Clinical Medicine
http://hdl.handle.net/10147/631914
2024-03-28T21:47:30ZCurriculum Framework for the Internship Programme in Ireland
http://hdl.handle.net/10147/638294
Curriculum Framework for the Internship Programme in Ireland
Boland, Josephine; Offiah, Gozie
This Curriculum Framework presents the outcome of development work initiated and led by
the MIB and undertaken by the Medical Intern Unit (MIU) team and Curriculum Development
Working Group (CDWG) during 2018-2022. It also includes development work completed
(2015-2022) as individuals and/or teams and part of the Modernisation of the Internship
projects.
2023-10-01T00:00:00ZAllantodapsone is a Pan-Inhibitor of Staphylococcus aureus Adhesion to Fibrinogen, Loricrin, and Cytokeratin 10.
http://hdl.handle.net/10147/635551
Allantodapsone is a Pan-Inhibitor of Staphylococcus aureus Adhesion to Fibrinogen, Loricrin, and Cytokeratin 10.
Prencipe, Filippo; Alsibaee, Aishah; Khaddem, Zainab; Norton, Padraig; Towell, Aisling M; Ali, Afnan F M; Reid, Gerard; Fleury, Orla M; Foster, Timothy J; Geoghegan, Joan A; Rozas, Isabel; Brennan, Marian P
Staphylococcus aureus infections have become a major challenge in health care due to increasing antibiotic resistance. We aimed to design small molecule inhibitors of S. aureus surface proteins to be developed as colonization inhibitors. We identified allantodapsone in an initial screen searching for inhibitors of clumping factors A and B (ClfA and ClfB). We used microbial adhesion assays to investigate the effect of allantodapsone on extracellular matrix protein interactions. Allantodapsone inhibited S. aureus Newman adhesion to fibrinogen with an IC50 of 21.3 μM (95% CI 4.5-102 μM), minimum adhesion inhibitory concentration (MAIC) of 100 μM (40.2 μg/mL). Additionally, allantodapsone inhibited adhesion of Lactococcus lactis strains exogenously expressing the clumping factors to fibrinogen (L. lactis ClfA, IC50 of 3.8 μM [95% CI 1.0-14.3 μM], MAIC 10 μM, 4.0 μg/mL; and L. lactis ClfB, IC50 of 11.0 μM [95% CI 0.9-13.6 μM], MAIC 33 μM, 13.3 μg/mL), indicating specific inhibition. Furthermore, the dapsone and alloxan fragments of allantodapsone did not have any inhibitory effect. Adhesion of S. aureus Newman to L2v loricrin is dependent on the expression of ClfB. Allantodapsone caused a dose dependent inhibition of S. aureus adhesion to the L2v loricrin fragment, with full inhibition at 40 μM (OD600 0.11 ± 0.01). Furthermore, recombinant ClfB protein binding to L2v loricrin was inhibited by allantodapsone (P < 0.0001). Allantodapsone also demonstrated dose dependent inhibition of S. aureus Newman adhesion to cytokeratin 10 (CK10). Allantodapsone is the first small molecule inhibitor of the S. aureus clumping factors with potential for development as a colonization inhibitor. IMPORTANCE S. aureus colonization of the nares and the skin provide a reservoir of bacteria that can be transferred to wounds that can ultimately result in systemic infections. Antibiotic resistance can make these infections difficult to treat with significant associated morbidity and mortality. We have identified and characterized a first-in-class small molecule inhibitor of the S. aureus clumping factors A and B, which has the potential to be developed further as a colonization inhibitor.
ABSTRACTStaphylococcus aureus infections have become a major challenge in health care due to increasing antibiotic resistance. We aimed to design small molecule inhibitors of S. aureus surface proteins to be developed as colonization inhibitors. We identified allantodapsone in an initial screen searching for inhibitors of clumping factors A and B (ClfA and ClfB). We used microbial adhesion assays to investigate the effect of allantodapsone on extracellular matrix protein interactions. Allantodapsone inhibited S. aureus Newman adhesion to fibrinogen with an IC50 of 21.3 μM (95% CI 4.5-102 μM), minimum adhesion inhibitory concentration (MAIC) of 100 μM (40.2 μg/mL). Additionally, allantodapsone inhibited adhesion of Lactococcus lactis strains exogenously expressing the clumping factors to fibrinogen (L. lactis ClfA, IC50 of 3.8 μM [95% CI 1.0–14.3 μM], MAIC 10 μM, 4.0 μg/mL; and L. lactis ClfB, IC50 of 11.0 μM [95% CI 0.9–13.6 μM], MAIC 33 μM, 13.3 μg/mL), indicating specific inhibition. Furthermore, the dapsone and alloxan fragments of allantodapsone did not have any inhibitory effect. Adhesion of S. aureus Newman to L2v loricrin is dependent on the expression of ClfB. Allantodapsone caused a dose dependent inhibition of S. aureus adhesion to the L2v loricrin fragment, with full inhibition at 40 μM (OD600 0.11 ± 0.01). Furthermore, recombinant ClfB protein binding to L2v loricrin was inhibited by allantodapsone (P < 0.0001). Allantodapsone also demonstrated dose dependent inhibition of S. aureus Newman adhesion to cytokeratin 10 (CK10). Allantodapsone is the first small molecule inhibitor of the S. aureus clumping factors with potential for development as a colonization inhibitor.
