Did physical activity and associated barriers change during COVID-19 restrictions in Ireland? Repeated cross-sectional study.

This repeated cross-sectional study investigated physical activity and associated barriers and facilitators during the first two waves of COVID-19 restrictions in Ireland. An online, anonymous questionnaire collated data from adults during May (n = 1274) and November (n = 810) 2020. Statistical analysis used a combination of traditional significance testing and Bayesian lasso logistic regression. The pattern of physical activity changed significantly between waves (χ2 86.8 on 3df; p < 0.001). During wave 1 restrictions, the majority [46.1% (n = 587)] of participants reported being more active than usual, decreasing to 26.3% (n = 213) during wave 2. More participants reported that their activity levels were less than usual [W1 29% (n = 369); W2 35% (n = 283)] during wave 2. Adherence to physical activity guidelines decreased from 56.5% (n = 705) to 43.7% (n = 35). Being unable to access their usual means of exercise [OR, 95% OR intervals; W1 1.611 (1.370-1.904), W2 1.638 (1.3731.968)] and advice not to leave home [OR, 95% OR intervals; W1 1.401 (1.164-1.697), W2 1.367 (1.106-1.696)] predicted less activity than usual during both waves. Increased time [OR, 95% OR intervals; W1 2.326 (1.948-2.794), W2 1.809 (1.478-2.233)], and valuing physical activity as important [OR, 95% OR intervals; W1 1.192 (1.001-1.444), W2 1.253 (1.003-1.637)] predicted increased activity during both waves, whilst finding new ways to be active [OR, 95% OR intervals; 2.515 (1.641-3.887)] predicted more activity in wave 2 only. Increases in physical activity of Irish adults during the first phase of COVID-19 restrictions were not maintained during the second wave and barriers to physical activity persisted.

Our study looked at the physical activity levels of Irish adults during the first two waves of COVID-19 restrictions. We also examined the factors that helped or hindered people to be active at this time. We used an anonymous, online questionnaire to collect responses during May and November 2020. In total, 1274 people responded in May and 810 in November. We found that in May, almost half of the respondents reported they were more active than usual. By November this had reduced to just over a quarter and about one in three people reported they were doing less activity than usual. People who were less active than usual reported that the closure of their usual means of getting activity, and the advice not to outdoors were the main factors preventing them from being active. People who were more active than usual reported that having more time and feeling that physical activity was important helped them to be more active. The things that helped or hindered people from being active generally did not change between May and November.

Statistical power in vitamin D randomized control trials investigating biomarkers as continuous outcomes.

It has long been suspected that mean vitamin D level and differences among individuals in the population might deteriorate power in vitamin D randomised controlled trials (RCTs). However, standard statistical planning tools cannot accommodate these considerations. Here, to accommodate the large within-person and between-people heterogeneity in naturally fluctuating 25-hydroxyvitamin D (25OHD) concentration, a simulation based approach was used to investigate the power and sample size requirements in vitamin D supplementation RCTs looking at the proportion of regulatory T cells, %Tregs, as a continuous outcome. A range of sample sizes, mean increases in 25OHD in the intervention arm, and population 25OHD heterogeneity were tested. We found that in a population with a mean 25OHD of 50▒nmol/L and moderate heterogeneity in 25OHD (defined as inter-quartile range IQR = 20), sample size of approximately 1000 participants per arm is required to achieve 80% power if 25OHD increased by 10▒nmol/L in the intervention arm, compared to 250, < 100 and < 50 participants per arm if this increase was 20▒nmol/L, 40▒nmol/L or 60▒nmol/L, respectively. Thus we conclude that the increase in 25OHD in the intervention arm and population heterogeneity impact the power of vitamin D RCTs substantially. Sample size determination through simulation is a powerful approach for non-standard trials, and the work presented can easily be adopted to other intervention-outcome pairs.

The association between ambient UVB dose and ANCA-associated vasculitis relapse and onset.

