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).
Phase 2, randomised, double-blind, placebo-controlled, pilot trial.
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 PaO
/FiO
ratio <200 mmHg), >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: 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.
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); PaO
/FiO
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 PaO
/FiO
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.
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.
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.
A total of 36 patients will be recruited and randomised in a 1:1:1 ratio to each of the trial arms.
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 1
2020, HPRA approval was granted on April 24
2020 and the HRCDC provided a conditional declaration on April 17
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 23
. 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.
EudraCT 2020-001391-15 (Registered 31 Mar 2020).
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).
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Seasonal calving, pasture-based dairy systems are widely practiced in countries with a temperate climate and plentiful rainfall such as Ireland and New Zealand. This approach maximizes milk ...production from pasture and, consequently, is a low-cost, low-input dairy production system. On the other hand, the majority of global milk supply is derived from high input indoor total mixed ration systems where seasonal calving is not practiced due to the dependence on ensiled silages, grains and concentrated feeds, which are available year-round. Synchronous changes in the macro and micronutrients in milk are much more noticeable as lactation progresses through early, mid and late stages in seasonal systems compared to non-seasonal systems-which can have implications on the processability and functionality of milk.
IntroductionChronic stable angina is common and disabling. Cardiac rehabilitation is routinely offered to people following myocardial infarction or revascularisation procedures and has the potential ...to help people with chronic stable angina. However, there is insufficient evidence of effectiveness and cost-effectiveness for its routine use in this patient group. The objectives of this study are to compare the effectiveness and cost-effectiveness of the ‘Activate Your Heart’ cardiac rehabilitation programme for people with chronic stable angina compared with usual care.Methods and analysisACTIVATE is a multicentre, parallel-group, two-arm, superiority, pragmatic randomised controlled trial, with recruitment from primary and secondary care centres in England and Wales and a target sample size of 518 (1:1 allocation; allocation sequence by minimisation programme with built-in random element). The study uses secure web-based allocation concealment. The two treatments will be optimal usual care (control) and optimal usual care plus the ‘Activate Your Heart’ web-based cardiac rehabilitation programme (intervention). Outcome assessment and statistical analysis will be performed blinded; participants will be unblinded. Outcomes will be measured at baseline and at 6 and 12 months’ follow-up. Primary outcome will be the UK version of Seattle Angina Questionnaire (SAQ-UK), physical limitations domain at 12 months’ follow-up. Secondary outcomes will be the remaining two domains of SAQ-UK, dyspnoea, anxiety and depression, health utility, self-efficacy, physical activity and the incremental shuttle walk test. All safety events will be recorded, and serious adverse events assessed to determine whether they are related to the intervention and expected. Concurrent economic evaluation will be cost–utility analysis from health service perspective. An embedded process evaluation will determine the mechanisms and processes that explain the implementation and impacts of the cardiac rehabilitation programme.Ethics and disseminationNorth of Scotland National Health Service Research Ethics Committee approval, reference 21/NS/0115. Participants will provide written informed consent. Results will be disseminated by peer-reviewed publication.Trial registration numberISRCTN10054455.
e13557 Background: Climate change has been acknowledged by the World Health Organisation (WHO) as a “fundamental threat” to healthcare delivery. However, healthcare now accounts for more than 5% of ...global emissions. Over 25% of the oncology services contribution to this relates to the development, transport and administration of systemic anticancer therapies (SACT), and represents a modifiable factor. In Ireland, the National Cancer Control Programme (NCCP) determines the standard of care systemic anticancer therapy (SACT) protocols. This study proposes to review existing protocols and assess for and highlight nationally implementable climate toxicity mitigation strategies. Methods: NCCP SACT protocols (available at https://www.hse.ie/eng/services/list/5/cancer/profinfo/chemoprotocols/) were reviewed for impact reduction potential under the following headings: 1) Baseline and regular tests and investigations; 2) Pre-medications; 3) De-escalation, and 4) ESMO Magnitude of Clinical Benefit. Results: A total of N = 333 protocols were reviewed. N = 32 protocols had multiple indications across more than one tumour stream. Overall, N = 702 opportunities were identified where the protocol impact could be reduced, either by consolidation of pre-medication and pre-hydration to oral administration, regimen or investigation de-escalation, dose banding, switching non-oral to equivalent oral SACT alternative or re-considering regimen use where clinical benefit is measured as non-substantial. In addition, there were a further N = 507 opportunities identified where baseline and regular investigations required by the protocol could be incorporated into routine visits, minimising hospital travel and time toxicity to patients. Conclusions: This study considered just one aspect of oncology care in Ireland, the delivery of SACT, and identified over 1200 opportunities across standardised national protocols where associated climate toxicity could be reduced without compromising standard of care. A sustainability matrix to promote identified action points is proposed for inclusion within all protocols and could be used in other jurisdictions. Further work to consider impact reduction opportunities in other areas of cancer care, including radiology and diagnostics should be considered.
