Comparison of performance in a four year graduate entry medical programme and a traditional five/six year programme.

Background In 2006 the Royal College of Surgeons in Ireland, (RCSI), introduced the first four year Graduate Entry Programme (GEP) in medicine in Ireland in line with national policy to broaden access to medical education. One concern considered at the time, was whether the GEP students could be trained to the same standard as their undergraduate Direct Entry Programme (DEP, five/ six year duration) counterparts in the shorter time frame. Since students from both cohorts undertake the same examinations in the final two years, it is possible to directly compare GEP vs DEP outcomes. The primary aim of the current study was to analyse the comparative performance of GEP and DEP students undergoing these examinations between 2008 and 2013.MethodsScores from five assessments performed during the final two years were transformed to z scores for each student and 4 scores for the penultimate year were summed to create a unit weighted composite score. The resultant scores for each of the two years were used to assess the comparative performance of GEP vs DEP cohorts and to perform sub-cohort analyses of GEP outcomes.ResultsIn all cohorts/years examined, evidence demonstrated significantly better assessment outcomes for the GEP group for the final two years¿ examinations as compared with the DEP group. In all but one cohort examined, this advantage was retained when nationality factors were excluded. Further analyses showed no difference in outcomes between GEP students having science vs. non-science backgrounds and or between those from EU vs non-EU backgrounds. Finally, data suggested weak correlations between total composite scores and entry scores in American (r¿=¿0.15) and Australian (r¿=¿0.08) medical school admissions tests.ConclusionsWe have shown for the first time in Ireland, that graduate-entry students perform at least as well, or even better, than a corresponding undergraduate-entry group. Moreover, having a scientific background on entry to the GEP confers no advantage in final assessments. These data provide evidence of the viability of the graduate entry route into medical education in Ireland

Reflections in Systemic Family Psychotherapy and Adult Mental Health Services in the South East of Ireland; and beyond.

Systemic Family Psychotherapy (SFP) has been involved in the Carlow Kilkenny South Tipperary Adult Mental Services since 1994: in the main this involved meeting with service users, their families, couples and friends. However, from 2012 to 2019 five SFPs retired. This occurred when decisions were made by some Mental Health Management not to replace those SFPs that retired: thereby reducing the number of SFPs in the Southeast Adult Mental Health Services (AMHS); presumably due to funding difficulties at that time. However, as the months and years went by it became oblivious that two AMHSs were not going to employ SPTs. It was obvious that the AMHS in Waterford had never employed any SFT, and Wexford AMHS has only employed a half-time SFT for four Community Mental Teams. Consequently, this had an impact on the availability of SFPs in AMHSs in the south east AMHSs. However, on the other hand, the Carlow Kilkenny AMHS continues to be supported from Management and colleagues; SFTs since 1997. This is obvious as all Community Mental Health Teams refer service users attends the AMHSs in Carlow and Kilkenny, as well as their families/partners/friends for SFP. This article will try to ascertain how this came about, and what can be done to influences AMHS managers’ and concerning supporting SFPs. Key words: Family Therapy; Families; Mental Health Services; Family Meetings; Context in family therapy

Targeting the 19S proteasomal subunit, Rpt4, for the treatment of colon cancer.

Deregulation of the ubiquitin-proteasome pathway has been frequently observed in a number of malignancies. Using quantitative Western blotting of normal and matched tumour tissue, we here identified a significant increase in the 19S proteasome subunit Rpt4 in response to chemoradiation in locally advanced rectal cancer patients with unfavourable outcome. We therefore explored the potential of Rpt4 reduction as a therapeutic strategy in colorectal cancer (CRC). Utilizing siRNA to down regulate Rpt4 expression, we show that silencing of Rpt4 reduced proteasomal activity and induced endoplasmic reticulum stress. Gene silencing of Rpt4 also inhibited cell proliferation, reduced clonogenic survival and induced apoptosis in HCT-116 colon cancer cells. We next developed a cell penetrating peptide-based nanoparticle delivery system to achieve in vivo gene silencing of Rpt4. Administration of Rpt4 siRNA nanoparticles reduced tumour growth and improved survival in a HCT-116 colon cancer xenograft tumour model in vivo. Collectively, our data suggest that inhibition of Rpt4 represents a novel strategy for the treatment of CRC

AKT1 (E17K) mutation profiling in breast cancer: prevalence, concurrent oncogenic alterations, and blood-based detection.

