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Abstract Background Clinical research nurses are a key part of the clinical trial team but typically get involved later in the trial, usually during recruitment. The purpose of our study was to establish if CRNs who read the trial protocol can predict the performance of the trial. Methods We randomly selected 18 trial protocols with three statuses, terminated, withdrawn, and completed, from ClinicalTrials.gov, between 2014 and 2018 inclusive. We gave the protocols to five CRNs, asked them to make a judgement and provide a reason for that judgement (via a 12-item questionnaire) on the status of the trial (terminated, withdrawn or completed), if the trial met its recruitment target, if it recruited on time, and if it retained its participants. We also asked if it was likely a CRN was involved in the design of the trial. The CRNs were blinded to the study outcomes, did not receive any training on how to read a protocol and were prohibited from using/abstained from using the internet while completing the task. Results Twenty-three questionnaires on 23 trial protocols (18 different trials) were completed by 5 CRNs. The CRNs correctly predicted the trial status 48%, 95% CI: 29–67% (11/23) of the time; successful/unsuccessful recruitment 74%, 95% CI: 54–87% (17/23) of the time; on-time recruitment 70%, 95% CI: 49–84% (16/23) of the time; and participant retention 52%, 95% CI: 33–71% (12/23). CRNs identified 100% (sensitivity) of sites that hit their target and 63%, 95% CI: 36–84% (specificity) of sites that missed their target. Conclusions CRNs are very good judges of trial recruitment and site performance issues and are a vital part of the clinical trial team. Taken with the ESP (Estimating Site Performance) study, we have made a strong case for broadening the trial team at the trial design stage. Early engagement of a broad skillset can potentially offset problems of recruitment, retention and trial failure.

Abstract Background Intestinal dysbiosis is implicated in the origins of necrotising enterocolitis and late-onset sepsis in preterm babies. However, the effect of modulators of bacterial growth (e.g. antibiotics) upon the developing microbiome is not well-characterised. In this prospectively-recruited, retrospectively-classified, case–control study, high-throughput 16S rRNA gene sequencing was combined with contemporaneous clinical data collection, to assess the within-subject relationship between antibiotic administration and microbiome development, in comparison to preterm infants with minimal antibiotic exposure. Results During courses of antibiotics, diversity progression fell in comparison to that seen outside periods of antibiotic use (-0.71units/week vs. + 0.63units/week, p

Abstract Background Public awareness of the carcinogenic effects of alcohol is low, particularly the association between alcohol use and the risk of developing breast cancer. Breast cancer is the third most common cancer in Ireland and alcohol use remains high. This study examined factors related to awareness of the association between alcohol use and breast cancer risk. Methods Using data from Wave 2 of the national Healthy Ireland Survey, a representative sample of 7,498 Irish adults aged 15 + years, descriptive and logistic regression analyses were conducted to investigate relationships between demographic characteristics, type of drinker and awareness of breast cancer risk. Results A low level of awareness of the risk of alcohol use (drinking more than the recommended low–risk limit) associated with breast cancer was found, with just 21% of respondents correctly identifying the relationship. Multivariable regression analyses found that factors most strongly associated with awareness were sex (female), middle age (45—54 years) and higher educational levels. Conclusion As breast cancer is a prevalent disease among women in Ireland, it is essential that the public, in particular women who drink, are made aware of this association. Public health messages that highlight the health risks associated with alcohol use, and which target individuals with lower educational levels, are warranted.

Abstract Background We investigated whether question format and access to the correct answers affect the pass mark set by standard-setters on written examinations. Methods Trained educators used the Angoff method to standard set two 50-item tests with identical vignettes, one in a single best answer question (SBAQ) format (with five answer options) and the other in a very short answer question (VSAQ) format (requiring free text responses). Half the participants had access to the correct answers and half did not. The data for each group were analysed to determine if the question format or having access to the answers affected the pass mark set. Results A lower pass mark was set for the VSAQ test than the SBAQ test by the standard setters who had access to the answers (median difference of 13.85 percentage points, Z = -2.82, p = 0.002). Comparable pass marks were set for the SBAQ test by standard setters with and without access to the correct answers (60.65% and 60.90% respectively). A lower pass mark was set for the VSAQ test when participants had access to the correct answers (difference in medians -13.75 percentage points, Z = 2.46, p = 0.014). Conclusions When given access to the potential correct answers, standard setters appear to appreciate the increased difficulty of VSAQs compared to SBAQs.

