• Differences in the structure of outpatient diabetes care between endocrinologist- led and general physician- led services

      O’Donnell, Máire; de Siún, Anna; O’Mullane, Monica; Smith, Diarmuid; Bradley, Colin; Finucane, Francis M; Dinneen, Sean F (2013-11-25)
      Abstract Background Despite a shift in diabetes care internationally from secondary to primary care, diabetes care in the Republic of Ireland remains very hospital-based. Significant variation in the facilities and resources available to hospitals providing outpatient diabetes care have been reported in the UK. The aim of this study was to ascertain the structure of outpatient diabetes care in public hospitals in the Republic of Ireland and whether differences existed in services provided across hospitals. Methods We conducted a cross sectional observational study of the 36 public general hospitals providing adult outpatient diabetes care in the Republic of Ireland. Data relating to numbers of specialist medical, nursing and allied health professionals, waiting times for new and return patients, patterns of discharge back to primary care and engagement in quality improvement initiatives were recorded. Results Thirty-five of the 36 eligible hospitals participated in the study. Sixty percent of these had at least one consultant endocrinologist in post, otherwise care delivery was led by a general physician. Waiting times for newly diagnosed patients exceeded six months in 30% of hospitals and this was higher where an endocrinologist was in place (47% V 7%, p = 0.013). Endocrinologists were more likely to have developed subspecialty clinics, access to allied health professionals and engage more in quality improvement initiatives but less likely to discharge patients back to primary care than general physicians (76 v 29%, p = 0.005). Conclusions Variations exist in the structure and provision of diabetes care in Irish hospitals. Endocrinology-led services have more developed subspecialty structures and access to specialist allied health professionals and engage more in quality improvement initiatives. Nonetheless, waiting times are longer and discharge rates to primary care are lower than for non-specialty led services. Further studies to determine the extent to which case-mix variation accounts for these observations are warranted. Aspects of hospital-based outpatient care could be developed further to ensure equitable services are provided nationally. At a time when the delivery of diabetes services in primary care is being promoted, further research is warranted on the factors influencing the successful transition to primary care.
    • Differential impact of smoking on mortality and kidney transplantation among adult men and women undergoing dialysis

      Stack, Austin G; Yermak, Darya; Roche, David G; Ferguson, John P; Elsayed, Mohamed; Mohammed, Waleed; Casserly, Liam F; Walsh, Stewart R; Cronin, Cornelius J (2016-07-26)
      Abstract Background The extent to which smoking contributes to adverse outcomes among men and women of all ages undergoing dialysis is uncertain. The objective of this study was to determine the differential impact of smoking on risks of mortality and kidney transplantation by age and by sex at dialysis initiation. Methods We conducted a population-based cohort of incident U.S dialysis patients (n = 1, 220, 000) from 1995–2010. Age- and sex-specific mortality and kidney transplantation rates were determined for patients with and without a history of cardiovascular disease. Multivariable Cox regression evaluated relative hazard ratios (HR) for death and kidney transplantation at 2 years stratified by atherosclerotic condition, smoking status and age. Analyses were adjusted for demographic characteristics, non-cardiovascular conditions, laboratory variables, socioeconomic and lifestyle factors. Results The average age was 62.8 (±15) years old, 54 % were male, and the majority was white. During 2-year follow-up, 40.5 % died and 5.7 % were transplanted. Age- and sex-specific mortality rates were significantly higher while transplantation rates were significantly lower for smokers with atherosclerotic conditions than non-smokers (P < 0.01). The adjusted mortality hazards were significantly higher for smokers with pre-existing coronary disease (HR 1.15, 95 % CI (1.11–1.18), stroke (HR 1.21, 1.16–1.27) and peripheral vascular disease (HR = 1.21, 1.17–1.25) compared to non-smokers without these conditions (HR 1.00, referent group). The magnitude of effect was greatest for younger patients than older patients. Contrastingly, the adjusted risks of kidney transplantation were significantly lower for smokers with coronary disease: (HR 0.60, 0.52–0.69), stroke; (HR 0.47, 0.37–0.60), and peripheral arterial disease (HR 0.55, 0.46–0.66) respectively compared to non-smokers without these conditions. Conclusions We provide compelling evidence that smoking is associated with adverse clinical outcomes and reduced lifespans among dialysis patients of all ages and sexes. The adverse impact is greatest for younger men and women.
    • The differential impact of subjective and objective aspects of social engagement on cardiovascular risk factors.