BACKGROUND: The aetiology of ANCA-associated vasculitis (AAV) and triggers of relapse are poorly understood. Vitamin D (vitD) is an important immunomodulator, potentially responsible for the observed latitudinal differences between granulomatous and non-granulomatous AAV phenotypes. A narrow ultraviolet B spectrum induces vitD synthesis (vitD-UVB) via the skin. We hypothesised that prolonged periods of low ambient UVB (and by extension vitD deficiency) are associated with the granulomatous form of the disease and an increased risk of AAV relapse. METHODS: Patients with AAV recruited to the Irish Rare Kidney Disease (RKD) (n = 439) and UKIVAS (n = 1961) registries were studied. Exposure variables comprised latitude and measures of ambient vitD-UVB, including cumulative weighted UVB dose (CW-D-UVB), a well-validated vitD proxy. An n-of-1 study design was used to examine the relapse risk using only the RKD dataset. Multi-level models and logistic regression were used to examine the effect of predictors on AAV relapse risk, phenotype and serotype. RESULTS: Residential latitude was positively correlated (OR 1.41, 95% CI 1.14-1.74, p = 0.002) and average vitD-UVB negatively correlated (0.82, 0.70-0.99, p = 0.04) with relapse risk, with a stronger effect when restricting to winter measurements (0.71, 0.57-0.89, p = 0.002). However, these associations were not restricted to granulomatous phenotypes. We observed no clear relationship between latitude, vitD-UVB or CW-D-UVB and AAV phenotype or serotype. CONCLUSION: Our findings suggest that low winter ambient UVB and prolonged vitD status contribute to AAV relapse risk across all phenotypes. However, the development of a granulomatous phenotype does not appear to be directly vitD-mediated. Further research is needed to determine whether sufficient vitD status would reduce relapse propensity in AAV.

Time and belief in exercise importance predict increased activity during initial COVID-19 restrictions in Ireland.

The aim of this work was to investigate physical activity levels and the associated barriers and facilitators to physical activity in Irish adults during initial COVID-19 restrictions. Members of the general population completed an online questionnaire. Responses from 1274 participants (1274/1568, 81% completion rate) indicated that the majority (46.1%, n = 587) of people were more active than usual during the restrictions, however, 28.6% (n = 365) reported being less active. Fifty-five percent (55.3%, n = 702) of participants were meeting public health physical activity guidelines and more than half (53.3%, n = 679) reported finding new ways to be active. Walking (86%, n = 1101), physical activity in the home (47%, n = 593) and online resources (38%, n = 483) were the most frequently reported types of physical activity people engaged in. Having more time to be physically active [OR 2.326 (SD 1.948-2.794)] and a greater belief in the importance of physical activity [OR 1.192 (SD 1.001-1.444)] were predictive of exercising more than usual. Being unable to access their usual means of exercise [OR 1.612 (SD 1.369-1.902)], advised not to go outside the home [OR 1.402 (SD 1.165-1.698)] and working more than usual [OR 1.201 (SD 1.013-1.443)] were predictive of exercising less than usual. There was a positive trend in physical activity engagement by Irish adults during initial COVID-19 restrictions, likely influenced by increased time, belief that exercise was important and increased use of home-based and online exercise resources. However, almost one in three people reported being less active than usual, highlighting the need for targeted support during restriction periods.

Our study aimed to find out what helped and what hindered people being physically active during the initial COVID-19 restrictions (May 2020). At this time, people in Ireland were advised to stay at home and only permitted to exercise within a limited distance from their homes. The vast majority of exercise facilities, such as gyms and swimming pools were closed. We collected our information using an online survey, which 1274 people completed. Results showed that close to half of people reported being more active than usual during this time, however almost one in three people reported being less active than usual. Those who were more active reported having more time than before and had a strong belief that exercise was important. A lot of people found new ways to exercise, such as online exercise classes. Walking was the most popular physical activity. Those who were exercising less than usual reported their usual means of exercise being unavailable to them, being advised not to leave their homes and having to work more than usual. Understanding what helps and prevents people from being physically active during COVID-19 restrictions helps governments, health professionals and exercise specialists plan how best to promote physical activity if periods of similar restrictions occur.

An age-structured SEIR model for COVID-19 incidence in Dublin, Ireland with framework for evaluating health intervention cost.