TPS615 Background: Predictive biomarkers of response to combination chemotherapy and immune-checkpoint inhibitors are urgently needed to tailor treatment recommendations for patients with early-stage ...triple negative breast cancer (eTNBC). Our group has demonstrated that tumour-associated microbiota in primary breast tumours represent promising and novel candidate biomarkers for patients with breast cancer. We aim to prospectively interrogate the breast cancer microbiome and tumour microenvironment (TME) of eTNBC treated with neoadjuvant chemo-immunotherapy, and correlate with clinical outcome. Methods: Trial design: This prospective translational biomarker study is enrolling patients with eTNBC suitable for standard neoadjuvant systemic therapy followed by definitive surgery. The primary objective is to evaluate the change in breast cancer microbiome composition pre- and post-therapy. Secondary objectives include correlation of the breast microbiome with pathologic complete response (pCR) and survival outcomes, tumor infiltrating lymphocytes (TILs), PDL-1 and immune subset analysis, extracellular vesicles analysis and analysis of gut microbiome. Tumor tissue samples will be collected at baseline (mandatory research biopsy) and at the time of surgery. Microbiome evaluation will be conducted using metagenomic sequencing to assess changes in the relative abundance of microbial taxa. Blood and stool samples will be collected and analysed at baseline, on-treatment, at the time of surgery and post-operatively for secondary endpoints. Statistical analysis: Hierarchical clustering of samples based on relative abundance of the operational taxonomic units (OTUs) with sample composition at family and genus level will be performed. Alpha Diversity (Shannon Diversity Index) and Beta Diversity (Jaccard Similarity Index) will be analysed. Principal component analysis (PCA) and Random Forest analysis will be performed for classification and clustering analysis. Comparison of taxa or functions between clinical cohorts will be performed (two tailed Z test) and corrected using the false discovery rate to determine Q-values. Thirty patients will be recruited over 18-24 months. Current status: This University College Cork sponsored trial received ethics approval from the CREC in January 2024 and recruitment is ongoing. Those interested can contact uccctg@ucc.ie. This trial will provide a deeper insight into the potential role of the local breast microbiome as a predictive biomarker for response to neoadjuvant therapy in patients with eTNBC. The results will guide further studies exploring optimal immunomodulatory combinations for the treatment of TNBC and may provide evidence regarding future therapeutic targeting of the breast cancer microbiome.
In pasture-based dairy production systems, identifying the appropriate stocking rate (SR; cows/ha) based on the farm grass growth is a key strategic decision for driving the overall farm business. ...This paper investigates a number of scenarios examining the effects of SR (2–3 cows/ha (0.25 unit changes)), annual nitrogen (N) fertilizer application rates (0–300 kg N/ha (50 kg/ha unit changes)), soil type (heavy and a free-draining soil) and agroclimate location ((south and northeast of Ireland) across 16 years) on pasture growth and forage self-sufficiency using the pasture-based herd dynamic milk model merged with the Moorepark St Gilles grass growth model. The modelled outputs were grass growth, grass dry matter intake, silage harvested and offered, overall farm forage self-sufficiency and N surplus. The model outputs calculated that annual grass yield increased from 9436 kg DM/ha/year when 0 kg N/ha/year was applied to 14 996 kg DM/ha/year when 300 kg N/ha/year were applied, with an average N response of 18.4 kg DM/kg N applied (range of 9.9–27.7 kg DM/kg N applied). Systems stocked at 2.5 cows/ha and applying 250–300 kg N fertilizer/ha/year were self-sufficient for forage. As N input was reduced from 250 kg N/ha/year, farm forage self-sufficiency declined, as did farm N surplus. The results showed that a reduction in N fertilizer application of 50 kg/ha/year will require a reduction in an SR of 0.18 cows/ha to maintain self-sufficiency (R2 = 0.90).
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.
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.
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%).
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.
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Management of chronic diseases requires patients to adhere to recommended health behavior change and complete tests for monitoring. While studies have shown an association between low income and lack ...of adherence, the reasons why people with low income may be less likely to adhere are unclear. We sought to determine the association between household income and receipt of health behavior change advice, adherence to advice, receipt of recommended monitoring tests, and self-reported reasons for non-adherence/non-receipt.