      Kamiya, Yumiko; Whelan, Brendan; Timonen, Virpi; Kenny, Rose Anne; Department of Medical Gerontology, Trinity College Dublin, Dublin, Ireland. kamiyay@tcd.ie (2010)
      This article provides new insights into the impact of social engagement on CVD risk factors in older adults. We hypothesized that objective (social participation, social ties and marital status) and subjective (emotional support) aspects of social engagement are independently associated with objective measures of cardiovascular risk.
    • Differential requirements of ciliogenic/ciliopathy module components in restricting Joubert syndrome-associated Arl13b to a C. elegans Inv-like ciliary compartment

      Blacque, O; Cevik, S; Clarke, L; Van Wijk, E; Sanders, A; Van Reeuwijk, J; Boldt, K; Ueffing, M; Roepman, R; Kremer, H (2012-11-16)
    • The difficulty identifying intoeing gait in cerebral palsy

      O’Sullivan, R; Kiernan, D; Walsh, M; O Brien, T (Irish Medical Journal, 2013-05)
    • Diffusion is capable of translating anisotropic apoptosis initiation into a homogeneous execution of cell death.

      Huber, Heinrich J; Laussmann, Maike A; Prehn, Jochen Hm; Rehm, Markus; Sytems Biology Group, Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland. heinhuber@rcsi.ie. (2010)
      ABSTRACT: BACKGROUND: Apoptosis is an essential cell death process throughout the entire life span of all metazoans and its deregulation in humans has been implicated in many proliferative and degenerative diseases. Mitochondrial outer membrane permeabilisation (MOMP) and activation of effector caspases are key processes during apoptosis signalling. MOMP can be subject to spatial coordination in human cancer cells, resulting in intracellular waves of cytochrome-c release. To investigate the consequences of these spatial anisotropies in mitochondrial permeabilisation on subsequent effector caspase activation, we devised a mathematical reaction-diffusion model building on a set of partial differential equations. RESULTS: Reaction-diffusion modelling suggested that even if strong spatial anisotropies existed during mitochondrial cytochrome c release, these would be eliminated by free diffusion of the cytosolic proteins that instantiate the apoptosis execution network. Experimentally, rapid sampling of mitochondrial permeabilisation and effector caspase activity in individual HeLa cervical cancer cells confirmed predictions of the reaction-diffusion model and demonstrated that the signalling network of apoptosis execution could efficiently translate spatial anisotropies in mitochondrial permeabilisation into a homogeneous effector caspase response throughout the cytosol. Further systems modelling suggested that a more than 10,000-fold impaired diffusivity would be required to maintain spatial anisotropies as observed during mitochondrial permeabilisation until the time effector caspases become activated. CONCLUSIONS: Multi-protein diffusion efficiently contributes to eliminating spatial asynchronies which are present during the initiation of apoptosis execution and thereby ensures homogeneous apoptosis execution throughout the entire cell body. For previously reported biological scenarios in which effector caspase activity was shown to be targeted selectively to specific subcellular regions additional mechanisms must exist that limit or spatially coordinate caspase activation and/or protect diffusing soluble caspase substrates from unwanted proteolysis.
    • Digital network of writers helps to foster spirit of collaboration.