Strategies adopted globally to mitigate the threat of COVID-19 have primarily involved lockdown measures with substantial economic and social costs with varying degrees of success. Morbidity patterns of COVID-19 variants have a strong association with age, while restrictive lockdown measures have association with negative mental health outcomes in some age groups. Reduced economic prospects may also afflict some age cohorts more than others. Motivated by this, we propose a model to describe COVID-19 community spread incorporating the role of age-specific social interactions. Through a flexible parameterisation of an age-structured deterministic Susceptible Exposed Infectious Removed (SEIR) model, we provide a means for characterising different forms of lockdown which may impact specific age groups differently. Social interactions are represented through age group to age group contact matrices, which can be trained using available data and are thus locally adapted. This framework is easy to interpret and suitable for describing counterfactual scenarios, which could assist policy makers with regard to minimising morbidity balanced with the costs of prospective suppression strategies. Our work originates from an Irish context and we use disease monitoring data from February 29th 2020 to January 31st 2021 gathered by Irish governmental agencies. We demonstrate how Irish lockdown scenarios can be constructed using the proposed model formulation and show results of retrospective fitting to incidence rates and forward planning with relevant "what if / instead of" lockdown counterfactuals. Uncertainty quantification for the predictive approaches is described. Our formulation is agnostic to a specific locale, in that lockdown strategies in other regions can be straightforwardly encoded using this model.

Altered Cytokine Endotoxin Responses in Neonatal Encephalopathy Predict MRI Outcomes.

Background: Neonatal encephalopathy (NE) is associated with adverse neurodevelopmental outcome and is linked with systemic inflammation. Pro-inflammatory and anti-inflammatory cytokines are known to play a role in the pathology of NE by activating innate immune cells. Methods: Eighty-seven infants were enrolled including 53 infants with NE of whom 52 received therapeutic hypothermia (TH) and 34 term infant healthy controls (TC). Whole blood sampling was performed in the first 4 days of life, and a 14-spot ELISA Multiplex Cytokine Array was carried out on baseline samples or after stimulation with lipopolysaccharide (LPS) as an additional inflammatory stimulus. The cytokine medians were examined for differences between infants with NE and healthy TC; and then short-term outcomes of Sarnat stage, seizures, and MRI brain were examined within the NE group. The potential of LPS stimulation to predict abnormal MRI was explored using receiver operating characteristic (ROC) curves. Results: At baseline, infants with NE had significantly higher levels of erythropoietin (Epo), interleukin (IL)-6, and IL-1ra and significantly lower vascular endothelial growth factor (VEGF) than had controls. All cytokines were increased after LPS stimulation in infants with NE with an excessive Epo and IL-1ra response than in controls. Infants with NE had lower IL-8, IL-2, IL-6, tumor necrosis factor (TNF)-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), VEGF, and interferon (IFN)-γ than controls had following LPS. GM-CSF and IFN-γ, IL-1ß, IL-1ra, and VEGF were higher on days 1-2 in NE infants with abnormal neuroimaging. GM-CSF, IFN-γ, and TNF-α levels with LPS stimulation were different upon stimulation between normal and abnormal neuroimaging. TNF-α is the only strong cytokine predictor both pre- and post-LPS stimulation of abnormal brain imaging. Conclusions: Altered cytokine responses are found in infants with NE vs. controls, and more significant differences are unmasked by the additional stimulus of LPS, which potentially improves the predictive power of these cytokines for the detection of abnormal MRIs. Infants with NE undergoing TH demonstrate both trained immunity and tolerance, and understanding these responses will facilitate adjunctive immunomodulatory treatments.

The Clinical Application of Urine Soluble CD163 in ANCA-Associated Vasculitis.