Background: Adverse childhood experiences (ACE) have been associated with poor later life health outcomes, including cardiovascular disease (CVD). Limited research investigating potential underlying biological mechanisms linking ACE to CVD exists, particularly regarding lipid biomarkers. Objectives: The aim of this study was to examine the associations between childhood adversity and unfavourable lipid profiles and derived atherogenic risk indices in a middle-to-older aged population. Methods: This cross-sectional study includes 1820 participants from the Mitchelstown cohort (49% male) in Ireland. Participants' self-reported history of childhood adversity (overall and by subtypes household dysfunction, abuse and neglect) were assessed through a validated 10-item ACE questionnaire. Lipid profiles were determined and atherogenic risk indices including Castelli's Risk Index 1 and 2 (CRI-I and CRI-II), Atherogenic Coefficient (AC) and Atherogenic Index Plasma (AIP) were generated. Logistic regression analysed ACE associations with unfavourable lipid outcomes, controlling for potential confounders. Results: ACE history (reported by 23% of sample), in particular childhood exposure to household dysfunction, was associated with later-life non-optimal TG and HDL-C concentrations and atherogenic risk indices CRI-II and AC in age and sex-adjusted models (all p

Background: The Cork and Kerry Diabetes and Heart Disease Study was established to investigate the prevalence of diabetes and cardiovascular disease among middle-aged adults in Ireland. The Mitchelstown cohort was recruited from a single large primary care centre between 2010–2011. A rescreen of this cohort was conducted in 2015. Methods: Data were collected on cardiovascular health and associated risk factors. In addition, the rescreen incorporated new measures which included information on cognition and frailty, medication adherence, dietary factors and the collection of stool samples with RNA sequencing of the gut microbiome. Results: Of 2047 participants in the original cohort, 237 (11.6%) were deceased, too ill to participate or were lost to follow-up. Of the remaining 1810 baseline study participants, 1378 men and women aged 51–77 years agreed to take part in the rescreen (response rate of 76.1%). The prevalence of hypertension was high, ranging from 50% to 64% depending on the measurement method. An investigation of the association of gut microbiota with metabolic syndrome and obesity indicated greater microbiome diversity in metabolically healthy non-obese individuals relative to their unhealthy counterparts. Analysis of prescribing data over time demonstrated a high prevalence of potentially inappropriate prescribing among older-aged people in primary care which increased as they progressed to more advanced old age. Conclusions: The rescreen has provided new insights into cardiovascular health. In addition, this study is embedded in a single primary care centre, enabling passive follow-up of study participants through electronic health records. All data collected at baseline and rescreen are maintained and stored at the School of Public Health, University College Cork and specific proposals for future collaborations are welcome.

Background: Estimates of ‘brain-predicted age’ quantify apparent brain age compared to normative trajectories of neuroimaging features. The brain age gap (BAG) between predicted and chronological age is elevated in symptomatic Alzheimer disease (AD) but has not been well explored in presymptomatic AD. Prior studies have typically modeled BAG with structural MRI, but more recently other modalities, including functional connectivity (FC) and multimodal MRI, have been explored. Methods: We trained three models to predict age from FC, structural (S), or multimodal MRI (S+FC) in 390 amyloid-negative cognitively normal (CN/A−) participants (18–89 years old). In independent samples of 144 CN/A−, 154 CN/A+, and 154 cognitively impaired (CI; CDR > 0) participants, we tested relationships between BAG and AD biomarkers of amyloid and tau, as well as a global cognitive composite. Results: All models predicted age in the control training set, with the multimodal model outperforming the unimodal models. All three BAG estimates were significantly elevated in CI compared to controls. FC-BAG was significantly reduced in CN/A+ participants compared to CN/A−. In CI participants only, elevated S-BAG and S+FC BAG were associated with more advanced AD pathology and lower cognitive performance. Conclusions: Both FC-BAG and S-BAG are elevated in CI participants. However, FC and structural MRI also capture complementary signals. Specifically, FC-BAG may capture a unique biphasic response to presymptomatic AD pathology, while S-BAG may capture pathological progression and cognitive decline in the symptomatic stage. A multimodal age-prediction model improves sensitivity to healthy age differences. Funding: This work was supported by the National Institutes of Health (P01-AG026276, P01- AG03991, P30-AG066444, 5-R01-AG052550, 5-R01-AG057680, 1-R01-AG067505, 1S10RR022984-01A1, and U19-AG032438), the BrightFocus Foundation (A2022014F), and the Alzheimer’s Association (SG-20-690363-DIAN).