      Klimas, J; Swan, D; McCombe, G; Henihan, A M (2015-07-29)
      Nurse Liz Charalambous has shown how a Facebook group can help boost writing (careers, June 3). We would like to take this idea one step further and argue that, contrary to a commonly held notion, 'too many cooks do not spoil the broth' when it comes to group writing. Instead, this approach fosters collaboration between writers, as Ms Charalambous suggests, and which has also been our experience.
    • The direct and indirect costs of both overweight and obesity: a systematic review

      Dee, Anne; Kearns, Karen; O’Neill, Ciaran; Sharp, Linda; Staines, Anthony; O’Dwyer, Victoria; Fitzgerald, Sarah; Perry, Ivan J (2014-04-16)
      Abstract Background The rising prevalence of overweight and obesity places a financial burden on health services and on the wider economy. Health service and societal costs of overweight and obesity are typically estimated by top-down approaches which derive population attributable fractions for a range of conditions associated with increased body fat or bottom-up methods based on analyses of cross-sectional or longitudinal datasets. The evidence base of cost of obesity studies is continually expanding, however, the scope of these studies varies widely and a lack of standardised methods limits comparisons nationally and internationally. The objective of this review is to contribute to this knowledge pool by examining direct costs and indirect (lost productivity) costs of both overweight and obesity to provide comparable estimates. This review was undertaken as part of the introductory work for the Irish cost of overweight and obesity study and examines inconsistencies in the methodologies of cost of overweight and obesity studies. Studies which evaluated the direct costs and indirect costs of both overweight and obesity were included. Methods A computerised search of English language studies addressing direct and indirect costs of overweight and obesity in adults between 2001 and 2011 was conducted. Reference lists of reports, articles and earlier reviews were scanned to identify additional studies. Results Five published articles were deemed eligible for inclusion. Despite the limited scope of this review there was considerable heterogeneity in methodological approaches and findings. In the four studies which presented separate estimates for direct and indirect costs of overweight and obesity, the indirect costs were higher, accounting for between 54% and 59% of the estimated total costs. Conclusion A gradient exists between increasing BMI and direct healthcare costs and indirect costs due to reduced productivity and early premature mortality. Determining precise estimates for the increases is mired by the large presence of heterogeneity among the available cost estimation literature. To improve the availability of quality evidence an international consensus on standardised methods for cost of obesity studies is warranted. Analyses of nationally representative cross-sectional datasets augmented by data from primary care are likely to provide the best data for international comparisons.
    • Directed evolution and targeted mutagenesis to murinize Listeria monocytogenes Internalin A for enhanced infectivity in the murine oral infection model

      Monk, Ian R; Casey, Pat G; Hill, Colin; Gahan, Cormac GM (2010-12-13)
      Abstract Background Internalin A (InlA) is a critical virulence factor which mediates the initiation of Listeria monocytogenes infection by the oral route in permissive hosts. The interaction of InlA with the host cell ligand E-cadherin efficiently stimulates L. monocytogenes entry into human enterocytes, but has only a limited interaction with murine cells. Results We have created a surface display library of randomly mutated InlA in a non-invasive heterologous host Lactococcus lactis in order to create and screen novel variants of this invasion factor. After sequential passage through a murine cell line (CT-26), multiple clones with enhanced invasion characteristics were identified. Competitive index experiments were conducted in mice using selected mutations introduced into L. monocytogenes EGD-e background. A novel single amino acid change was identified which enhanced virulence by the oral route in the murine model and will form the basis of further engineering approaches. As a control a previously described EGD-InlAm murinized strain was also re-created as part of this study with minor modifications and designated EGD-e InlA m*. The strain was created using a procedure that minimizes the likelihood of secondary mutations and incorporates Listeria-optimized codons encoding the altered amino acids. L. monocytogenes EGD-e InlA m* yielded consistently higher level murine infections by the oral route when compared to EGD-e, but did not display the two-fold increased invasion into a human cell line that was previously described for the EGD-InlAm strain. Conclusions We have used both site-directed mutagenesis and directed evolution to create variants of InlA which may inform future structure-function analyses of this protein. During the course of the study we engineered a murinized strain of L. monocytogenes EGD-e which shows reproducibly higher infectivity in the intragastric murine infection model than the wild type, but does not display enhanced entry into human cells as previously observed. This murinized L. monocytogenes strain will provide a useful tool for the analysis of the gastrointestinal phase of listeriosis.
    • Directed evolution and targeted mutagenesis to murinize Listeria monocytogenes internalin A for enhanced infectivity in the murine oral infection model.