IMPORTANCE S. aureus colonization of the nares and the skin provide a reservoir of bacteria that can be transferred to wounds that can ultimately result in systemic infections. Antibiotic resistance can make these infections difficult to treat with significant associated morbidity and mortality. We have identified and characterized a first-in-class small molecule inhibitor of the S. aureus clumping factors A and B, which has the potential to be developed further as a colonization inhibitor.
2022-06-01T00:00:00ZSteroid use for established bronchopulmonary dysplasia: study protocol for a systematic review and meta-analysis.
http://hdl.handle.net/10147/635549
Steroid use for established bronchopulmonary dysplasia: study protocol for a systematic review and meta-analysis.
Strashun, Sabina; Chioma, Roberto; Zielińska, Kinga; Włodarczyk, Krzysztof; Villamor, Eduardo; Philip, Roy K; Assaf, Niazy Al; Pierro, Maria; Włodarczyk, Krzysztof
Postnatal steroids during the first few weeks of life have been demonstrated to be effective in decreasing the incidence of bronchopulmonary dysplasia (BPD), a serious chronic respiratory condition affecting preterm infants. However, this preventive option is limited by the concern of neurological side effects. Steroids are used to treat established BPD in an attempt to reduce mortality, and length of stay and home oxygen therapy, both of which associated with high levels of parental stress and healthcare costs. Moreover, a late timing for steroid treatment may show a more favourable safety profile in terms of neurodevelopment outcomes, considering the added postnatal brain maturation of these infants. Here, we report a protocol for a systematic review, which aims to determine the efficacy and long-term safety of postnatal steroids for the treatment of established BPD in preterm infants.
Methods and analysis
MEDLINE, Embase, Cochrane databases and sources of grey literature for conference abstracts and trial registrations will be searched with no time or language restriction. We will include case–control studies, cohort studies and non-randomised or randomised trials that evaluate postnatal steroids for infants diagnosed with moderate or severe established BPD at 36 weeks’ postmenstrual age. We will pool data from studies that are sufficiently similar to make this appropriate. Data extraction forms will be developed a priori. Observational studies and non-randomised and randomised clinical trials will be analysed separately. We will combine OR with 95% CI for dichotomous outcomes and the mean difference (95% CI) for continuous outcomes. We will account for the expected heterogeneity by using a random-effects model. We will perform subgroup analysis based on the a priori determined covariate of interest.
Ethics and dissemination
Systematic reviews are exempted from approval by an ethics committee. Attempts will be sought to publish all results.
2022-06-15T00:00:00ZThe past, present and future of genomics and bioinformatics: A survey of Brazilian scientists.
http://hdl.handle.net/10147/635547
The past, present and future of genomics and bioinformatics: A survey of Brazilian scientists.
Massarani, Luisa; Souza, Sandro José de; Vasconcelos, Ana Tereza R de; Rocha, Mariana
Brazil has one of the highest rates of scientific production, occupying the ninth position among countries with genome-sequencing projects. Considering the rapid development of this research area and the diversity of professionals involved, the present study aims to understand the expectations, past experiences and the current scenario of Brazilian research in bioinformatics and genomics. The present research was carried out by analyzing the perceptions of 576 researchers in genomics and bioinformatics in Brazil through content and sentiment analysis techniques. This group of participants is equivalent to 48% of the members of the research community. The results suggest that most researchers have a positive perception of the potential of this research area. However, there is concern about the lack of funding for investing in equipment and professional training. As part of a wish list for the future, researchers highlighted the need for higher funding, formal education, and collaboration among research networks. When asked about genomics and bioinformatics in other countries, the participants recognize that sequencing technologies and infrastructure are more accessible, allowing better data volume expansion.
