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To highlight the current diagnostic pathway for children with Spinal Muscular Atrophy (SMA) in Ireland. We look to identify points along the diagnostic pathway that may impede a timely diagnosis, and argue that newborn screening for SMA is the single best measure to remediate these delays.Through retrospective chart review and an online questionnaire, we gathered SMA patient data outlining clinical characteristics and the route to diagnosis of the SMA cohort attending the National SMA Treatment centre at Children's Health Ireland.We found that 32 children were diagnosed with SMA in Ireland in the 15-years from 2007 to 2021, with twelve cases of SMA type I. Muscle weakness is the most commonly reported initial sign, and the GP is usually the first health provider to address parental concerns. Patients commonly experience delays in diagnosis due to factors such as varied SMA clinical phenotypes, and a lack of experience or awareness of SMA amongst community based health care practitioners. In spite of this, when patients do gain early access to tertiary diagnostics through prenatal or neonatal genetic testing, they then report rapid diagnosis and initiation of disease modifying therapy in the crucial pre-symptomatic window.We conclude that delays to diagnosis inherent within the current Irish system are pervasive and arise prior to engagement with tertiary services. All of these delays are remediable through the establishment of a dedicated SMA newborn screening programme.

Background Minimising the effects of unconscious bias in selection for clinical academic training is essential to ensure that allocation of training posts is based on merit. We looked at the effect of anonymising applications to a training programme for junior doctors on the scores of the applications and on gender balance; and whether female candidates were more likely to seek gender-concordant mentors. Methods Applications to the training programme were reviewed and scored independently by reviewers who received either an anonymised or named copy. Scores were compared using a paired t-test, and differences in scores compared by gender. The gender of named supervisors for male and female candidates was compared. Results Scores of 101 applications were reviewed. When their identity was known, male candidates scored 1.72% higher and female candidates scored 0.74% higher, but these findings were not statistically significant (p value = 0.279 and 0.579). Following introduction of anonymisation, the proportion of successful female candidates increased from 27 to 46%. Female candidates were more likely to name a female supervisor compared to male (41% vs. 25% of supervisors). Conclusions Anonymising applications did not significantly change scores, although gender balance improved. Gender-concordant mentoring initiatives should consider effects on mentors as well as mentees.

Purpose To better prepare for potential future large-scale redeployments, this study examines quality of supervision and care as perceived by redeployed residents, fellows, and attendings during a COVID-19 surge. Method During April and May 2020, attendings, fellows, and residents redeployed at 2 teaching hospitals were invited to participate in a survey, which included questions on respondents' prior experience; redeployed role; amount of supervision needed and received; and perceptions of quality of supervision, patient care, and interprofessional collaboration. Frequencies, means, and P values were calculated to compare perceptions by experience and trainee status. Narrative responses to 2 open-ended questions were independently coded; themes were constructed. Results Overall, 152 of 297 (51.2%) individuals responded, including 64 of 142 attendings (45.1%), 40 of 79 fellows (50.6%), and 48 of 76 residents (63.2%). Fellows and attendings, regardless of prior experience, perceived supervision as adequate. In contrast, experienced residents reported receiving more supervision than needed, while inexperienced residents reported receiving less supervision than needed and rated overall supervision as poor. Attendings, fellows, and experienced residents rated the overall quality of care as acceptable to good whereas inexperienced residents perceived overall quality of care as worse to much worse, particularly when compared to baseline. Conclusions Narrative themes indicated that the quality of supervision and care was buffered by strong camaraderie, a culture of informal consultation, team composition (mixing experienced with inexperienced), and clinical decision aids. The markedly negative view of inexperienced residents suggests a higher risk for disillusionment, perhaps even moral injury, during future redeployments. Implications for planning are explored.

The management of hypertension is primarily performed in primary care settings in many health systems. However, two groups of patients often require specialist input: patients with resistant hypertension (RH) and young adults with hypertension.To elucidate these groups by examining the characteristics of patients attending an Irish hypertension service, thus informing future management of hypertension.Patients were recruited at consecutive hypertension clinics at St James Hospital, Dublin from July to September 2019. Following patient consent, patient data were recorded to identify patient characteristics as well as the results of investigations, blood pressure (BP) measurements and the anti-hypertensive treatment of the study participants which were then analysed.Two hundred thirty-six patients were included in the study. Compared to those without RH, the RH group were more likely to be obese (OR 2.59 [95% CI 1.06 to 6.33]), to have cardiovascular disease (OR 3.07 [95% CI 1.56 to 6.02]) and to have a non-dipping BP pattern (OR 3.86 [95% CI 1.57 to 9.47]). Young adults comprised 27% of the cohort. Forty-seven percent of these patients were obese, 15.9% had hypertension in pregnancy and 22.2% had chronic headaches. Despite being prescribed less anti-hypertensives (1.41 vs 2.28; p 0.05), the majority of young patients had a BP less than 140/90 mmHg, comparing favourably with older patients (OR 2.25 [95% CI 1.20 to 4.27]).This contemporary study highlights the high prevalence of obesity among RH patients and young adults with hypertension. Findings suggest that programs to combat hypertension must include interventions to address obesity.

Further information is needed on how community exercise facilities can be effectively utilised to engage people living with chronic health conditions in exercise. The aim of this study was to identify the exercise barriers, facilitators and needs of patients with chronic disease in the community; and to provide recommendations to support the transition from hospital-based to community-based exercise. Using a qualitative approach, four focus groups were conducted with patients who had completed hospital-based exercise programmes (n = 11) and fitness instructors (n = 10). Data were audio recorded, member checked and transcribed verbatim for thematic analysis using NVivo. The side effects of chronic health conditions, the gym environment and a need for support when joining/attending a gym were perceived as barriers to exercising in the community. In contrast, the presence of supportive staff was perceived by patients as a facilitator to engaging in exercise in the community. A total of three themes emerged from participants views on exercise needs in the community; the referral and induction process in community gyms, fitness instructor training and experience and creating a supportive exercise environment. Themes informed eight key recommendations to support patients to exercise in the community, including supportive gym referral and induction processes for patients with chronic conditions, increased professional training for fitness instructors in the area of chronic disease management and exercise prescription, and exercise support at regular intervals for those with chronic conditions attending community gyms. This study found that there is potential for community gyms to play a key role in promoting health among people with chronic conditions. However, more can be done to foster an inclusive atmosphere in this space. Patients living with chronic conditions need information and advice on exercising in their communities. Community gyms require further support to ensure that facilities meet the exercise needs of people with chronic conditions.

