phenotype which is not typical of Milroy disease is very small (<5%). For the 22 mutation positive patients, 14 novel VEGFR3 mutations were identified, two of which were in exon 22 and one in exon 17, confirming that these exons should be included in VEGFR3 analysis. No mutations were found outside the kinase domains, showing that analysis of this part of the gene is not useful for Milroy disease patients. VEGFC, which encodes the ligand for VEGFR3, was sequenced in all patients with typical Milroy disease (groups I and II) and no mutations were identified.

Utilization of primary health care facilities: lessons from a rural community in southwest Nigeria.

BACKGROUND: This study assessed service/organisational factors and clients' perceptions that influenced utilisation of Primary Health Care (PHC) facilities in a rural community in Nigeria. METHOD: A cross-sectional household survey in the community as well as key-informant interviews of opinion leaders and health care providers and participant observations of health facilities and utilisation pattern was used to collect data. RESULTS: Forty-four percent of respondents to the survey who were ill in the preceding six months visited a PHC facility for treatment, while others relied on self-medication/self-treatment. Education was positively associated with utilisation of PHC services (P<0.05). Maternal and child health (45.4%), prompt attention (23.0%), and appropriate outpatient (20.5%) services attracted respondents to use PHC services. Poor education about when to seek care, poverty, perceived high cost of PHC services, lack of drugs and basic laboratory services, and a regular physician on site at the facility were identified as barriers to utilisation. CONCLUSION: We conclude that community perceptions of poor quality and inadequacy of available services was responsible for low use of PHC services.

Utilization of Primary Health Care Facilities: Lessons from a Rural Community in Southwest Nigeria

Background: This study assessed service/organisational factors and clients' perceptions that influenced utilisation of Primary Health Care (PHC) facilities in a rural community in Nigeria. Method: A cross-sectional household survey in the community as well as key-informant interviews of opinion leaders and health care providers and participant observations of health facilities and utilisation pattern was used to collect data. Results: Forty-four percent of respondents to the survey who were ill in the preceding six months visited a PHC facility for treatment; while others relied on self-medication/self-treatment. Education was positively associated with utilisation of PHC services (P0.05). Maternal and child health (45.4); prompt attention (23.0); and appropriate outpatient (20.5) services attracted respondents to use PHC services. Poor education about when to seek care; poverty; perceived high cost of PHC services; lack of drugs and basic laboratory services; and a regular physician on site at the facility were identified as barriers to utilisation. Conclusion: We conclude that community perceptions of poor quality and inadequacy of available services was responsible for low use of PHC services

Smoking profile of non-consultant hospital doctors.

BACKGROUND: In 1994 Doll and colleagues published smoking mortality figures for British doctors over 40 years. AIMS: To assess smoking prevalence among junior doctors in a major Dublin teaching hospital. METHODS: One hundred and fourteen non-consultant doctors (NCHDs) at St James's Hospital received a confidential smoking questionnaire. RESULTS: One hundred and six NCHDs responded (93%). Three refused, five were not available. Ninety per cent were aged 24-35 years. Twenty-six per cent of the doctors had smoked for 10 to 15 years. Seventy-five per cent were smoking more than 10 cigarettes daily. Ninety-seven per cent (20) of smokers wanted to stop smoking. Seventy-four per cent (17) had unsuccessfully attempted to quit. The smoking cessation method most commonly used was'cold turkey' in 60%. Others included nicotine replacement, bupropion and hypnotherapy. CONCLUSION: A significant per centage of NCHDs (22%) continue to smoke, despite overwhelming evidence that this causes health problems. The prevalence in our study is lower than the national figure of 29%.

Cannonball metastases with favourable prognosis.

BACKGROUND: Secondary 'cannonball' metastases to the lung are frequent and usually associated with disseminated malignancy and poor prognosis. AIM: To report the case of a patient with metastatic pulmonary endometrial stromal sarcoma who had a previous hysterectomy for benign uterine fibroids and no past history of malignancy. RESULT: A 70-year-old female presented with cannonball metastases in her lung. Four years previously she had a hysterectomy for 'fibroids'. Review of the original histology revealed endometrial stromal sarcoma, similar to the lung metastasis. She currently has a good prognosis. CONCLUSION: A patient with 'cannonball' metastases can have a favourable prognosis. A female patient with a previous hysterectomy for uterine fibroids, should be considered to have metastatic sarcoma until proven otherwise.