2022-06-01T00:00:00ZStent Optimization Using Optical Coherence Tomography and Its Prognostic Implications After Percutaneous Coronary Intervention.
http://hdl.handle.net/10147/635546
Stent Optimization Using Optical Coherence Tomography and Its Prognostic Implications After Percutaneous Coronary Intervention.
Antuña, Paula; Blachutzik, Florian; Koppara, Tobias; Nef, Holger; Seguchi, Masaru; Aytekin, Alp; Rai, Himanshu; Byrne, Robert; Kufner, Sebastian; Alfonso, Fernando; Harzer, Fiona; Otsuka, Tatsuhiko; Cassese, Salvatore; Kastrati, Adnan; Joner, Michael; Lorenz, Räber; Laugwitz, Karl-Ludwig; Abdelwahed, Youssef; Xhepa, Erion; Leistner, David
Background Stent underexpansion has been known to be associated with worse outcomes. We sought to define optical coherence tomography assessed optimal stent expansion index (SEI), which associates with lower incidence of follow-up major adverse cardiac events (MACEs). Methods and Results A total of 315 patients (involving 370 lesions) who underwent optical coherence tomography-aided coronary stenting were retrospectively included. SEI was calculated separately for equal halves of each stented segment using minimum stent area/mean reference lumen area ([proximal reference area+distal reference area]/2). The smaller of the 2 was considered to be the SEI of that case. Follow-up MACE was defined as a composite of all-cause death, myocardial infarction, stent thrombosis, and target lesion revascularization. Average minimum stent area was 6.02 (interquartile range, 4.65-7.92) mm2, while SEI was 0.79 (interquartile range, 0.71-0.86). Forty-seven (12.7%) incidences of MACE were recorded for 370 included lesions during a median follow-up duration of 557 (interquartile range, 323-1103) days. Receiver operating characteristic curve analysis identified 0.85 as the best SEI cutoff (<0.85) to predict follow-up MACE (area under the curve, 0.60; sensitivity, 0.85; specificity, 0.34). MACE was observed in 40 of 260 (15.4%) lesions with SEI <0.85 and in 7 of 110 (6.4%) lesions with SEI ≥0.85 (P=0.02). Least absolute shrinkage and selection operator regression identified SEI <0.85 (odds ratio, 3.55; 95% CI, 1.40-9.05; P<0.01) and coronary calcification (odds ratio, 2.47; 95% CI, 1.00-6.10; P=0.05) as independent predictors of follow-up MACE. Conclusions The present study identified SEI <0.85, associated with increased incidence of MACE, as the optimal cutoff in daily practice. Along with suboptimal SEI (<0.85), coronary calcification was also found to be a significant predictor of follow-up MACE.
Background Stent underexpansion has been known to be associated with worse outcomes. We sought to define optical coherence tomography assessed optimal stent expansion index (SEI), which associates with lower incidence of follow-up major adverse cardiac events (MACEs). Methods and Results A total of 315 patients (involving 370 lesions) who underwent optical coherence tomography-aided coronary stenting were retrospectively included. SEI was calculated separately for equal halves of each stented segment using minimum stent area/mean reference lumen area ([proximal reference area+distal reference area]/2). The smaller of the 2 was considered to be the SEI of that case. Follow-up MACE was defined as a composite of all-cause death, myocardial infarction, stent thrombosis, and target lesion revascularization. Average minimum stent area was 6.02 (interquartile range, 4.65-7.92) mm2, while SEI was 0.79 (interquartile range, 0.71-0.86). Forty-seven (12.7%) incidences of MACE were recorded for 370 included lesions during a median follow-up duration of 557 (interquartile range, 323-1103) days. Receiver operating characteristic curve analysis identified 0.85 as the best SEI cutoff (<0.85) to predict follow-up MACE (area under the curve, 0.60; sensitivity, 0.85; specificity, 0.34). MACE was observed in 40 of 260 (15.4%) lesions with SEI <0.85 and in 7 of 110 (6.4%) lesions with SEI ≥0.85 (P=0.02). Least absolute shrinkage and selection operator regression identified SEI <0.85 (odds ratio, 3.55; 95% CI, 1.40-9.05; P<0.01) and coronary calcification (odds ratio, 2.47; 95% CI, 1.00-6.10; P=0.05) as independent predictors of follow-up MACE. Conclusions The present study identified SEI <0.85, associated with increased incidence of MACE, as the optimal cutoff in daily practice. Along with suboptimal SEI (<0.85), coronary calcification was also found to be a significant predictor of follow-up MACE.