Background: The current coronavirus disease 2019 (COVID-19) pandemic began in Ireland with the first confirmed positive case in March 2020. In the early stages of the pandemic clinicians and researchers in two affiliated Dublin hospitals identified the need for a COVID-19 biobanking initiative to support and enhance research into the disease. Through large scale analysis of clinical, regional, and genetic characteristics of COVID-19 patients, biobanks have helped identify, and so protect, at risk patient groups The STTAR Bioresource has been created to collect and store data and linked biological samples from patients with SARS-CoV-2 infection and healthy and disease controls. Aim: The primary objective of this study is to build a biobank, to understand the clinical characteristics and natural history of COVID-19 infection with the long-term goal of research into improved disease understanding, diagnostic tests and treatments. Methods: This is a prospective dual-site cohort study across two tertiary acute university teaching hospitals. Patients are recruited from inpatient wards or outpatient clinics. Patients with confirmed COVID-19 infection as well as healthy and specific disease control groups are recruited. Biological samples are collected and a case report form detailing demographic and medical background is entered into the bespoke secure online Dendrite database. Impact: The results of this study will be used to inform national and international strategy on health service provision and disease management related to COVID-19. In common with other biobanks, study end points evolve over time as new research questions emerge. They currently include patient survival, occurrence of severe complications of the disease or its therapy, occurrence of persistent symptoms following recovery from the acute illness and vaccine responses.

Abstract Aims COVID-19 resulted in significant changes across medical wards and ICU in St James’s Hospital Dublin. This included the implementation of ward-based medical teams (WBMT). The purpose of this study was to identify how these structural changes affected inter-professional collaboration, supervision and patient safety. Methods Questionnaires were distributed to doctors working on medical wards and ICU at the height of the first wave of COVID-19. The sense of collaboration, patient safety and supervision were assessed. Results Fifty-three doctors took part in the study. Thirty-three (62%) felt that collaboration was better than normal. Forty-six (87%) of participants described supervision as “good” or “excellent”. Thirty-one out of 40 participants (77%) felt that patient safety was better than normal. Discussion Implementation of WBMT may result in improved sense of collaboration, supervision and patient safety during COVID-19; however, the increased sense of solidarity and comradery felt during the initial surge make drawing these conclusions challenging.

Background Links between air pollution and asthma are less well established for older adults than some younger groups. Nitrogen dioxide (NO2) concentrations are widely used as an indicator of transport-related air pollution, and some literature suggests NO2 may directly affect asthma. Methods This study used data on 8162 adults >50 years old in the Republic of Ireland to model associations between estimated annual outdoor concentration of NO2 and the probability of having asthma. Individual-level geo-coded survey data from The Irish Longitudinal Study on Ageing (TILDA) were linked to model-based estimates of annual average NO2 at 50 m resolution. Asthma was identified using two methods: self-reported diagnoses and respondents’ use of medications related to obstructive airway diseases. Logistic regressions were used to model the relationships. Results NO2 concentrations were positively associated with the probability of asthma [marginal effect (ME) per 1 ppb of airborne NO2 = 0.24 percentage points asthma self-report, 95% confidence interval (CI) 0.06–0.42, mean asthma prevalence 0.09; for use of relevant medications ME = 0.21 percentage points, 95% CI 0.049–0.37, mean prevalence 0.069]. Results were robust to varying model specification and time period. Respondents in the top fifth percentile of NO2 exposure had a larger effect size but also greater standard error (ME = 2.4 percentage points asthma self-report, 95% CI −0. 49 to 5.3). Conclusions Associations between local air pollution and asthma among older adults were found at relatively low concentrations. To illustrate this, the marginal effect of an increase in annual average NO2 concentration from sample minimum to median (2.5 ppb) represented about 7–8% of the sample average prevalence of asthma.

(1) Background: Recent advances in the pharmacological treatment of obesity with glucagon-like peptide-1 receptor agonists (GLP-1 RA) highlight the potential to target excess body weight to improve blood pressure (BP). This review aimed to determine the BP reduction in trials of semaglutide for weight reduction in patients without diabetes. (2) Methods: Relevant studies were identified via a search of research databases. Studies were screened to include randomized controlled trials (RCTs) of semaglutide versus a placebo in adults. Pooled and sensitivity analyses were performed, and risk of bias was assessed. (3) Results: six RCTs, with 4744 participants, were included in the final analysis. At baseline, the cohorts in these studies had a mean BP in the normotensive range. The mean difference in systolic BP was −4.83 mmHg (95% CI: −5.65 to −4.02), while that for diastolic BP was −2.45 mmHg (95% CI: −3.65 to −1.24). All included studies were of a high methodological quality. (4) Conclusions: A clinically significant reduction in BP was evident following semaglutide treatment in normotensive populations without diabetes. The effect of semaglutide in those with obesity and hypertension is as yet undetermined. Targeting excess body weight may be a novel therapeutic strategy for these patients.

Background Hospital-based healthcare workers have experienced significant psychological stressors during the COVID-19 pandemic. Aim To evaluate the mental health of hospital workers during the third wave of the COVID-19 pandemic in Dublin, Ireland. Methods Cross-sectional anonymous online survey of hospital workers (n = 377; 181 doctors (48.0%), 166 nurses (44.0%), 30 radiographers (8.0%)), collecting demographic information, COVID-19 exposure history and mental health measures. Results There were significant differences between profession groups in gender, experience, COVID-19 infection history, exposure to COVID-19 positive acquaintances, and work areas. Moderate-severe post-traumatic stress disorder (PTSD) symptoms were found in 45.1% (95% CI 40.1–50.1%) of all participants; significantly fewer doctors reported moderate-severe PTSD symptoms (26%; 95% CI 22–36%). A World Health Organisation-5 Wellbeing Index (WHO-5) score ≤ 32, indicating low mood, was reported by 52% (95% CI 47–57%) of participants; significantly fewer doctors reported low mood (46%; 95% CI 39–53%). One-week suicidal ideation and planning were reported respectively by 13% (95% CI 10–16%) and 5% (95% CI 3–7%) of participants with no between-group differences. Doctors reported significantly less moral injury than other groups. There were no significant between-group differences regarding coping styles. Work ability was insufficient in 39% (95% CI 34–44%) of staff; no between-group differences. Conclusions Dublin hospital workers reported high levels of PTSD symptoms, mood disturbance, and moral injury during the COVID-19 pandemic. Concerning levels of suicidal ideation and planning existed in this cohort. Differences in degrees of post-traumatic stress, moral injury, and wellbeing were found between profession groups, which should be considered when planning any supports.

Background Clinicians who divide their time between clinical work and research have contributed to some of the most fundamental breakthroughs in medicine in recent history, yet their role is not always well-understood or valued. Understanding the factors which contribute to career success for clinical academics is critical for supporting this workforce. Social Cognitive Career Theory (SCCT) provides a conceptual framework for career success, incorporating personal and environmental factors. Purpose The aim of this study is to explore clinical academics’ construal of successful clinical academic practice and to contribute to a holistic view of the professional identity of the clinical academic. Methodology Using a constructivist technique, repertory grid, the authors interviewed ten clinical academics at different career stages in one-to-one structured interviews conducted virtually between November 2020 and April 2021. Data from the interviews were analysed qualitatively and quantitatively. Common themes were identified, analysed, and ranked according to importance with respect to successful clinical academic practice. Using SCCT as a framework, constructs were categorised as personal factors, organisational factors, competencies and person-environment fit. A differential analysis between established/trainee and female/male participants was carried out. Summary of results One hundred and thirty-three constructs were elicited and categorised into 20 themes (constructs). There was consensus among participants that 6 were of high importance with respect to successful clinical academic practice, 8 of intermediate and 4 of low importance, with no consensus on 2 constructs. Personal factors of high importance include innovation and integrity. Competencies including research and teaching skills are highly important, and ability to collaborate is also considered central to successful clinical academic practice. Female participants expressed greater concerns about the impact of familial responsibilities on career progression. Discussion and conclusions This study highlights the importance of interactions between the person and environment, and characterises the important attributes of successful clinical academics including personal factors such as integrity and innovation.