BACKGROUND: Up to 70% of patients with ANCA-associated vasculitis (AAV) develop GN, with 26% progressing to ESKD. Diagnostic-grade and noninvasive tools to detect active renal inflammation are needed. Urinary soluble CD163 (usCD163) is a promising biomarker of active renal vasculitis, but a diagnostic-grade assay, assessment of its utility in prospective diagnosis of renal vasculitis flares, and evaluation of its utility in proteinuric states are needed. METHODS: We assessed a diagnostic-grade usCD163 assay in (1) a real-world cohort of 405 patients with AAV and 121 healthy and 488 non-AAV disease controls; (2) a prospective multicenter study of 84 patients with potential renal vasculitis flare; (3) a longitudinal multicenter cohort of 65 patients with podocytopathy; and (4) a cohort of 29 patients with AAV (with or without proteinuria) and ten controls. RESULTS: We established a diagnostic reference range, with a cutoff of 250 ng/mmol for active renal vasculitis (area under the curve [AUC], 0.978). Using this cutoff, usCD163 was elevated in renal vasculitis flare (AUC, 0.95) but remained low in flare mimics, such as nonvasculitic AKI. usCD163's specificity declined in patients with AAV who had nephrotic-range proteinuria and in those with primary podocytopathy, with 62% of patients with nephrotic syndrome displaying a "positive" usCD163. In patients with AAV and significant proteinuria, usCD163 normalization to total urine protein rather than creatinine provided the greatest clinical utility for diagnosing active renal vasculitis. CONCLUSIONS: usCD163 is elevated in renal vasculitis flare and remains low in flare mimics. Nonspecific protein leakage in nephrotic syndrome elevates usCD163 in the absence of glomerular macrophage infiltration, resulting in false-positive results; this can be corrected with urine protein normalization.

Power determination in vitamin D randomised control trials and characterising factors affecting it through a novel simulation-based tool.

Thousands of observational studies have linked vitamin D deficiency with numerous diseases, but randomised controlled trials (RCTs) often fail to show benefit of supplementation. Population characteristics and trial design have long been suspected to undermine power but were not systematically investigated. We propose a flexible generative model to characterise benefit of vitamin D supplementation at the individual level, and use this to quantify power in RCTs. The model can account for seasonality and population heterogeneity. In a simulated 1-year trial with 1000 participants per arm and assuming a 25-hydroxyvitamin D (25OHD) increase of 20 nmol/L due to the intervention, with baseline 25OHD in the population of 15, 35, 50, 60 and 75 nmol/L, the power to detect intervention effect was 77%, 99%, 95%, 68% and 19%, respectively. The number of participants required per arm to achieve 80% power according to baseline 25OHD of 15-60 nmol/L was 1200, 400, 600 and 1400, respectively. As expected, larger increases in 25OHD due to supplementation improved power in certain scenarios. For a population baseline of 50 nmol/L, with 1500 participants in each arm, there was 100% power to detect a 20 nmol/L 25OHD increase while it was 76% for a 10 nmol/L increase. Population characteristics and trial design, including temporal considerations, have a dramatic impact on power and required sample size in vitamin D RCTs.

Investigation of type I interferon responses in ANCA-associated vasculitis.

Type I interferon (IFN) dysregulation is a major contributory factor in the development of several autoimmune diseases, termed type I interferonopathies, and is thought to be the pathogenic link with chronic inflammation in these conditions. Anti-neutrophil cytoplasmic antibody (ANCA)-Associated Vasculitis (AAV) is an autoimmune disease characterised by necrotising inflammation of small blood vessels. The underlying biology of AAV is not well understood, however several studies have noted abnormalities in type I IFN responses. We hypothesised that type I IFN responses are systemically dysregulated in AAV, consistent with features of a type I interferonopathy. To investigate this, we measured the expression of seven interferon regulated genes (IRGs) (ISG15, SIGLEC1, STAT1, RSAD2, IFI27, IFI44L and IFIT1) in peripheral blood samples, as well as three type I IFN regulated proteins (CXCL10, MCP-1 and CCL19) in serum samples from AAV patients, healthy controls and disease controls. We found no difference in type I IFN regulated gene or protein expression between AAV patients and healthy controls. Furthermore, IRG and IFN regulated protein expression did not correlate with clinical measurements of disease activity in AAV patients. Thus, we conclude that systemic type I IFN responses are not key drivers of AAV pathogenesis and AAV should not be considered a type I interferonopathy.