2022-04-26T00:00:00ZThe Vibrio vulnificus stressosome is an oxygen-sensor involved in regulating iron metabolism.
http://hdl.handle.net/10147/635545
The Vibrio vulnificus stressosome is an oxygen-sensor involved in regulating iron metabolism.
Jäckel, Wenke; Bedrunka, Patricia; Graf, Anica; Reder, Alexander; Michalik, Stephan; Dhople, Vishnu M; Conway, Maria; Lechner, Marcus; Riedel, Katharina; Boyd, Aoife; Lewis, Richard J; Ziegler, Christine; Heinz, Veronika; Kaltwasser, Susann; Cutugno, Laura; Madej, M. Gregor; Bange, Gert; Völker, Uwe; Pané-Farré, Jan; Marles-Wright, Jon
Stressosomes are stress-sensing protein complexes widely conserved among bacteria. Although a role in the regulation of the general stress response is well documented in Gram-positive bacteria, the activating signals are still unclear, and little is known about the physiological function of stressosomes in the Gram-negative bacteria. Here we investigated the stressosome of the Gram-negative marine pathogen Vibrio vulnificus. We demonstrate that it senses oxygen and identified its role in modulating iron-metabolism. We determined a cryo-electron microscopy structure of the VvRsbR:VvRsbS stressosome complex, the first solved from a Gram-negative bacterium. The structure points to a variation in the VvRsbR and VvRsbS stoichiometry and a symmetry breach in the oxygen sensing domain of VvRsbR, suggesting how signal-sensing elicits a stress response. The findings provide a link between ligand-dependent signaling and an output - regulation of iron metabolism - for a stressosome complex.
2022-06-27T00:00:00ZContextualizing National Policies Regulating Access to Low‐Dose Aspirin in America and Europe Using the Full Report of a Transatlantic Patient Survey of Aspirin in Preventive Cardiology
http://hdl.handle.net/10147/635544
Contextualizing National Policies Regulating Access to Low‐Dose Aspirin in America and Europe Using the Full Report of a Transatlantic Patient Survey of Aspirin in Preventive Cardiology
Jacobsen, Alan P.; Lim, Zi Lun; Chang, Blair; Lambeth, Kaleb D.; Das, Thomas M.; Gorry, Colin; McCague, Michael; Sharif, Faisal; Mylotte, Darren; Wijns, William; Serruys, Patrick W. J .C.; Blumenthal, Roger S.; Martin, Seth S.; McEvoy, John W.
BACKGROUND Aspirin is widely administered to prevent cardiovascular disease (CVD). However, appropriate use of aspirin depends on patient understanding of its risks, benefits, and indications, especially where aspirin is available over the counter (OTC).
METHODS AND RESULTS We did a survey of patient‐reported 10‐year cardiovascular risk; aspirin therapy status; form of aspirin access (OTC versus prescription); and knowledge of the risks, benefits, and role of aspirin in CVD prevention. Consecutive adults aged ≥50 years with ≥1 cardiovascular risk factor attending outpatient clinics in America and Europe were recruited. We also systematically reviewed national policies regulating access to low‐dose aspirin for CVD prevention. At each site, 150 responses were obtained (300 total). Mean±SD age was 65±10 years, 40% were women, and 41% were secondary prevention patients. More than half of the participants at both sites did not know (1) their own level of 10‐year CVD risk, (2) the expected magnitude of reduction in CVD risk with aspirin, or (3) aspirin’s bleeding risks. Only 62% of all participants reported that aspirin was routinely indicated for secondary prevention, whereas 47% believed it was routinely indicated for primary prevention (P=0.048). In America, 83.5% participants obtained aspirin OTC compared with 2.5% in Europe (P<0.001). Finally, our review of European national policies found only 2 countries where low‐dose aspirin was available OTC.
CONCLUSIONS Many patients have poor insight into their objectively calculated 10‐year cardiovascular risk and do not know the risks, benefits, and role of aspirin in CVD prevention. Aspirin is mainly obtained OTC in America in contrast to Europe, where most countries restrict access to low‐dose aspirin.
2022-04-19T00:00:00ZA rare paediatric 'floating elbow'; a supracondylar fracture with an ipsilateral Monteggia fracture: A case report.
http://hdl.handle.net/10147/635543
A rare paediatric 'floating elbow'; a supracondylar fracture with an ipsilateral Monteggia fracture: A case report.
Ismaili, Granit; Mahmoud, Elsiddig; O' Toole, Pat
Introduction and importance
A paediatric floating elbow involves fractures of the supracondylar region of the humerus with ipsilateral fracture of the forearm bones. A floating elbow is very uncommon with an incidence of 3 to 13% of all supracondylar fractures. A concomitant supracondylar and Monteggia fracture is extremely rare with only six cases reported in the literature.