BackgroundPolicymakers need robust data to respond to the COVID-19 pandemic. We describe demographic features, treatments and clinical outcomes in the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) COVID-19 cohort, the world’s largest international, standardised cohort of hospitalised patients.MethodsThe dataset analysed includes COVID-19 patients hospitalised between January 2020 and May 2021. We investigated how symptoms on admission, comorbidities, risk factors, and treatments varied by age, sex, and other characteristics. We used Cox proportional hazards models to investigate associations between demographics, symptoms, comorbidities, and other factors with risk of death, admission to intensive care unit (ICU), and invasive mechanical ventilation (IMV).Findings439,922 patients with laboratory-confirmed (91.7%) or clinically-diagnosed (8.3%) SARS-CoV-2 infection from 49 countries were enrolled. Age (adjusted hazard ratio [HR] per 10 years 1.49 [95% CI 1.49-1.50]) and male sex (1.26 [1.24-1.28]) were associated with a higher risk of death. Rates of admission to ICU and use of IMV increased with age up to age 60, then dropped. Symptoms, comorbidities, and treatments varied by age and had varied associations with clinical outcomes. Tuberculosis was associated with an 86% higher risk of death, and HIV with an 87% higher risk of death. Case fatality ratio varied by country partly due to differences in the clinical characteristics of recruited patients.InterpretationThe size of our international database and the standardized data collection method makes this study a reliable and comprehensive international description of COVID-19 clinical features. This is a viable model to be applied to future epidemics.FundingUK Foreign, Commonwealth and Development Office, the Bill & Melinda Gates Foundation and Wellcome. See acknowledgements section for funders of sites that contributed data.Research in contextEvidence before this studyTo identify large, international analyses of hospitalised COVID-19 patients that used standardised data collection, we conducted a systematic review of the literature from 1 Jan 2020 to 28 Apr 2020. We identified 78 studies, with data from 77,443 people (1) predominantly from China. We could not find any studies including data from low and middle-income countries. We repeated our search on 18 Aug 2021 but could not identify any further studies that met our inclusion criteria.Added value of this studyOur study uses standardised clinical data collection to collect data from a vast number of patients across the world, including patients from low-, middle-, and high-income countries. The size of our database gives us great confidence in the accuracy of our descriptions of the global impact of COVID-19. We can confirm findings reported by smaller, country-specific studies and compare clinical data between countries. We have demonstrated that it is possible to collect large volumes of standardised clinical data during a pandemic of a novel acute respiratory infection. The results provide a valuable resource for present policymakers and future global health researchers.Implications of all the available evidencePresenting symptoms of SARS-CoV-2 infection in patients requiring hospitalisation are now well-described globally, with the most common being fever, cough, and shortness of breath. Other symptoms also commonly occur, including altered consciousness in older adults and gastrointestinal symptoms in younger patients, and age can influence the likelihood of a patient having symptoms that match one or more case definitions. There are geographic and temporal variations in the case fatality rate (CFR), but overall, CFR was 20.6% in this large international cohort of hospitalised patients with a median age of 60 years (IQR: 45 to 74 years).

The recent STEP trials reported blood pressure reductions for obese patients treated with semaglutide. We analyzed a cohort of patients attending our hypertension clinic and found that 26% were severely or morbidly obese and morbidly obese patients frequently had resistant hypertension (41%). We suggest semaglutide may be an effective anti-hypertensive agent for obese patients with resistant hypertension and this hypothesis should be assessed in randomized clinical trials.