Athlete concussion history recall is underestimated: a validation study of self-reported concussion history among current professional rugby union players.

Objective: To assess the concurrent validity and test re-test reliability of the Michigan Traumatic Brain Injury Identification Method (MTBIIM). The psychometric properties of this concussion index were investigated by comparing the agreement between player self-reported diagnosed concussions and medical record diagnosed concussions among professional rugby union players.Study Design: Cross-sectional study i) validation and ii) test re-test reliability.Methods: The MTBIIM was administered via a structured interview to obtain the number and nature of player self-reported concussion histories from players, while contracted to the host club. Self-reported concussion history information was compared to medically recorded data captured between 2008 and 2017. A mixed-effects logistic regression model explored predictors of player self-report accuracy.Results: Data from 62 players (25.39[4.36] years) included 99 unique rugby related concussions. Medically documented concussions (n = 92) per player (1.48 [1.96]) were 30% more than the mean number of self-reported diagnosed (n = 63) concussions per player (1.02 [1.21] events). Overall, self-reported diagnosed concussions and medical record diagnosed concussion histories had a 'fair' level of agreement (k=0.274; SE [0.076]), p=.001). Self-reported lifetime concussion history was signicantly negatively correlated with recall of concussions.Conclusions: Initial concurrent validity of the MTBIIM was found to be fair with the average athlete under-reporting the number of clinically diagnosed concussions.

Increases in DXA-Derived Visceral Fat Across One Season in Professional Rugby Union Players: Importance of Visceral Fat Monitoring in Athlete Body Composition Assessment.

INTRODUCTION: In rugby, the average player body mass has increased by approximately 25% since 1955. Visceral adipose tissue (VAT) is associated with low grade inflammation, and chronic diseases, such as cardiovascular diseases. The purpose of this study was to investigate changes in VAT in relation to other indices of body composition, across 1 season in professional rugby. METHODOLOGY: One hundred and sixteen male rugby union players' (age: 26.2 ± 4.6 y, BMI: 29.40 ± 3.22 kg.m2) total body composition dual energy X-ray absorptiometry scans from 4 time points across the season (baseline, preseason, midseason, and postseason) were analyzed. Players were grouped by playing position, forwards (n = 65) and backs (n = 51). Players followed individually tailored diet plans. RESULTS: Mean baseline VAT was 404.67 ± 229.43 g (forwards: 469.36 ± 263.16 g, backs: 311.40 ± 121.15 g). Total mass, lean mass, body fat percentage (%BF), and VAT were greater in forwards than backs at all 4 timepoints. Meaningful increases in VAT across the season, were observed in 37.5% of backs and 53.6% of forwards. There was a positive linear relationship between lean mass and total mass, up to 116.04 kg total mass. Beyond this threshold, lean mass accumulation reduced and %BF and VAT mass increased. There were significant relationships between %BF, VAT, and BMI (p < 0.001), but no physiological relevant pattern was discerned. CONCLUSIONS: Despite regular high-intensive exercise and individually tailored dietary control across a professional rugby season, players from both playing positions demonstrated increases in VAT, although the cause remains unknown. Our findings indicate the importance of monitoring VAT in athletes alongside standard measures of body composition. Additionally, our findings suggest there may be an upper threshold of body mass beyond which lean mass may not increase further and instead %BF and VAT are more likely to accumulate. Further research is required to identify how increasing player size may impact long-term cardiometabolic health given the known links between VAT and cardiometabolic risk.

Pro-inflammatory Stimulation of Monocytes by ANCA Is Linked to Changes in Cellular Metabolism.