      Monk, Ian R; Casey, Pat G; Hill, Colin; Gahan, Cormac G M; Alimentary Pharmabiotic Centre & Department of Microbiology, University College Cork, Western Road, Cork, Ireland. (2010)
      Internalin A (InlA) is a critical virulence factor which mediates the initiation of Listeria monocytogenes infection by the oral route in permissive hosts. The interaction of InlA with the host cell ligand E-cadherin efficiently stimulates L. monocytogenes entry into human enterocytes, but has only a limited interaction with murine cells.
    • Discourse on medicine: meditative and calculative approaches to ethics from an international perspective

      Malloy, David C; Martin, Ronald; Hadjistavropoulos, Thomas; Liu, Peilai; McCarthy, Elizabeth F; Park, Ilhyeok; Shalani, N; Murakami, Masaaki; Paholpak, Suchat (2014-11-07)
      Abstract Heidegger’s two modes of thinking, calculative and meditative, were used as the thematic basis for this qualitative study of physicians from seven countries (Canada, China, India, Ireland, Japan, Korea, & Thailand). Focus groups were conducted in each country with 69 physicians who cared for the elderly. Results suggest that physicians perceived ethical issues primarily through the lens of calculative thinking (76%) with emphasis on economic concerns. Meditative responses represented 24% of the statements and were mostly generated by Canadian physicians whose patients typically were not faced with economic barriers to treatment due to Canada’s universal health care system.
    • Dissociation of activated protein C functions by elimination of protein S cofactor enhancement.

      Harmon, Shona; Preston, Roger J S; Ainle, Fionnuala Ni; Johnson, Jennifer A; Cunningham, Moya S; Smith, Owen P; White, Barry; O'Donnell, James S; Haemostasis Research Group, Institute of Molecular Medicine, St James's Hospital, Trinity College, Dublin 8, Ireland. (2008-11-07)
      Activated protein C (APC) plays a critical anticoagulant role in vivo by inactivating procoagulant factor Va and factor VIIIa and thus down-regulating thrombin generation. In addition, APC bound to the endothelial cell protein C receptor can initiate protease-activated receptor-1 (PAR-1)-mediated cytoprotective signaling. Protein S constitutes a critical cofactor for the anticoagulant function of APC but is not known to be involved in regulating APC-mediated protective PAR-1 signaling. In this study we utilized a site-directed mutagenesis strategy to characterize a putative protein S binding region within the APC Gla domain. Three single amino acid substitutions within the APC Gla domain (D35T, D36A, and A39V) were found to mildly impair protein S-dependent anticoagulant activity (<2-fold) but retained entirely normal cytoprotective activity. However, a single amino acid substitution (L38D) ablated the ability of protein S to function as a cofactor for this APC variant. Consequently, in assays of protein S-dependent factor Va proteolysis using purified proteins or in the plasma milieu, APC-L38D variant exhibited minimal residual anticoagulant activity compared with wild type APC. Despite the location of Leu-38 in the Gla domain, APC-L38D interacted normally with endothelial cell protein C receptor and retained its ability to trigger PAR-1 mediated cytoprotective signaling in a manner indistinguishable from that of wild type APC. Consequently, elimination of protein S cofactor enhancement of APC anticoagulant function represents a novel and effective strategy by which to separate the anticoagulant and cytoprotective functions of APC for potential therapeutic gain.
    • Distinct configurations of protein complexes and biochemical pathways revealed by epistatic interaction network motifs