Objectives The primary objective is to demonstrate that, in patients with PCR-confirmed SARS-CoV-2 resulting in Acute Respiratory Distress Syndrome (ARDS), administration of 120mg/kg of body weight of intravenous Prolastin®(plasma-purified alpha-1 antitrypsin) reduces circulating plasma levels of interleukin-6 (IL-6). Secondary objectives are to determine the effects of intravenous Prolastin® on important clinical outcomes including the incidence of adverse events (AEs) and serious adverse events (SAEs). Trial design Phase 2, randomised, double-blind, placebo-controlled, pilot trial. Participants The study will be conducted in Intensive Care Units in hospitals across Ireland. Patients with a laboratory-confirmed diagnosis of SARS-CoV-2-infection, moderate to severe ARDS (meeting Berlin criteria for a diagnosis of ARDS with a PaO2/FiO2 ratio 18 years of age and requiring invasive or non-invasive mechanical ventilation. All individuals meeting any of the following exclusion criteria at baseline or during screening will be excluded from study participation: more than 96 hours has elapsed from onset of ARDS; age < 18 years; known to be pregnant or breastfeeding; participation in a clinical trial of an investigational medicinal product (other than antibiotics or antivirals) within 30 days; major trauma in the prior 5 days; presence of any active malignancy (other than nonmelanoma skin cancer) which required treatment within the last year; WHO Class III or IV pulmonary hypertension; pulmonary embolism prior to hospital admission within past 3 months; currently receiving extracorporeal life support (ECLS); chronic kidney disease receiving dialysis; severe chronic liver disease with Child-Pugh score > 12; DNAR (Do Not Attempt Resuscitation) order in place; treatment withdrawal imminent within 24 hours; Prisoners; non-English speaking patients or those who do not adequately understand verbal or written information unless an interpreter is available; IgA deficiency. Intervention and comparator Intervention: Either a once weekly intravenous infusion of Prolastin® at 120mg/kg of body weight for 4 weeks or a single dose of Prolastin® at 120mg/kg of body weight intravenously followed by once weekly intravenous infusion of an equal volume of 0.9% sodium chloride for a further 3 weeks. Comparator (placebo): An equal volume of 0.9% sodium chloride intravenously once per week for four weeks. Main outcomes The primary effectiveness outcome measure is the change in plasma concentration of IL-6 at 7 days as measured by ELISA. Secondary outcomes include: safety and tolerability of Prolastin® in the respective groups (as defined by the number of SAEs and AEs); PaO2/FiO2 ratio; respiratory compliance; sequential organ failure assessment (SOFA) score; mortality; time on ventilator in days; plasma concentration of alpha-1 antitrypsin (AAT) as measured by nephelometry; plasma concentrations of interleukin-1β (IL-1β), interleukin-8 (IL-8), interleukin-10 (IL-10), soluble TNF receptor 1 (sTNFR1, a surrogate marker for TNF-α) as measured by ELISA; development of shock; acute kidney injury; need for renal replacement therapy; clinical relapse, as defined by the need for readmission to the ICU or a marked decline in PaO2/FiO2 or development of shock or mortality following a period of sustained clinical improvement; secondary bacterial pneumonia as defined by the combination of radiographic findings and sputum/airway secretion microscopy and culture. Randomisation Following informed consent/assent patients will be randomised. The randomisation lists will be prepared by the study statistician and given to the unblinded trial personnel. However, the statistician will not be exposed to how the planned treatment will be allocated to the treatment codes. Randomisation will be conducted in a 1:1:1 ratio, stratified by site and age. Blinding (masking) The investigator, treating physician, other members of the site research team and patients will be blinded to treatment allocation. The clinical trial pharmacy personnel and research nurses will be unblinded to facilitate intervention and placebo preparation. The unblinded individuals will keep the treatment information confidential. The infusion bag will be masked at the time of preparation and will be administered via a masked infusion set to maintain blinding. Numbers to be randomised (sample size) A total of 36 patients will be recruited and randomised in a 1:1:1 ratio to each of the trial arms. Trial status In March 2020, version 1.0 of the trial protocol was submitted to the local research ethics committee (REC), Health Research Consent Declaration Committee (HRCDC) and the Health Products regulatory Authority (HPRA). REC approval was granted on April 1st 2020, HPRA approval was granted on April 24th 2020 and the HRCDC provided a conditional declaration on April 17th 2020. In July 2020 a substantial amendment (version 2.0) was submitted to the REC, HRCDC and HPRA. Protocol changes in this amendment included: the addition of trial sites; extending the duration of the trial to 12 months from 3 months; removal of inclusion criteria requiring the need for vasopressors; amendment of randomisation schedule to stratify by age only and not BMI and sex; correction of grammatical error in relation to infusion duration; to allow for inclusion of subjects who may have been enrolled in a clinical trial involving either antibiotics or anti-virals in the past 30 days; to allow for inclusion of subjects who may be currently enrolled in a clinical trial involving either antibiotics or anti-virals; to remove the need for exclusion based on alpha-1 antitrypsin phenotype; removal of mandatory isoelectric focusing of plasma to confirm Pi*MM status at screening; removal of need for mandatory echocardiogram at screening; amendment on procedures around plasma analysis to reflect that this will be conducted at the central site laboratory (as trial is multi-site and no longer single site); wording amended to reflect that interim analysis of cytokine levels taken at 7 days may be conducted. HRCDC approved version 2.0 on September 14th 2020, and HPRA approved on October 22nd 2020. REC approved the substantial amendment on November 23rd. In November 2020, version 3.0 of the trial protocol was submitted to the REC and HPRA. The rationale for this amendment was to allow for patients with moderate to severe ARDS from SARS-CoV-2 with non-invasive ventilation. HPRA approved this amendment on December 1st 2020 and the REC approved the amendment on December 8th 2020. Patient recruitment commenced in April 2020 and the last patient will be recruited to the trial in April 2021. The last visit of the last patient is anticipated to occur in April 2021. At time of writing, patient recruitment is now complete, however follow-up patient visits and data collection are ongoing. Trial registration EudraCT 2020-001391-15 (Registered 31 Mar 2020). Full protocol The full protocol (version 3.0 23.11.2020) is attached as an additional file accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Background Prescribing error represent a significant source of preventable harm to patients. Prescribing errors at discharge, including omission of pre-admission medications (PAM), are particularly harmful as they frequently propagate following discharge. This study assesses the impact of an educational intervention and introduction of an electronic patient record (EPR) in the same centre on omission of PAM at discharge using a pragmatic design. A survey of newly qualified doctors is used to contextualise findings. Methods Discharge prescriptions and discharge summaries were reviewed at discharge, and compared to admission medicine lists, using a paper-based chart system. Discrepancies were noted, using Health Information and Quality Authority guidelines for discharge prescribing. An educational intervention was conducted. Further review of discharge prescriptions and discharge summaries took place. Following introduction of an EPR, review of discharge summaries and discharge prescriptions was repeated. A survey was administered to recently qualified doctors (interns), and analysed using descriptive statistics and thematic analysis. Results Omission of PAM as prescribed or discontinued items at discharge occurs frequently. An educational intervention did not significantly change prescribing error rates (U = 1255.5, p = 0.206). EPR introduction did significantly reduce omission of PAM on discharge prescribing (U = 694, p p = 0.007). Survey results demonstrated that multiple sources are required to develop a discharge prescription. Time pressure, access to documentation and lack of admission medicine reconciliation are frequently cited causes of discharge prescribing error. Conclusion This study verified passive educational interventions alone do not improve discharge prescribing. Introduction of EPR improved discharge prescribing, but negatively impacted deliberate discontinuation of PAM at discharge. This is attributable to reduced access to key sources of information used in formulating discharge prescriptions, and separation of the discontinuation function from the prescribing function on the EPR discharge application.

Patients with severe coronavirus disease 2019 (COVID-19) develop a febrile pro-inflammatory cytokinemia with accelerated progression to acute respiratory distress syndrome (ARDS). Here we report the results of a phase 2, multicenter, randomized, double-blind, placebo-controlled trial of intravenous (IV) plasma-purified alpha-1 antitrypsin (AAT) for moderate to severe ARDS secondary to COVID-19 (EudraCT 2020-001391-15).Patients (n = 36) were randomized to receive weekly placebo, weekly AAT (Prolastin, Grifols, S.A.; 120 mg/kg), or AAT once followed by weekly placebo. The primary endpoint was the change in plasma interleukin (IL)-6 concentration at 1 week. In addition to assessing safety and tolerability, changes in plasma levels of IL-1β, IL-8, IL-10, and soluble tumor necrosis factor receptor 1 (sTNFR1) and clinical outcomes were assessed as secondary endpoints.Treatment with IV AAT resulted in decreased inflammation and was safe and well tolerated. The study met its primary endpoint, with decreased circulating IL-6 concentrations at 1 week in the treatment group. This was in contrast to the placebo group, where IL-6 was increased. Similarly, plasma sTNFR1 was substantially decreased in the treatment group while remaining unchanged in patients receiving placebo. IV AAT did not definitively reduce levels of IL-1β, IL-8, and IL-10. No difference in mortality or ventilator-free days was observed between groups, although a trend toward decreased time on ventilator was observed in AAT-treated patients.In patients with COVID-19 and moderate to severe ARDS, treatment with IV AAT was safe, feasible, and biochemically efficacious. The data support progression to a phase 3 trial and prompt further investigation of AAT as an anti-inflammatory therapeutic.ECSA-2020-009; Elaine Galwey Research Bursary.

This case series identified a sub cohort of healthcare workers with COVID-19 who experienced a prolonged symptomatic course and remained unable to return to work for many weeks. It notes their demographic and clinical characteristics and suggest ways to support them returning to work in a graded and supported manner.