Clinical and experimental data suggest that pathogenesis in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is driven by ANCA-mediated activation of neutrophils and monocytes. While the role of neutrophils has been extensively investigated, the function of monocytes remains relatively understudied. We have previously demonstrated that stimulation of monocytes with anti-myeloperoxidase (MPO), but not anti-proteinase-3 (PR3), antibodies results in production of the pro-inflammatory cytokine IL-1ß. Changes in cellular metabolism, particularly a switch to glycolysis, have recently been linked to activation of immune cells and production of IL-1ß. Therefore, we investigated the metabolic profile of monocytes following ANCA stimulation. We found a significant increase in glucose uptake in anti-MPO stimulated monocytes. Interestingly, both anti-MPO and anti-PR3 stimulation resulted in an immediate increase in glycolysis, measured by Seahorse extracellular flux analysis. However, this increase in glycolysis was sustained (for up to 4 h) in anti-MPO- but not anti-PR3-treated cells. In addition, only anti-MPO-treated cells exhibited increased oxidative phosphorylation, a metabolic response that correlated with IL-1ß production. These data indicate that monocyte metabolism is altered by ANCA, with divergent responses to anti-MPO and anti-PR3 antibodies. These metabolic changes may underlie pathologic immune activation in ANCA associated vasculitis, as well as potentially contributing to the differing clinical phenotype between PR3- and MPO-ANCA positive patients. These metabolic pathways may therefore be potential targets for therapeutic intervention.

Urinary soluble CD163 and monocyte chemoattractant protein-1 in the identification of subtle renal flare in anti-neutrophil cytoplasmic antibody-associated vasculitis.

BACKGROUND: Prior work has shown that urinary soluble CD163 (usCD163) displays excellent biomarker characteristics for detection of active renal vasculitis using samples that included new diagnoses with highly active renal disease. This study focused on the use of usCD163 in the detection of the more clinically relevant state of mild renal flare and compared results of usCD163 testing directly to testing of urinary monocyte chemoattractant protein-1 (uMCP-1). METHODS: Patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV, n = 88) were identified within a serially sampled, longitudinal and multicentre cohort. Creatinine-normalized usCD163 and uMCP-1 levels were measured by enzyme-linked immunosorbent assay and, both alone and in combination, were compared between times of active renal AAV and during remission and/or active non-renal AAV. RESULTS: Samples from 320 study visits included times of active renal vasculitis (n = 39), remission (n = 233) and active extrarenal vasculitis (n = 48). Median creatinine levels were 0.9 mg/dL [interquartile range (IQR) 0.8-1.2] in remission and 1.4 mg/dL (IQR 1.0-1.8) during renal flare. usCD163 levels were higher in patients with active renal vasculitis compared with patients in remission and those with active extrarenal vasculitis, with median values of 162 ng/mmol (IQR 79-337), 44 (17-104) and 38 (7-76), respectively (P < 0.001). uMCP-1 levels were also higher in patients with active renal vasculitis compared with patients in remission and those with active extrarenal vasculitis, with median values of 10.6 pg/mmol (IQR 4.6-23.5), 4.1 (2.5-8.4) and 4.1 (1.9-6.8), respectively (P < 0.001). The proposed diagnostic cut-points for usCD163 and uMCP-1 were 72.9 ng/mmol and 10.0 pg/mmol, respectively. usCD163 and uMCP-1 levels were marginally correlated (r2 = 0.11, P < 0.001). Combining novel and existing biomarkers using recursive tree partitioning indicated that elevated usCD163 plus either elevated uMCP-1 or new/worse proteinuria improved the positive likelihood ratio (PLR) of active renal vasculitis to 19.2. CONCLUSION: A combination of usCD163 and uMCP-1 measurements appears to be useful in identifying the diagnosis of subtle renal vasculitis flare.

Interlocking directorates in Irish companies using a latent space model for bipartite networks.

We analyze the temporal bipartite network of the leading Irish companies and their directors from 2003 to 2013, encompassing the end of the Celtic Tiger boom and the ensuing financial crisis in 2008. We focus on the evolution of company interlocks, whereby a company director simultaneously sits on two or more boards. We develop a statistical model for this dataset by embedding the positions of companies and directors in a latent space. The temporal evolution of the network is modeled through three levels of Markovian dependence: one on the model parameters, one on the companies' latent positions, and one on the edges themselves. The model is estimated using Bayesian inference. Our analysis reveals that the level of interlocking, as measured by a contraction of the latent space, increased before and during the crisis, reaching a peak in 2009, and has generally stabilized since then.