Abstract Introduction Health disparities arise from biological‐environmental interactions. Neuroimaging cohorts are reaching sufficiently large sample sizes such that analyses could evaluate how the environment affects the brain. We present a practical guide for applying geospatial methods to a neuroimaging cohort. Methods We estimated brain age gap (BAG) from structural magnetic resonance imaging (MRI) from 239 city‐dwelling participants in St. Louis, Missouri. We compared these participants to population‐level estimates from the American Community Survey (ACS). We used geospatial analysis to identify neighborhoods associated with patterns of altered brain structure. We also evaluated the relationship between Area Deprivation Index (ADI) and BAG. Results We identify areas in St. Louis, Missouri that were significantly associated with higher BAG from a spatially representative cohort. We provide replication code. Conclusion We observe a relationship between neighborhoods and brain health, which suggests that neighborhood‐based interventions could be appropriate. We encourage other studies to geocode participant information to evaluate biological‐environmental interaction.

“Brain-predicted age” quantifies apparent brain age compared to normative neuroimaging trajectories. Advanced brain-predicted age has been well established in symptomatic Alzheimer disease (AD), but is underexplored in preclinical AD. Prior brain-predicted age studies have typically used structural MRI, but resting-state functional connectivity (FC) remains underexplored. Our model predicted age from FC in 391 cognitively normal, amyloid-negative controls (ages 18–89). We applied the trained model to 145 amyloid-negative, 151 preclinical AD, and 156 symptomatic AD participants to test group differences. The model accurately predicted age in the training set. FC-predicted brain age gaps (FC-BAG) were significantly older in symptomatic AD and significantly younger in preclinical AD compared to controls. There was minimal correspondence between networks predictive of age and AD. Elevated FC-BAG may reflect network disruption during symptomatic AD. Reduced FC-BAG in preclinical AD was opposite to the expected direction, and may reflect a biphasic response to preclinical AD pathology or may be driven by inconsistency between age-related vs. AD-related networks. Overall, FC-predicted brain age may be a sensitive AD biomarker.

Abstract Background From a secondary prevention perspective, it is useful to know who is at greatest risk of progressing from substance initiation to riskier patterns of future use. Therefore, the aim of this study was to determine relationships between age at first use of alcohol, tobacco and cannabis and patterns of cannabis use, frequency of use and whether age of substance use onset is related to having a cannabis use disorder (CUD). Methods We analysed data from Ireland’s 2010/11 and 2014/15 National Drug Prevalence Surveys, which recruited 5134 and 7005 individuals respectively, aged 15 years and over, living in private households. We included only those people who reported lifetime cannabis use. Multinomial, linear and binary logistic regression analyses were used to determine relationships between age of substance use onset and patterns of cannabis use, frequency of use and having a CUD. Results When compared to former users, the odds of being a current cannabis user were found to be reduced by 11% (OR = 0.89; 95% CI: 0.83, 0.95) and 4% (OR = 0.96; 95% CI: 0.92, 1.00) for each year of delayed alcohol and cannabis use onset, respectively. Among current users, significant inverse linear relationships were noted, with increasing age of first use of tobacco (β = − 0.547; P

The infant immune system is continuously shaped by environmental factors. Here the authors demonstrate that rapid immune development in preterm babies is modulated by perinatal inflammation more than gut microbiota, and that lower CXCL8-producing T cells may identify infants susceptible to infection.

Abstract Background According to the prevention paradox, the majority of alcohol-related harms in the population occur among low-to-moderate risk drinkers, simply because they are more numerous in the population, although high-risk drinkers have a higher individual risk of experiencing alcohol-related harms. In this study we explored the prevention paradox in the Irish population by comparing alcohol-dependent drinkers (high-risk) to low-risk drinkers and non-dependent drinkers who engage in heavy episodic drinking (HED). Methods Data were generated from the 2013 National Alcohol Diary Survey (NADS), a nationally representative cross-sectional survey of Irish adults aged 18–75. Data were available for 4338 drinkers. Respondents dependent on alcohol (as measured by DSM-IV criteria), respondents who engaged in monthly HED or occasional HED (1–11 times a year) and low-risk drinkers were compared for distribution of eight alcohol-related harms. Results Respondents who were dependent on alcohol had a greater individual risk of experiencing each harm (p