Background: Chronic spontaneous urticaria is a common disorder that is poorly understood and frequently misdiagnosed. Psychological difficulties are a significant factor in dermatological diseases and may also aggravate symptom burden. Mind-body interventions are used as a complementary approach to alleviate symptoms in chronic diseases and may represent a valuable non-pharmacological approach in CSU.Methods: We sought to develop and evaluate the feasibility of an 8-week Attention-based Training (ABT) programme, coupled to biofeedback technology for CSU. Through convergent interviews, we gathered information from individuals with urticaria about possible links between stress, mood and skin symptoms. Using these data, we recruited 12 participants to engage in an amended ABT programme for patients with CSU, comprising eight ninety minute sessions held weekly. Participants completed psychometric measures and measures of urticaria symptomatology prior to and after the intervention. Adherence to ABT practice was measured using individual Inner Balance devices which tracked heart rate variability. We completed qualitative interviews after the intervention to obtain feedback on participant experience of the programme. Results: Participants with CSU described how their psychological wellbeing can be linked to skin symptoms, poor sleep and difficulty concentrating. An amended ABT programme was found to be an acceptable component of care in the management of CSU. Retention of participants in the programme was challenging with 33% participants dropping out of the programme. For those who did complete the programme, adherence to ABT practice was impressive with 25% of participants exceeding weekly practice at week 8. A statistically significant fall in severity of urticaria symptomatology was observed upon completion of the intervention (x = 12.3 SD 3.3, p < 0.03). The most commonly cited barrier to implementation of the programme was the time commitment required.Conclusions: An ABT programme can be integrated into clinical care for CSU patients and is valued by individuals who take part. Further formal evaluation of ABT for CSU including the analysis of biochemical parameters is required to determine its role in the management of this distressing condition.

The management of hypertension is suboptimal in Ireland and internationally. The role of a specialist hypertension clinic is not always defined but an analysis of the reasons for referral are likely informative. Also, a description of the clinical characteristics of patients with hypertension will inform requirements for comprehensive hypertension management in the community and secondary care. Patients were recruited at consecutive hypertension clinics at St James Hospital, Dublin from July to September 2019. Reasons for referral, clinical characteristics of patients, their investigations and treatment were analyzed. 236 patients were included in the study. The majority of patients, 83%, were obese or overweight. A family history of hypertension was a frequent finding with 70.8% of patients reporting same. 26.7% of patients were under the age of 40. 78% of referrals were from primary care and the most referrals were to investigate secondary causes of hypertension or because the patient was ≤40 years of age. Calcium channel blockers were the treatment most frequently prescribed (51.7%). Clinic blood pressure for the cohort was 137/81 mmHg and this was replicated by their ambulatory BP. This insight into the contemporary management of hypertension highlights the frequency of obesity and a positive family history in those with hypertension. Most referrals were consistent with international guidance though deviations were evident. Findings suggest a national program for hypertension with greater focus on public health interventions and better resourcing of primary care is required.

Objectives Peer-assisted learning (PAL) is a form of collaborative learning where members of a peer group act as teachers for each other. A reciprocal PAL program was designed to investigate whether there were differential gains in knowledge acquisition among tutors compared with tutees. Design Bayesian statistical analysis was used to quantitatively assess the effect of tutor status on performance in a knowledge-based examination. Subgroup analysis according to student achievement and question difficulty was performed. Participants and Setting Final year undergraduate medical students in a 5-year degree program ( n = 126). Results The overall probability of getting a correct answer on the knowledge examination was 49.7%. For questions on topics where a student had acted as a tutor this improved to 57.3%. However, students who performed in the upper quartile had a greater percentage gain in the probability of a correct answer in topics that they had taught vs students who performed in the lowest quartile. Conclusions There was demonstrable overall knowledge gain associated with acting as a tutor in a PAL program but the greatest gain occurred in students of highest academic ability.

A combined academic and clinical training programme for junior doctors in Ireland, the academic track for internship, has recently been launched. The academic track offers newly graduated doctors protected time within the working week to undertake a research project in addition to funding, an academic supervisor, and additional training in research skills. This study seeks to investigate the views of undergraduate medical students. The study population was undergraduate medical students at Trinity College Dublin in their penultimate year of study. An online questionnaire was designed and disseminated via a gatekeeper. Descriptive statistics were used to carry out data analysis on students’ responses. The response rate was 50/203 (24.6%). All respondents indicated that protected time would be ‘very important’ or ‘important’. The most frequently cited reason for participating in the academic track was ‘To progress my career in a particular specialty’ (28/42). The most frequently cited anticipated achievement was research publication (39/42). The most common response when asked what concerns (if any) students had about participating in the programme was ‘I am not sure I could achieve all the clinical competencies of an intern in addition to research’ (58%). There was a significant interest in the academic track for internship, and it is perceived by students as being of benefit to their careers. The value of protected time and an academic supervisor were recognised, and a research publication was the most frequently cited anticipated outcome. The data gathered in this questionnaire will help inform curriculum development and the identification of suitable learning outcomes.

Background This study sought to investigate the potential of a subinternship apprentice role as a structured experiential learning opportunity by enabling final-year medical students to learn through action rather than observation. Methods A convenience sample of 65 final-year medical students was allocated to " intern shadow " (control group) or " subintern " (research group) for 2 weeks during the first clinical attachment of their final year. " Intern shadow " involved direct observation of the intern role, whereas " subintern " involved a fully immersive performance of the intern role under direct supervision by the surgical team. All students completed an evaluation form that was devised in-house and based on course learning objectives. This consisted of Likert scales and free text. Results Wilcoxon rank sum test results showed that students participating in the " subintern " group had a statistically significantly better clinical experience than the " intern-shadow " group regarding role modeling (p = 0.0002), learning and teaching (p = 0.0021), organization and support (p = 0.0219), and patient interaction (p = 0.0063). Conclusion The " subintern " apprentice role shows strong potential for enabling final-year students to learn on the job by actually performing the intern role rather than merely observing an intern at work. Subinterns reported feeling valued within the team structure and expressed a desire to emulate expert practice directly experienced through close collaboration with consultant surgeons.

Unmet needs persist in pediatric HIV programs : lessons from selected case studies in Uganda

Background and Purpose Antiretroviral (ARV) drugs activate pregnane X receptors and constitutive androstane receptors, increasing the risk of drug interactions due to altered drug metabolism and disposition. The closely related liver X receptors (LXRα/β), oestrogen receptors (ERα/β) and glucocorticoid receptor (GR) regulate many endogenous processes such as lipid/cholesterol homeostasis, cellular differentiation and inflammation. However, ARV drug activation of these nuclear receptors has not been thoroughly investigated. Experimental Approach The ability of an ARV drug library to activate LXRα/β, ERα/β and GR was assessed using a combined in silico and in vitro approach encompassing computational docking and molecular descriptor filtering, cell-free time-resolved fluorescence resonance energy transfer co-activator assays to assess direct binding to ligand-binding domains (LBDs), cell-based reporter assays and target gene expression. Key Results Direct LBD interactions with LXRα and/or LXRβ were predicted in silico and confirmed in vitro for darunavir, efavirenz, flavopiridol, maraviroc and tipranavir. Likewise, efavirenz was also predicted and confirmed as a ligand of ERα-LBD. Interestingly, atazanavir and ritonavir also activated LXRα/β in reporter assays, while tipranavir enhanced transcriptional activity of ERα. Effects on ER and LXR target gene expression were confirmed for efavirenz and tipranavir. Conclusions and Implications There was good agreement between in silico predictions and in vitro results. However, some nuclear receptor interactions identified in vitro were probably due to allosteric effects or nuclear receptor cross-talk, rather than direct LBD binding. This study indicates that some of the adverse effects associated with ARV use may be mediated through ‘off-target’ effects involving nuclear receptor activation.