We conducted a population-weighted survey, with 1849 respondents with cardiovascular-related chronic diseases (heart disease, hypertension, diabetes, stroke) from Western Canada (n = 1849). We used log-binomial regression to examine the association between household income and the outcome variables of interest: receipt of advice for and adherence to health behavior change (sodium reduction, dietary improvement, increased physical activity, smoking cessation, weight loss), reasons for non-adherence, receipt of recommended monitoring tests (cholesterol, blood glucose, blood pressure), and reasons for non-receipt of tests.
Behavior change advice was received equally by both low and high income respondents. Low income respondents were more likely than those with high income to not adhere to recommendations regarding smoking cessation (adjusted prevalence rate ratio (PRR): 1.55, 95%CI: 1.09-2.20), and more likely to not receive measurements of blood cholesterol (PRR: 1.72, 95%CI 1.24-2.40) or glucose (PRR: 1.80, 95%CI: 1.26-2.58). Those with low income were less likely to state that non-adherence/non-receipt was due to personal choice, and more likely to state that it was due to an extrinsic factor, such as cost or lack of accessibility.
There are important income-related differences in the patterns of health behavior change and disease monitoring, as well as reasons for non-adherence or non-receipt. Among those with low income, adherence to health behavior change and monitoring may be improved by addressing modifiable barriers such as cost and access.
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This study evaluated the effects of 3 widely practiced cow feeding systems in the United States, Europe, and Southern Hemisphere regions on the characteristics, quality, and consumer perception of ...sweet cream butter. Fifty-four multiparous and primiparous Friesian cows were divided into 3 groups (n=18) for an entire lactation. Group 1 was housed indoors and fed a total mixed ration diet (TMR) of grass silage, maize silage, and concentrates; group 2 was maintained outdoors on perennial ryegrass-only pasture (GRS); and group 3 was maintained outdoors on a perennial ryegrass/white clover pasture (CLV). Mid-lactation butter was manufactured in triplicate with milk from each group in June 2015 (137±7d in milk) and was analyzed over a 6-mo storage period at 5°C for textural and thermal properties, fatty acid composition, sensory properties, and volatile compounds. The nutritional value of butters was improved by pasture feeding, and butter from pasture-fed cows had significantly lower thrombogenicity index scores compared with butters from TMR-fed cows. In line with these results, pasture-derived milks (GRS and CLV) produced butter with significantly higher concentrations of conjugated linoleic acid (cis-9,trans-11) and trans-β-carotene than TMR butter. Alterations in the fatty acid composition of butter contributed to significant differences in textural and thermal properties of the butters. Total mixed ration–derived butters had significantly higher hardness scores at room temperature than those of GRS and CLV. Onset of crystallization for TMR butters also occurred at significantly higher temperatures compared with pasture butters. Volatile analysis of butter by gas chromatography-mass spectrometry identified 25 compounds present in each of the butters, 5 of which differed significantly based on feeding system, including acetone, 2-butanone, 1-pentenol, toluene, and β-pinene. Toluene was very significantly correlated with pasture-derived butter. Sensory analysis revealed significantly higher scores for GRS-derived butter in several attributes including “liking” of appearance, flavor, and color over those of TMR butter. Partial least square regression plots of fatty acid profiles showed clear separation of butter derived from grazed pasture-based perennial ryegrass or perennial rye/white clover diets from that of a TMR system, offering further insight into the ability of fatty acid profiling to verify such pasture-derived dairy products.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To estimate the risk of work loss due to illness or disability in a cohort of employed persons with OA compared with matched non-OA individuals.
We performed a population-based cohort analysis using ...the last six cycles of the Canadian longitudinal National Population Health Survey from 2000 to 2010. OA cases and up to four age- and sex-matched non-OA individuals were selected. Discrete time hazard regression models were used to estimate the hazard of work loss due to illness or disability. To analyse the effect of a self-reported OA measure on the outcome, we performed a sensitivity analyses for case selection.
From 7273 employed individuals between the ages of 20 and 70 years in the National Population Health Survey, 659 OA cases were selected and matched to 2144 non-OA individuals. The proportion of OA cases who experienced work loss due to illness or disability during the follow-up period was 12.6%, compared with 9.3% for non-OA individuals (P < 0.001). OA cases had a 90% hazard ratio (HR) 1.90 (95% CI 1.36, 3.23) higher hazard of work loss due to illness or disability compared with their matched non-OA individuals after adjusting for sociodemographic, health and work-related status. The adjusted HRs were 1.61 (95% CI 1.13, 2.30) and 2.04 (95% CI 1.74, 4.75) for females and males, respectively.
OA is independently associated with an increased risk of work loss due to illness or disability. Given the high prevalence of OA in the population of working age, future research may wish to investigate ways to improve occupational participation among OA patients.
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