Background and objectivesEpidemiological studies show that the use of cannabis is related to the use of other illicit drugs, including stimulants such as cocaine and ecstasy. However, few studies have examined how patterns of cannabis use relate to the use of stimulants. In this research we determined relationships between patterns of cannabis use and recent stimulant use, drawing on data from two large nationally representative surveys. We also explored how frequency of cannabis use relates to stimulant use and whether subjects with a cannabis use disorder (CUD)-defined as cannabis abuse or dependence-are more likely to be recent users of cocaine or ecstasy.Materials and methodsWe analysed data from Ireland's 2010/11 and 2014/15 National Drug Prevalence Surveys,which recruited 5,134 and 7,005 individuals respectively, aged 15 years and over, living in private households. We included only those people who reported some past cannabis use. Multivariable logistic regression analysis was used to examine associations between patterns of cannabis use and recent stimulant use.ResultsAmong survey participants who had used cannabis in the last month, 17.9% reported recent cocaine use, while almost one-quarter (23.6%) reported recent ecstasy use. There was a significant linear relationship between patterns of cannabis use and recent use of cocaine, ecstasy or any stimulant, with last month cannabis users displaying greater odds (OR = 12.03, 95% CI: 8.15-17.78) of having recent stimulant use compared to last year (OR = 4.48, 95% CI: 2.91-6.91) and former (reference) cannabis users. Greater frequency of cannabis use in the last 30 days was also significantly related to the use of stimulants. In addition, results demonstrated an association between CUD and recent use of cocaine or ecstasy (OR = 2.28, 95% CI: 1.55-3.35).ConclusionsFindings from this study suggest a relationship between patterns and frequency of cannabis use and recent use of stimulants and an association between CUD and stimulant use. As the use of cannabis with stimulants may increase the risk of negative health consequences, education in community and medical settings about polydrug use and its increased risks may be warranted.

Background and objectivesType 2 diabetes is a leading cause of death and disability worldwide and pre-diabetes is a strong predictor of diabetes development. To date, studies estimating the prevalence of pre-diabetes in the Irish population are sparse and conflicting. Monitoring the prevalence of pre-diabetes and a knowledge of associated factors is required to inform policies and to prevent development of type 2 diabetes. Therefore, this research examined the prevalence and correlates of pre-diabetes in a sample of middle- to older-aged Irish adults using three different methods for diagnosis.Materials and methodsThe Mitchelstown Cohort Rescreen (2016/17) was a follow-up, cross-sectional study of the Mitchelstown Cohort Study (2010/11). 1,378 participants were recruited from a random sample of patients attending a single primary care centre. Pre-diabetes was defined using three diagnostic criteria: American Diabetes Association (ADA) glycated haemoglobin A1c (HbA1c) cut-offs between 5.7%-6.4% (39-46 mmol/mol), World Health Organization International Expert Committee (WHO-IEC) HbA1c cut-offs between 6.0%-6.4% (42-46 mmol/mol) and ADA fasting plasma glucose (FPG) cut-offs between 5.6-6.9 mmol/l. Univariate and multivariable logistic regression analyses were used to determine factors associated with pre-diabetes.ResultsThe prevalence of pre-diabetes was found to be 43.9% (95% CI: 41.2%─46.5%), 14.5% (95% CI: 12.7%─16.5%) and 15.8% (95% CI: 13.9%─17.8%) according to HbA1c ADA, HbA1c WHO-IEC and FPG ADA definitions, respectively. Depending on diagnostic method, factors associated with pre-diabetes in univariate analyses included sex, age, marital status, health rating, education and poor diet quality. In multivariable analysis, subjects classified by the FPG ADA pre-diabetes criterion displayed the least optimal metabolic profile defined by overweight and obesity (OR = 2.88, 95% CI: 1.53-5.43), hypertension (OR = 2.27, 95% CI: 1.51-3.40) and low high-density lipoprotein cholesterol concentrations (OR = 1.75, 95% CI: 1.07-2.87).ConclusionsThe discordance between prevalence estimates according to method of diagnosis is concerning. A National Diabetes Prevention Programme is currently being developed in Ireland. Monitoring the prevalence of pre-diabetes over time will be important to assess the effectiveness of this programme. This study will inform national decision-makers on which definition of pre-diabetes to use for monitoring purposes.

Background: The prevalence of overweight and obesity among children may have reached a plateau in some developed countries, including Ireland. The aim of this study was to examine 12-year trends in the prevalence of overweight and obesity among primary-school-aged children in the Republic of Ireland between 2002 and 2014. Methods: Two large-scale oral health cross-sectional surveys of primary-school-aged children aged 4–13 years were conducted 12 years apart in 2002 (n=14,055; response rate=68%) and 2014 (n=5,223; response rate=67%). Both surveys included standardised and calibrated height and weight measures. Ownership of a means-tested medical card determined economic status. Standard International Obesity Task Force criteria were applied to determine the prevalence of overweight and obesity. Results: The overall prevalence of overweight/obesity among 4–13-year-olds significantly decreased from 26% (95% CI: 25.1%–26.5%) in 2002 to 24% (95% CI: 22.4%–24.7%) in 2014. Among boys and girls aged 4–13 years, the significant decrease was from 23% (95% CI: 22.1%–24.1%) to 20% (95% CI: 18.9%–22.0 and 28% (95% CI: 27.4%–29.5%) to 27% (95% CI: 25.0%–28.4%), respectively. Among 5-year-old children, the overall prevalence of overweight and obesity significantly decreased from 25% (95% CI: 23.7%–26.2%) to 22% (95% CI: 19.9%–23.4%). In 2002, the estimated prevalence of overweight/obesity was similar in children with and without medical cards, whereas in 2014, overall prevalence was higher in those with medical cards. Conclusions: Results suggest a fall in the prevalence of overweight/obesity between 2002 and 2014, and may suggest a favourable cohort effect. Despite this fall, the overall prevalence remains high and socioeconomic disparities have increased.