The inclusion of medical humanities with medical curricula is a question that has been the focus of attention for many within the evolving field. This study addressed the question from a medical education perspective and aimed to investigate what students at Trinity College Dublin learned from participating in a short medical humanities student-selected module in their first year of an undergraduate medical programme. A total of 156 students provided a written reflection on a memorable event that occurred during their student-selected module. The reflections were analysed using the Reflection Evaluation for Learners' Enhanced Competencies Tool (REFLECT) and through qualitative thematic analysis of the written reflections. Evidence of learning from the REFLECT quantitative analysis showed that 50% of students displayed higher levels of reflection when describing their experience. The reflection content analysis supported the heterogeneous nature of learning outcome for students, with evidence to support the idea that the module provided opportunities for students to explore their beliefs, ideas and feelings regarding a range of areas outside their current experience or world view, to consider the views of others that they may have not previously been aware of, to reflect on their current views, and to consider their future professional practice.

The role of statin therapy in heart failure (HF) is unclear. The amino-terminal propeptide of procollagen type III (PIIINP) predicts outcome in HF, and yet there are conflicting reports of statin therapy effects on PIIINP.This study determined whether there was an increase in serum markers of inflammation, fibrosis (including PIIINP), and B-type natriuretic peptide (BNP) in patients with systolic HF and normal total cholesterol and determined the effects of long-term treatment with atorvastatin on these markers.Fifty-six white patients with systolic HF and normal cholesterol levels (age 72 [13] years; 68% male; body mass index 27.0 [7.3] kg/m(2); ejection fraction 35 [13]%; 46% with history of smoking) were randomly allocated to atorvastatin treatment for 6 months, titrated to 40 mg/d (A group) or not (C group). Age- and/or sex-matched subjects without HF (N group) were also recruited. Biomarkers were measured at baseline (all groups) and 6 months (A and C groups).Serum markers of collagen turnover, inflammation, and BNP were significantly elevated in HF patients compared with normal participants (all P0.05). There were correlations between these markers in HF patients but not in normal subjects. Atorvastatin treatment for 6 months caused a significant reduction in the following biomarkers compared with baseline: BNP, from median (interquartile range) 268 (190-441) pg/mL to 185 (144-344) pg/mL; high-sensitivity C-reactive protein (hs-CRP), from 5.26 (1.95 -9.29) mg/L to 3.70 (2.34-6.81) mg/L; and PIIINP, from 4.65 (1.86) to 4.09 (1.25) pg/mL (all P0.05 baseline vs 6 months). Between-group differences were significant for PIIINP only (P = 0.027). There was a positive interaction between atorvastatin effects and baseline hs-CRP and PIIINP (P0.01).Long-term statin therapy reduced PIIINP in this small, selected HF population with elevated baseline levels. Further evaluation of statin therapy in the management of HF patients with elevated PIIINP is warranted.

BACKGROUND AND PURPOSE Interactions between protein phosphatase inhibition and matrix metalloproteinase (MMP)-9 expression have implications for tissue remodelling after injury. Stimulation of β-adrenoceptors could affect such interactions as isoprenaline increases protein phosphatase 2A (PP2A) activity and MMP-9 abundance. We investigated the effect of okadaic acid (OA) on MMP-9 expression to assess interactions between phosphatase inhibition and β-adrenoceptor signalling in fibroblasts. EXPERIMENTAL APPROACH Fibroblasts were exposed to OA alone and in combination with isoprenaline. Effects on MMP-9 expression and intracellular signalling were studied using promoter assays, Western blot analysis and siRNA methodologies. KEY RESULTS Okadaic acid increased MMP-9 abundance in human cardiac ventricular fibroblasts, NIH3T3 fibroblasts and hepatic stellate cells. This effect was unaffected by PP2A knockdown in NIH3T3 cells. OA increased phosphorylation of NF-κB, but not NF-κB promoter activity, IκBα degradation, or nuclear translocation of p65-NF-κB. Exposure to SB202190 (p38 MAPK), U0126 (ERK1/2) and NF-κB III inhibitor revealed that OA induced MMP-9 activity through p38 MAPK. Isoprenaline inhibited OA-mediated MMP-9 expression in NIH3T3, in a β-arrestin 2- and PP2A-dependent manner. Mutation of the activator protein-1 (AP-1) and NF-κB binding sites demonstrated that OA-induced MMP-9 activity was mediated through the AP-1 but not NF-κB sites. The latter mediated the inhibitory effect of isoprenaline on OA-induced MMP-9 promoter activity. CONCLUSION AND IMPLICATIONS Okadaic acid induced MMP-9 activity through p38 MAPK and was inhibited by isoprenaline via a pathway involving β-arrestin 2, PP2A and an NF-κB binding motif. These findings elucidate how phosphoprotein phosphatases and adrenoceptors may modulate tissue remodelling by affecting fibroblast function.

A significant proportion of medical students in Ireland have demonstrated strong intentions to migrate following their graduation. Factors influencing these intentions are poorly understood. Our study aimed to investigate ‘push’ and ‘stay’ factors that may influence the migration plans of medical students. Cross-sectional survey of 2273 medical students in Ireland using a mixed methods approach. Survey was completed by 2273 medical students, of which 263 provided free text data that are analysed in this paper. Identified push factors include negative perception regarding career opportunities, working conditions and lifestyle, while family was the only identified strong stay factor. Qualitative analysis of free text responses revealed themes that included training, career, personal and financial factors. This study has provided insight into the factors that influence medical student migration intentions. There is a strong need for all stakeholders to collectively discuss and engage in possible solutions.

Objectives:To validate and evaluate a short answer question paper and objective structured clinical examination. Validity and effect on overall performance were considered.Methods:Students completed a voluntary short answer question paper during their otolaryngology attachment. Short answer question paper results were collated and compared to the essay examination and new end of year objective structured clinical examination.Results:The study comprised 160 students. Questions were validated for internal consistency (Cronbach's alpha = 0.76). Correlations were determined for: short answer question paper and essay results (r = 0.477), short answer question paper and objective structured clinical examination results (r = 0.355), and objective structured clinical examination and essay results (r = 0.292). On unpaired t-tests comparing the short answer question paper group and non-short answer question paper group, essay results were 1.2 marks higher (p = 0.45) and the objective structured clinical examination results were 0.09 marks lower (p = 0.74) in the short answer question paper group.Conclusion:Two new valid summative assessments of student ability have been introduced, which contribute to an enhanced programme of assessment to drive student learning.