      Casey, Fergal; Krogan, Nevan; Shields, Denis; Cagney, Gerard (2011-08-22)
      Abstract Background Gene and protein interactions are commonly represented as networks, with the genes or proteins comprising the nodes and the relationship between them as edges. Motifs, or small local configurations of edges and nodes that arise repeatedly, can be used to simplify the interpretation of networks. Results We examined triplet motifs in a network of quantitative epistatic genetic relationships, and found a non-random distribution of particular motif classes. Individual motif classes were found to be associated with different functional properties, suggestive of an underlying biological significance. These associations were apparent not only for motif classes, but for individual positions within the motifs. As expected, NNN (all negative) motifs were strongly associated with previously reported genetic (i.e. synthetic lethal) interactions, while PPP (all positive) motifs were associated with protein complexes. The two other motif classes (NNP: a positive interaction spanned by two negative interactions, and NPP: a negative spanned by two positives) showed very distinct functional associations, with physical interactions dominating for the former but alternative enrichments, typical of biochemical pathways, dominating for the latter. Conclusion We present a model showing how NNP motifs can be used to recognize supportive relationships between protein complexes, while NPP motifs often identify opposing or regulatory behaviour between a gene and an associated pathway. The ability to use motifs to point toward underlying biological organizational themes is likely to be increasingly important as more extensive epistasis mapping projects in higher organisms begin.
    • Distressed relationship : Does counselling help?

      McKeown, Kieran; Haase, Trutz; Pratschke, Jonathan; Kieran McKeown Limited (Marriage and Relationship Counselling Services (MRCS), 2004-02)
    • Distribution of tract deficits in schizophrenia

      Ellison-Wright, Ian; Nathan, Pradeep J; Bullmore, Edward T; Zaman, Rashid; Dudas, Robert B; Agius, Mark; Fernandez-Egea, Emilio; Müller, Ulrich; Dodds, Chris M; Forde, Natalie J; et al. (2014-04-02)
      Abstract Background Gray and white matter brain changes have been found in schizophrenia but the anatomical organizing process underlying these changes remains unknown. We aimed to identify gray and white matter volumetric changes in a group of patients with schizophrenia and to quantify the distribution of white matter tract changes using a novel approach which applied three complementary analyses to diffusion imaging data. Methods 21 patients with schizophrenia and 21 matched control subjects underwent brain magnetic resonance imaging. Gray and white matter volume differences were investigated using Voxel-based Morphometry (VBM). White matter diffusion changes were located using Tract Based Spatial Statistics (TBSS) and quantified within a standard atlas. Tracts where significant regional differences were located were examined using fiber tractography. Results No significant differences in gray or white matter volumetry were found between the two groups. Using TBSS the schizophrenia group showed significantly lower fractional anisotropy (FA) compared to the controls in regions (false discovery rate <0.05) including the genu, body and splenium of the corpus callosum and the left anterior limb of the internal capsule (ALIC). Using fiber tractography, FA was significantly lower in schizophrenia in the corpus callosum genu (p = 0.003). Conclusions In schizophrenia, white matter diffusion deficits are prominent in medial frontal regions. These changes are consistent with the results of previous studies which have detected white matter changes in these areas. The pathology of schizophrenia may preferentially affect the prefrontal-thalamic white matter circuits traversing these regions.
    • District health managers' perceptions of supervision in Malawi and Tanzania

      Bradley, Susan; Kamwendo, Francis; Masanja, Honorati; de Pinho, Helen; Waxman, Rachel; Boostrom, Camille; McAuliffe, Eilish (2013-09-05)
      Abstract Background Mid-level cadres are being used to address human resource shortages in many African contexts, but insufficient and ineffective human resource management is compromising their performance. Supervision plays a key role in performance and motivation, but is frequently characterised by periodic inspection and control, rather than support and feedback to improve performance. This paper explores the perceptions of district health management teams in Tanzania and Malawi on their role as supervisors and on the challenges to effective supervision at the district level. Methods This qualitative study took place as part of a broader project, “Health Systems Strengthening for Equity: The Power and Potential of Mid-Level Providers”. Semi-structured interviews were conducted with 20 district health management team personnel in Malawi and 37 council health team members in Tanzania. The interviews covered a range of human resource management issues, including supervision and performance assessment, staff job descriptions and roles, motivation and working conditions. Results Participants displayed varying attitudes to the nature and purpose of the supervision process. Much of the discourse in Malawi centred on inspection and control, while interviewees in Tanzania were more likely to articulate a paradigm characterised by support and improvement. In both countries, facility level performance metrics dominated. The lack of competency-based indicators or clear standards to assess individual health worker performance were considered problematic. Shortages of staff, at both district and facility level, were described as a major impediment to carrying out regular supervisory visits. Other challenges included conflicting and multiple responsibilities of district health team staff and financial constraints. Conclusion Supervision is a central component of effective human resource management. Policy level attention is crucial to ensure a systematic, structured process that is based on common understandings of the role and purpose of supervision. This is particularly important in a context where the majority of staff are mid-level cadres for whom regulation and guidelines may not be as formalised or well-developed as for traditional cadres, such as registered nurses and medical doctors. Supervision needs to be adequately resourced and supported in order to improve performance and retention at the district level.
    • Diversity, ecology and intestinal function of bifidobacteria