Case presentation
We present the unusual case of an eight-year-old girl with a concomitant ipsilateral supracondylar humerus fracture and open Monteggia fracture. Physical examination showed a neurovascularly intact limb. Surgical management was carried out in the form of closed and open reduction, percutaneous pinning using Kirschner (K) wires and Titanium Elastic Nails (TENs), and wound washout and debridement of the open lesion.
The patient developed pin site infection six weeks post operation and subsequently underwent surgery for removal of pins. She was later followed up with normal radiographic and physical examination findings.
Clinical discussion
The complexity of these fractures can lead to debilitating complications if proper management is not initiated. It is imperative that neurovascular and motor function be assessed in great detail and early surgical fixation be carried out in order to prevent these complications.
Conclusion
A paediatric floating elbow is a rare surgical emergency. Although no guidelines for the management of these fractures exist, we recommend surgical management in a step-by-step approach be used over conservative management. We also stress the importance of regular follow up to address any post operative complications that may arise such as the one in our case.
2022-04-13T00:00:00ZIdentification and characterization of novel endolysins targeting Gardnerella vaginalis biofilms to treat bacterial vaginosis.
http://hdl.handle.net/10147/635542
Identification and characterization of novel endolysins targeting Gardnerella vaginalis biofilms to treat bacterial vaginosis.
Arroyo-Moreno, Sara; Cummings, Matthew; Corcoran, David B; Coffey, Aidan; McCarthy, Ronan R
Bacterial vaginosis (BV) is a recurrent dysbiosis that is frequently associated with preterm birth, increased risk for acquisition of human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs). The overgrowth of a key pathobiont, Gardnerella vaginalis, as a recalcitrant biofilm is central to the development of this dysbiosis. Overgrowth of vaginal biofilms, seeded by initial G. vaginalis colonization, leads to recurrent symptomatic BV which is poorly resolved by classically used antibiotics. In this light, the use of bacteriophages and/or their proteins, represents a promising alternative. Here we identify 84 diverse anti-Gardnerella endolysins across 7 protein families. A subset of 36 endolysin candidates were refactored and overexpressed in an E. coli BL21 (DE3) system and 5 biochemically and structurally diverse endolysins were fully characterized. Each candidate endolysin showed good lytic activity against planktonic G. vaginalis ATCC14018, as well as G. vaginalis clinical isolates. These endolysin candidates were assayed in biofilm prevention and disruption assays, with biofilm disruption at low microgram concentrations (5 μg/ml) observed. In addition to clonal G. vaginalis biofilms, endolysin candidates could also successfully disrupt polyspecies biofilms. Importantly, none of our candidates showed lytic activity against commensal lactobacilli present in the vaginal microbiota such as L. crispatus, L. jensenii, L. gasseri, and L. iners or against Atopobium vaginae (currently classified as Fannyhessa vaginae). The potency and selectivity of these novel endolysins constitute a promising alternative treatment to combat BV, avoiding problems associated with antibiotic resistance, while retaining beneficial commensal bacteria in the vaginal flora. The diverse library of candidates reported here represents a strong repository of endolysins for further preclinical development.
2022-04-19T00:00:00ZHydroxychloroquine does not function as a direct zinc ionophore.
http://hdl.handle.net/10147/635541
Hydroxychloroquine does not function as a direct zinc ionophore.
Kavanagh, Oisín N; Bhattacharya, Shayon; Marchetti, Luke; Elmes, Robert; O'Sullivan, Finbarr; Farragher, John P; Robinson, Shane; Thompson, Damien; Walker, Gavin M
Drug-mediated correction of abnormal biological zinc homeostasis could provide new routes to treating neurodegeneration, cancer, and viral infections. Designing therapeutics to facilitate zinc transport intracellularly is hampered by inadequate concentrations of endogenous zinc, which is often protein-bound in vivo. We found strong evidence that hydroxychloroquine, a drug used to treat malaria and employed as a potential treatment for COVID-19, does not bind and transport zinc across biological membranes through ionophoric mechanisms, contrary to recent claims. In vitro complexation studies and liposomal transport assays are correlated with cellular zinc assays in A549 lung epithelial cells to confirm the indirect mechanism of hydroxychloroquine-mediated elevation in intracellular zinc without ionophorism. Molecular simulations show hydroxychloroquine-triggered helix perturbation in zinc-finger protein without zinc chelation, a potential alternative non-ionophoric mechanism.
2022-04-20T00:00:00Z