BACKGROUND: The single hotspot mutation AKT1 [G49A:E17K] has been described in several cancers, with the highest incidence observed in breast cancer. However, its precise role in disease etiology remains unknown. METHODS: We analyzed more than 600 breast cancer tumor samples and circulating tumor DNA for AKT1 (E17K) and alterations in other cancer-associated genes using Beads, Emulsions, Amplification, and Magnetics digital polymerase chain reaction technology and targeted exome sequencing. RESULTS: Overall AKT1 (E17K) mutation prevalence was 6.3 % and not correlated with age or menopausal stage. AKT1 (E17K) mutation frequency tended to be lower in patients with grade 3 disease (1.9 %) compared with those with grade 1 (11.1 %) or grade 2 (6 %) disease. In two cohorts of patients with advanced metastatic disease, 98.0 % (n = 50) and 97.1 % (n = 35) concordance was obtained between tissue and blood samples for the AKT1 (E17K) mutation, and mutation capture rates of 66.7 % (2/3) and 85.7 % (6/7) in blood versus tissue samples were observed. Although AKT1-mutant tumor specimens were often found to harbor concurrent alterations in other driver genes, a subset of specimens harboring AKT1 (E17K) as the only known driver alteration was also identified. Initial follow-up survival data suggest that AKT1 (E17K) could be associated with increased mortality. These findings warrant additional long-term follow-up. CONCLUSIONS: The data suggest that AKT1 (E17K) is the most likely disease driver in certain breast cancer patients. Blood-based mutation detection is achievable in advanced-stage disease. These findings underpin the need for a further enhanced-precision medicine paradigm in the treatment of breast cancer

The Hydroxylase Inhibitor Dimethyloxallyl Glycine Attenuates Endotoxic Shock Via Alternative Activation of Macrophages and IL-10 Production by B1 Cells

Localized tissue hypoxia is a feature of infection and inflammation, resulting in the upregulation of the transcription factors HIF-1α and NF-κB via inhibition of oxygen sensing hydroxylase enzymes. Previous studies have demonstrated a beneficial role for the hydroxylase inhibitor dimethyloxallyl glycine (DMOG) in inflammatory conditions, including experimental colitis, by regulating the activity of HIF-1 and NF-κB. We have demonstrated in vivo that pre-treatment with DMOG attenuates systemic LPS-induced activation of the NF-κB pathway. Furthermore, mice treated with DMOG had significantly increased survival in LPS-induced shock. Conversely, in models of polymicrobial sepsis, DMOG exacerbates disease severity. DMOG treatment of mice promotes M2 polarization in macrophages within the peritoneal cavity, resulting in the downregulation of pro-inflammatory cytokines such as TNFα. In addition, in vivo DMOG treatment upregulates IL-10 expression, specifically in the peritoneal B-1 cell population. This study demonstrates cell type specific roles for hydroxylase inhibition in vivo and provides insight into the mechanism underlying the protection conveyed by DMOG in models of endotoxic shock

Auditory complications among childhood cancer survivors and health-related quality of life: a PanCareLIFE study.

PURPOSE Auditory complications are potential side effects from childhood cancer treatment. Yet, limited evidence exists about the impact of auditory complications-particularly tinnitus-on health-related quality of life (HRQoL) among childhood cancer survivors (CCS). We determined the prevalence of hearing loss and tinnitus in the European PanCareLIFE cohort of CCS and examined its effect on HRQoL. METHODS We included CCS from four European countries who were diagnosed at age ≤ 18 years; survived ≥ 5 years; and aged 25-44 years at study. We assessed HRQoL (Short Form 36), hearing loss, and tinnitus using questionnaires. We used multivariable linear regression to examine associations between these two auditory complications and HRQoL adjusting for socio-demographic and clinical factors. RESULTS Our study population consisted of 6,318 CCS (53% female; median age at cancer diagnosis 9 years interquartile range [IQR] 5-13 years) with median age at survey of 31 years (IQR 28-35 years). Prevalence was 7.5% (476/6,318; confidence interval [CI]: 6.9-8.2) for hearing loss and 7.6% (127/1,668; CI: 6.4-9.0) for tinnitus. CCS with hearing loss had impaired physical (coefficient [coef.] -4.3, CI: -7.0 to -1.6) and mental (coef. -3.2, CI: -5.5 to -0.8) HRQoL when compared with CCS with normal hearing. Tinnitus was associated with impaired physical (coef. -8.2, CI: -11.8 to -4.7) and mental (coef. -5.9, CI: -8.8 to -3.1) HRQoL. CONCLUSION We observed reduced HRQoL among CCS with hearing loss and tinnitus. Our findings indicate timely treatment of hearing loss and tinnitus may contribute to quality of life of survivors. IMPLICATIONS FOR CANCER SURVIVORS CCS who experience auditory complications should be counseled about possible therapeutic and supportive measures during follow-up care

Colorectal tumour simulation using agent based modelling and high performance computing