      Bottacini, Francesca; Ventura, Marco; Sinderen, Douwe; Motherway, Mary OC (2014-08-29)
      Abstract The human gastrointestinal tract represents an environment which is a densely populated home for a microbiota that has evolved to positively contribute to host health. At birth the essentially sterile gastrointestinal tract (GIT) is rapidly colonized by microorganisms that originate from the mother and the surrounding environment. Within a short timeframe a microbiota establishes within the (breastfed) infant's GIT where bifidobacteria are among the dominant members, although their numerical dominance disappears following weaning. The numerous health benefits associated with bifidobacteria, and the consequent commercial relevance resulting from their incorporation into functional foods, has led to intensified research aimed at the molecular understanding of claimed probiotic attributes of this genus. In this review we provide the current status on the diversity and ecology of bifidobacteria. In addition, we will discuss the molecular mechanisms that allow this intriguing group of bacteria to colonize and persist in the GIT, so as to facilitate interaction with its host.
    • DNA vaccination for prostate cancer, from preclinical to clinical trials where-we stand?

      Ahmad, Sarfraz; Sweeney, Paul; Sullivan, Gerald C; Tangney, Mark (2012-10-09)
      Abstract Development of various vaccines for prostate cancer (PCa) is becoming an active research area. PCa vaccines are perceived to have less toxicity compared with the available cytotoxic agents. While various immune-based strategies can elicit anti-tumour responses, DNA vaccines present increased efficacy, inducing both humoural and cellular immunity. This immune activation has been proven effective in animal models and initial clinical trials are encouraging. However, to validate the role of DNA vaccination in currently available PCa management paradigms, strong clinical evidence is still lacking. This article provides an overview of the basic principles of DNA vaccines and aims to provide a summary of preclinical and clinical trials outlining the benefits of this immunotherapy in the management of PCa.
    • Do differences in the administrative structure of populations confound comparisons of geographic health inequalities?

      Jackson, Andrew L; Davies, Carolyn A; Leyland, Alastair H (2010-08-18)
      Abstract Background Geographical health inequalities are naturally described by the variation in health outcomes between areas (e.g. mortality rates). However, comparisons made between countries are hampered by our lack of understanding of the effect of the size of administrative units, and in particular the modifiable areal unit problem. Our objective was to assess how differences in geographic and administrative units used for disseminating data affect the description of health inequalities. Methods Retrospective study of standard populations and deaths aggregated by administrative regions within 20 European countries, 1990-1991. Estimated populations and deaths in males aged 0-64 were in 5 year age bands. Poisson multilevel modelling was conducted of deaths as standardised mortality ratios. The variation between regions within countries was tested for relationships with the mean region population size and the unequal distribution of populations within each country measured using Gini coefficients. Results There is evidence that countries whose regions vary more in population size show greater variation and hence greater apparent inequalities in mortality counts. The Gini coefficient, measuring inequalities in population size, ranged from 0.1 to 0.5 between countries; an increase of 0.1 was accompanied by a 12-14% increase in the standard deviation of the mortality rates between regions within a country. Conclusions Apparently differing health inequalities between two countries may be due to differences in geographical structure per se, rather than having any underlying epidemiological cause. Inequalities may be inherently greater in countries whose regions are more unequally populated.