Objectives Ireland has high per capita alcohol consumption and also has high levels of problematic drinking patterns. While it is accepted that patterns of alcohol consumption in Ireland are a cause for concern, it is not clear if Irish people are actually aware of the extent of their hazardous or harmful pattern of drinking. The aim of this study was to determine awareness of drinking pattern in an Irish population using a representative random sample and to identify characteristics associated with self-awareness of hazardous or harmful drinking.Methods We analysed data from Ireland’s 2014/2015 Drug Prevalence Survey which recruited a stratified clustered sample of 7005 individuals aged 15 years and over living in private households. Logistic regression analysis was used to determine characteristics associated with self-awareness of hazardous or harmful drinking.Results Almost one half of drinkers had a hazardous or harmful pattern of drinking; 38% engaged in monthly risky single occasion drinking (RSOD) and 10.5% met Diagnostic and Statistical Manual version IV (DSM-IV) criteria for alcohol dependence. Of the 2420 respondents who had a hazardous or harmful pattern of drinking, 67% were unaware of this and misclassified themselves as being either a light or moderate drinker who did not engage in RSOD. An adjusted logistic regression model identified that hazardous and harmful drinkers were more likely to be aware of their drinking pattern if they had completed third level education (OR=1.80, 95% CI: 1.30 to 2.49) while older drinkers (aged 65 and over) were less likely to be aware of their drinking pattern (OR=0.30, 95% CI: 0.14 to 0.65). Subjects who engaged in risk taking behaviours such as illicit drug use and gambling were also significantly more likely to be aware of their drinking pattern.Conclusions The results of this study suggest that patterns of alcohol use in Ireland are problematic. Older respondents and those with lower educational attainment are less likely to be aware of their hazardous or harmful drinking pattern. There is also a population of younger, more-educated drinkers who engage in potentially risk-taking behaviours and these subjects are aware of their harmful drinking pattern. Initiatives to reduce overall alcohol consumption and raise awareness around drinking patterns are required.

Background: Early combination antiretroviral therapy (cART) reduces the size of the viral reservoir in paediatric and adult HIV infection. Very early-treated children may have higher cure/remission potential. Methods: In an observational study of 151 in utero (IU)-infected infants in KwaZulu-Natal, South Africa, whose treatment adhered strictly to national guidelines, 76 infants diagnosed via point-of-care (PoC) testing initiated cART at a median of 26 h (IQR 18–38) and 75 infants diagnosed via standard-of-care (SoC) laboratory-based testing initiated cART at 10 days (IQR 8–13). We analysed mortality, time to suppression of viraemia, and maintenance of aviraemia over the first 2 years of life. Findings: Baseline plasma viral loads were low (median 8000 copies per mL), with 12% of infants having undetectable viraemia pre-cART initiation. However, barely one-third (37%) of children achieved suppression of viraemia by 6 months that was maintained to >12 months. 24% had died or were lost to follow up by 6 months. Infant mortality was 9.3%. The high-frequency virological failure in IU-infected infants was associated not with transmitted or acquired drug-resistant mutations but with cART non-adherence (plasma cART undetectable/subtherapeutic, p

Lung cancer is the most lethal cancer type worldwide, with the majority of patients presenting with advanced stage disease. Targeting early stage disease pathogenesis would allow dramatic improvements in lung cancer patient survival. Recently, cell migration has been shown to be an integral process in early lung cancer ontogeny, with preinvasive lung cancer cells shown to migrate across normal epithelium prior to developing into invasive disease. TP53 mutations are the most abundant mutations in human nonsmall cell lung cancers and have been shown to increase cell migration via regulation of Rho-GTPase protein activity. In this review, we explore the possibility of targeting TP53-mediated Rho-GTPase activity in early lung cancer and the opportunities for translating this preclinical research into effective therapies for early stage lung cancer patients.