450,000 European citizens are diagnosed every year with colorectal cancer (CRC) and more than 230,000 succumb to the disease annually. For this reason, significant resources are dedicated to the identification of more effective therapies for this disease. However, classical assessment techniques for these treatments are slow and costly. Consequently, systems biology researchers at the Royal College of Surgeons in Ireland (RCSI) are developing computational agent-based models simulating tumour growth and treatment responses with the objective of speeding up the therapeutic development process while, at the same time, producing a tool for adapting treatments to patient-specific characteristics. However, the model complexity and the high number of agents to be simulated require a thorough optimisation of the process in order to execute realistic simulations of tumour growth on currently available platforms. We propose to apply the most advanced HPC techniques to achieve the efficient and realistic simulation of a virtual tissue model that mimics tumour growth or regression in space and time. These techniques combine extensions of the previously developed agent-based simulation software platform (FLAME) with autotuning capabilities and optimisation strategies for the current tumour model. Development of such a platform could advance the development of novel therapeutic approaches for the treatment of CRC which can also be applied other solid tumours.This work has been partially supported by MICINN-Spain under contract TIN2011- 28689-C02-01 and TIN2014-53234-C2-1-R and GenCat-DIUiE(GRR) 2014-SGR-576. This research was also funded by the European Community’s Framework Programme Seven (FP7) Programme under contract No. 278981 680 AngioPredict and supported by the DJEI/DES/SFI/HEA Irish Centre for High- End Computing (ICHEC).Peer ReviewedPostprint (author's final draft

Supplementary data for article: O’Connor, S.; Szwej, E.; Nikodinović-Runić, J.; O’Connor, A.; Byrne, A. T.; Devocelle, M.; O’Donovan, N.; Gallagher, W. M.; Babu, R. P.; Kenny, S. T.; et al. The Anti-Cancer Activity of a Cationic Anti-Microbial Peptide Derived from Monomers of Polyhydroxyalkanoate. Biomaterials 2013, 34 (11), 2710–2718. https://doi.org/10.1016/j.biomaterials.2012.12.032

Supplementary material for: [https://doi.org/10.1016/j.biomaterials.2012.12.032]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1609

Identical Genes, Unique Environments: A Qualitative Exploration of Persistent Monozygotic-Twin Discordance in Literacy and Numeracy

This study aimed to explore unique environmental factors impacting differential academic trajectories among Australian school students. Monozygotic (MZ) twin pairs who were consistently discordant in results of nationwide standardized tests of reading, numeracy or writing between Grades 3 and 9 were identified. MZ twins control for genes, gender, age, and aspects of the home and school environment shared by twins. Thus, any difference between MZ twins in academic outcomes can be attributed to the unique environment experienced by each twin. From 551 MZ twin pairs with three or four sets of test results, we identified 55 pairs who were substantially and consistently discordant in reading, numeracy or writing between Grades 3 and 9. Parents were contacted for interview, resulting in 40 semi-structured interviews. Qualitative data analysis revealed three major themes, interpreted by parents as possible contributors to persistent academic discordance: biological mechanisms, school-based factors, and personal factors. We discuss implications for educational practice, policy, and research

Mechanistic interrogation of combination Bevacizumab/dual PI3K/mTOR inhibitor response in Glioblastoma implementing novel MR and PET imaging biomarkers.

Purpose: Resistance to bevacizumab (BEV) in glioblastoma (GBM) is believed to occur via activation of molecular networks including the mTOR/PI3K pathway. Implementing an MRI/PET molecular imaging biomarker approach, we sought to interrogate response to combining BEV with the mTOR/PI3K inhibitor BEZ235. Methods: Tumors were established by orthotopically implanting U87MG-luc2 in mice. Animals were treated with BEZ235 and/or BEV, and imaged using diffusion weighted-MRI, T2 weighted (T2w), and T2* weighted (T2*w) before and following delivery of superparamagnetic iron oxide (SPIO) contrast. Maps for changes in relaxation rates: ΔR2, ΔR2* and apparent diffusion coefficient (ADC) were calculated. Vessel Size Index (VSI) and micro vessel density index (MDI) were derived. 3´-deoxy-3´-[18F]fluorothymidine ([18F]FLT)- and O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) PET was further performed and tumor endothelium/proliferation markers assessed by immunohistochemistry. Results: Treatment with BEV resulted in a pronounced decrease in tumor volume (T2w MRI). No additive effect on tumour volume was observed in BEV/BEZ235 combination compared with BEV monotherapy. Ki67 proliferation index staining and [18F]FLT uptake studies were used to support observations. Using ΔR2* and ΔR2 values respectively, BEZ235 + BEV combination significantly reduced tumor microvessel volume in comparison to BEV alone. Decreased MDI was further observed in the combination group; supported by von Willebrand Factor (vWF) immunohistochemistry. We observed decreased [18F]FET uptake following BEV, but failed to observe further reduced [18F]FET uptake in the combination cohort. vWF IHC analysis showed mean tumor vessel size increased in all cohorts. Conclusions: Assessing MR imaging biomarker parameters together with [18F]FET and [18F]FLT PET, informed drug combination mechanism of action and provided clues as to potential clinical response. Translation of a BEZ35/BEV combination regimen could support reduction of peritumoral edemaobviating the requirement for steroids. Implementing hypothesis driven molecular imaging studies facilitates the interrogation of drug response in the pre-clinic. These data may more accurately predict the clinical potential of novel therapeutic approaches in oncology