Background: To provide the optimum level of healthcare, it is important that the supply of well-trained doctors meets the demand. However, despite many initiatives, Ireland continues to have a shortfall of physicians, which has been projected to persist. Our study aimed to investigate the migration intentions of Irish medical students and identify the factors that influence their decisions in order to design appropriate interventions to sustain the supply of trained doctors in order to maintain a viable medical system. Methods: An online cross-sectional survey was undertaken of all Irish medical students studying in the Republic of Ireland. The survey included nominal, ordinal, and scale items to determine migration intentions, factors influencing their decisions, and understanding of the Irish healthcare system. Results: A total of 2 273 medical students responded (37% response rate), of whom 1 519 were classified as Irish medical students (having completed secondary school in Ireland). Of these, 88% indicated they were either definitely migrating or contemplating migrating following graduation or completion of the pre-registration intern year. Forty percent expressed an intention of returning to Ireland within 5 years. The factors most influencing their decision to leave were career opportunities (85%), working conditions (83%), and lifestyle (80%). Conclusion: The migration intentions expressed in this study predict an immediate and severe threat to the sustainability of the Irish healthcare service. Urgent interventions such as providing information about career options and specialty training pathways are required. These must begin in the undergraduate phase and continue in postgraduate training and are needed to retain medical school graduates.

OBJECTIVE To determine the effects of age and dual endothelin (ET)A/ETB receptor antagonism (bosentan) on aortic matrix metalloproteinase (MMP) abundance and tissue inhibitor of metalloproteinase (TIMP) expression in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). METHODS Male SHR and control WKY rats were randomly assigned to receive placebo or bosentan (100 mg/kg per day) for 3 months. Animals were killed under terminal anaesthesia at either 20 weeks (adult) or 17-20 months (senescent). Aortic gelatinase activity was determined by zymography, whereas MT-1 MMP and TIMP-1 expression were assessed by immunoblotting. RESULTS In WKY rats, aortic MMP-2 but not proMMP-2 activity was 3.6-fold higher (P < 0.02) in the senescent compared with the adult group. TIMP-1 (twofold) and MT-1 MMP (3.8-fold) expression increased (P < 0.05) with age in the WKY groups. Short-term hypertension (adult SHR versus adult WKY) increased MMP-2 to 74.7 +/- 14.1 from 18.9 +/- 3.5 arbitrary units (AU) (P = 0.0012), but did not alter proMMP-2 activity. This increased further on progression to chronic hypertension (117.4 +/- 12.2 versus 74.7 +/- 14.1 AU; P < 0.02). Bosentan decreased MMP-2 (78.9 +/- 3.8 versus 117.4 +/- 12.2 AU; P = 0.014) and proMMP-2 activity (P < 0.006) in the senescent SHR group. CONCLUSION Ageing and the development/progression of hypertension are associated with increased MMP-2 activity in the aorta, which is consistent with ongoing remodelling of the vasculature. However, the underlying mechanisms regulating MMP-2 abundance in ageing and hypertension appear to be divergent, as MT-1 MMP expression is differentially altered. Dual ETA/ETB receptor antagonism did not alter the age-dependent increase in aortic MMP activity in normotensive rats. However, bosentan decreased pro and active MMP-2 activity in senescent SHR rats, indicating that ET modulates late events in vascular remodelling in hypertension.

Aims St John's Wort (SJW) is widely used in the treatment of depression but concerns have been raised about its potential to interact with other drugs. Co-administration with SJW has resulted in significant reductions in trough plasma concentrations of indinavir and cyclosporin [1, 2]. Induction of cytochrome P450 3A4 (CYP3A4) has been implicated as the most likely interaction mechanism. However, the magnitude of the interaction seen in clinical practice is greater than that predicted by in vitro studies suggesting additional interaction mechanisms may exist. As indinavir and cyclosporin are substrates for both CYP3A4 and the multi drug transporter P-glycoprotein we hypothesized that modulation of P-glycoprotein expression and function by SJW may contribute to the development of potentially harmful drug–drug interactions.

Summary Background Traditionally, the formalised teaching of medical students has begun at senior trainee level, with teaching from junior trainees being very limited and informal. A pilot programme was set up in a large university teaching hospital for interns to provide structured bedside clinical teaching to final-year medical students as an adjunct to their formal teaching. Derived from the success of this, a similar programme was run the following year. Methods Feedback from the pilot programme and its successor was evaluated using a five-point Likert scale, and open illustrative comments were also collected. Results There was a highly positive response to the initial programme, with final-year students being very positive about participating as teachers the following year. Some proceeded to run the programme the following year, providing feedback to suggest improvements on the pilot programme. Discussion Junior trainees can organise and provide an additional option to traditional formal undergraduate clinical bedside teaching, which is well received by students. It also provides a forum through which trainees can hone teaching methods and improve clinical skills. A programme was set up for interns to provide structured bedside clinical teaching to final-year medical students

This is a study of three models of partnership between Trinity College Dublin and higher education institutes in six African countries. The goal is to deliver collaborative doctoral training programmes in global health, natural sciences and economics, to train researchers and build research and teaching capacity in African institutions, which is increasingly seen as a key influence on economic development. The purpose of this study was to assess the three models employed in order to understand their strengths and weaknesses, capture lessons from our partnerships and make recommendations to others establishing North-South doctoral training programmes. Findings from qualitative interviews revealed strengths, weaknesses, opportunities and threats for each model, and the specific strengths, challenges, recommendations and implications for future programme improvements are highlighted and discussed.

HIV-1 Tat exhibits clade-specific cytokine induction in monocytes. We investigated if Tat clades A-D can alter tumour necrosis factor (TNF)-α and interferon (IFN)-γ production by total and Vγ9Vδ2 T cells in vitro. Tat clade B, but not C, augmented TNF-α production by THP-1 cells. However, Tat clades A-D did not affect TNF-α or IFN-γ production or secretion by resting or activated conventional and Vγ9Vδ2 T cells. Therefore, transactivation of cytokines by Tat is immune cell-specific.

Summary Background A doctor performs 160 000–300 000 interviews during a lifetime career, thus making the medical interview the most common procedure in clinical medicine. It is reported that 60–80 per cent of diagnosis is based on history taking, yet there is little published data advising on the best method for medical students to initially attain and further refine these core skills during their medical degree. Methods Medical students interviewed two patients: using an open interview first, based on the Calgary–Cambridge approach, and then using a structured pro forma. The students' medical data were assessed by a senior lecturer, and their communication skills were assessed by a behavioural scientist and by the patients. Results An exact Wilcoxon paired signed rank test was conducted to determine whether there was a difference between the open interview and pro forma methods for history taking and communication skills. The test yielded p-values of 0.0017 and 0.069, respectively, with the pro forma method providing a statistically significantly higher history-taking score and communication score than the open interview method. Subjectively, patients reported the pro forma method as being preferable. Conclusion Medical students in the early years of training benefit from a structured history-taking pro forma to assist them gather an accurate data set without compromising their interpersonal and communication skills.

Educators seek to influence attitudes as well as enhance knowledge and skills. We wanted to know how a one week course on global health had altered the attitudes of the learners. We were aware that analysing group responses to Likert items using an interval approach has methodological flaws. All 126 third-year students at Trinity College Medical School were invited to complete an attitude survey before and after the course, with 18 Likert items. Changes in attitudes to each item were analysed by interval and ordinal methods. A total of 82 (65%) students completed both surveys and gave consent. There was a nine-fold difference in attitude change by individual students. Attitudes changed markedly in relation to some items and little to others. Analysing responses using an ordinal method revealed significant change regardless of whether responses to each item before the course were clustered at one end of the scale or were more neutral. The most sensitive and reliable analysis was an ordinal approach, presenting degrees of attitude change by individuals to each item. When presented by the change step method in a histogram important attitude change by individuals within the group is revealed, that the interval method conceals.

Background Matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs) are central to tissue remodelling during HIV–HCV infection. Here, we assess the potential for antiviral therapy to modulate MMP abundance in THP-1 monocyte/macrophages and LX-2 hepatic stellate cells, and in a coinfected patient cohort. Methods THP-1 and LX-2 cells were treated with ribavirin (RBV)/interferon-α (IFN-α) and select HIV antivirals. Venous blood was reserved from HIV–HCV-coinfected patients, HIV- and HCV-monoinfected patients, and healthy controls, with the HIV–HCV cohort being sampled again at day 3 and 14 subsequent to the start of combination therapy with RBV/pegylated IFN-α. Samples were subjected to gelatin zymography, real-time RT-PCR and/or ELISA, where appropriate. Results RBV/IFN-α decreased MMP-9 activity, and increased MMP-9 mRNA and protein expression in THP-1 cells, but not in LX-2 cells. Decreases in MMP-9 activity were mediated by IFN-α, which also attenuated RBV induction of MMP-9 activity and protein expression in THP-1 cells. Saquinavir and lopinavir, HIV protease inhibitors, reduced MMP-9 activity in THP-1 and LX-2 cells, respectively. Plasma MMP-9 activity and expression was higher in HIV–HCV and HIV patients compared with HCV patients and healthy controls. MMP-2 and TIMP-2 levels were similar in all groups. RBV/pegylated IFN-α decreased plasma MMP-9 abundance in HIV–HCV patients. Conclusions These data demonstrate that RBV/pegylated IFN-α reduce plasma MMP-9 abundance in vivo and may reduce its activity in vitro through immune cells, such as monocyte/macrophages, rather than hepatic stellate cells. The results of this study indicate that such therapy may mediate tissue remodelling associated with HIV–HCV coinfection through effects on MMP-9.

Background: Antiretroviral therapy including HIV protease inhibitors and nonnucleoside reverse transcriptase inhibitors can both inhibit and induce expression of cytochrome P450s, potentially leading to drug interactions. However, information is lacking on the impact of genetic polymorphism on this interaction. Methods: This study examines the prevalence of 33 polymorphisms in NR1I2 (pregnane X receptor [PXR]), CYP3A4, and CYP2B6 in 1013 white and sub-Saharan African patients with HIV; explores the inductive ability of 16 antiretrovirals on CYP3A4 and CYP2B6 promoter activity through nuclear receptors PXR and constitutive androstane receptor (CAR); and evaluates the influence of naturally occurring PXR genetic variants on antiretroviral activation. Results: Seventeen polymorphisms were present at different frequencies between the two ethnicities. Darunavir, fosamprenavir, lopinavir, nelfinavir, tipranavir, efavirenz, and abacavir increased CYP3A4 and/or CYP2B6 promoter activity, some through constitutive androstane receptor but mainly through PXR. Addition of low-dose ritonavir enhanced levels of CYP promoter activity for several protease inhibitors. Some PXR variants displayed lower fosamprenavir- and lopinavir-induced CYP3A4 promoter activity than the PXR reference sequence, whereas efavirenz and nelfinavir induction was unchanged. Conclusions: The presence of NR1I2 polymorphisms can alter the induction of CYP3A4 and CYP2B6 promoter activity, potentially adding to the unpredictable nature of antiretroviral drug interactions. These polymorphisms differ in prevalence between whites and sub-Saharan Africans.

The use of student-selected modules and the application of the medical humanities was recommended in the General Medical Council Tomorrow's Doctors 2003.1 Since then, increasing attention has been given to the inclusion of the arts and humanities into the medical education framework. It is intended that this would act as a complementary strand to the scientific approach in achieving the outcome of a ‘humane doctor’. Humanities as a group of disciplines develop the interpretive ability and insight of students by demonstrating the connectivity and relevance of art, literature and other disciplines to the practice of medicine and vice versa. In 2009–2010, the School of Medicine at Trinity College Dublin instituted a series of medical humanities modules to be undertaken in the first year of undergraduate study. These consisted of modules in traditional humanities such as philosophy in medicine, creative writing and literature in medicine. All students in the first year were required to select a module in which to participate. A list of modules with course descriptors enables the students to make their choice, and the modules are populated on a first come, first served basis, with students having selected their top three choices. In recognition of the fact that not all students would naturally gravitate towards the study of humanities, a climate was fostered in the classroom where ideas could be exchanged and challenged in a safe, non-threatening environment. The modules are student centred, where active learning is encouraged and numbers are limited to 12 per group. Each module is encouraged to include a relevant field trip. The strategy of integration of the humanities within a medical …

The primary purpose was to determine the prevalence of renal artery stenosis (RAS) in patients presenting with acute ("flash") pulmonary oedema (FPE), without identifiable cause using contrast-enhanced magnetic resonance angiography (CE-MRA) of renal arteries. A secondary goal was to correlate clinical parameters at presentation with the presence or absence of RAS.Patients presenting with acute pulmonary oedema without identifiable cause prospectively underwent CE-MRA.50% renal artery stenosis was considered significant. Clinical parameters (blood pressure, serum creatinine, history of hypertension/hyperlipidaemia) were compared in patients with and without RAS using an unpaired t-test. Results expressed; mean (+/-SD).20 patients (4 male, 16 female, age 78.5+/-11 years) underwent CE-MRA. 9 patients (45%) had significant RAS (6 (30%) bilateral, 3 (15%) unilateral). Systolic BP was higher in patients with RAS (192+/-38 mm Hg) than those without (134+/-30 mm Hg) (p.005). Diastolic BP was higher in patients with RAS (102+/-23 mm Hg) than those without (76+/-17 mm Hg) (p.01). All patients with RAS and 6/11(55%) patients without RAS had a history of hypertension. No significant difference in creatinine or hyperlipidaemia history was observed.The prevalence of RAS in patients presenting with FPE is 45%. The diagnosis should be considered in patients presenting with unexplained acute pulmonary oedema, particularly if hypertensive at presentation.

Associations between plasma cell dyscrasia and peripheral neuropathy were well recognized as early as the 1950s. In 1980, Bardwick coined the acronym POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes).We report a 56-year-old woman who presented with excessive sweating, lethargy, intermittent clawing of fingers and painful limb spasms for 2 years. Clinical examination showed hyperpigmented skin lesions, bilateral pleural effusions and organomegaly. Relevant investigations revealed the presence of sensorimotor polyneuropathy, raised cerebrospinal fluid protein, IgM monoclonal band on serum protein electrophoresis, and reactive bone marrow. The patient was treated with combination therapy which included cyclophosphamide, dexamethasone, and intravenous immunoglobulin with moderate response.Presence of cryoglobulinemia in this case has not been described in the literature.