Exploring circadian blood pressure patterns

Despite our comprehensive knowledge of the importance of reducing mean levels of blood pressure (BP), we are less informed about the benefits of reducing other parameters of BP, specifically BP variability (BPV). Ambulatory blood pressure monitoring (ABPM), which can be used to obtain estimates of BP over a 24h period, offers a powerful tool in the analysis of circadian patterns and short-term BPV. The main aims of this thesis were to explore and identify circadian BP patterns between individuals and groups, and extract meaningful measures that describe these patterns while appropriately accounting for the inherent cyclical structure of ABPM data. Specifically, the thesis includes a systematic review which identifies summary measures of BPV, such as standard deviation. A meta-analysis exploring the correlation between short-term BPV and subclinical target organ damage (TOD) is included. The association between the identified summary measures and subclinical TOD is then explored in a group of middle aged adults. In an attempt to maximise the power of the repeated cyclical readings in ABPM and incorporate the data together in one model, different random-effects models were explored which allowed us to obtain estimates of both within and between-individual variation of model parameters. A piece-wise linear mixed-effects model was considered as a simple but suitable approach to capture BP trajectory throughout the day. Finally, a two-component cosinor random-effects model is outlined where derivatives of the model fit presents a novel alternative method to locate and quantify the magnitude of slopes at critical points along the trajectory. This is used to obtain a measure of morning BP surge. We compare the random-effects from this model to principle component scores obtained through functional principle component analysis. Our motivating data comes from the Mitchelstown Study, a population based study of Irish adults where a subsample underwent 24h ABPM

Prescribing and sales of intramammary antimicrobials in Ireland in 2019 and 2020: the role of milk purchasers

Background: In Ireland between 2008 and 2022, intramammary antimicrobial (AM) products could be prescribed by a veterinary practitioner under what was known as Schedule 8 (or remote) prescribing. Under this prescribing route, an annual herd visit was not required when criteria were met as outlined in Animal Remedies Regulation 2007 to 2017 (statutory instruments No. 786/2007 and 558/2017). Under this prescribing route, the responsibilities of the milk purchaser, the farmer and the veterinary practitioner were each outlined, and a written mastitis control programme (MCP) was required. Milk purchasers implemented MCPs on participating farms (so-called MCP herds) with support from veterinary practitioner(s) who undertook Schedule 8 prescribing of intramammary AM tubes. This study seeks a clearer understanding of the role of milk purchasers in the prescribing and sale of intramammary AM products in Ireland during 2019 and 2020, whilst this Regulation was in force. Specifically, the study sought insights into the role of milk purchasers in the prescribing and sale of intramammary AM products in the Irish dairy industry during 2019 and 2020, using anonymised and highly aggregated milk purchaser data. The study also provided insights into milk quality among supplying herds during this period. Methods: For this study, we had access to anonymised, highly aggregated data from all milk purchasers that operated a MCP on at least some of their supplying herds during 2019 or 2020. Data collection was undertaken by the Department of Agriculture, Food and Marine. Data analysis was primarily descriptive. Results: Data were available on 11 milk purchasers (64.7% of all) and 13,251 supplying herds. Of these, 52% were MCP herds. The quality of milk from supplying herds varied significantly by month, year and milk purchaser. During 2019 and 2020, there was a single Schedule 8 prescriber (a private veterinary practitioner prescribing intramammary AMs as part of a MCP), on average, for 549.3 herds. The sale of intramammary AM products through milk purchasers represented 15.2% and 26.9% of national sales in in-lactation and dry cow tubes, respectively. There was an overall 2% increase in sales through milk purchasers between 2019 and 2020. Few European Medicines Agency (EMA) category B (‘Restrict’) intramammary AM products were sold by milk purchasers. For both in-lactation and dry cow tubes, there was a statistically significant association between EMA classification and route of sale (through milk purchasers or otherwise).Department of Agriculture, Food and the Marin

Prevalence of diabetes in the Republic of Ireland: results from the National Health Survey (SLAN) 2007

Background: Current estimates of diabetes prevalence in the Republic of Ireland (RoI) are based on UK epidemiological studies. This study uses Irish data to describe the prevalence of doctor-diagnosed diabetes amongst all adults aged 18+ years and undiagnosed diabetes amongst those aged 45+ years. Methods: The survey of lifestyle attitudes and nutrition (SLAN) 2007 is based on a nationally representative sample of Irish adults aged 18+ years (n = 10,364). Self-reported doctor-diagnosed diabetes was recorded for respondents in the full sample. Diabetes medication use, measured height and weight, and non-fasting blood samples were variously recorded in sub-samples of younger (n = 967) and older (n = 1,207) respondents. Results: The prevalence of doctor-diagnosed diabetes amongst adults aged 18+ years was 3.5% (95% CI 3.1% - 3.9%). After adjustment for other explanatory variables; the risk of self-reported doctor-diagnosed diabetes was significantly related to age (p < 0.0001), employment status (p = 0.0003) and obesity (p = 0.0003). Amongst adults aged 45+ years, the prevalence of doctor-diagnosed diabetes was 8.9% (95% CI 7.3% -10.5%) and undiagnosed diabetes was 2.8% (95% CI 1.4% - 4.1%). This represented 31.2% of diabetes cases in this age group. Conclusion: Notwithstanding methodological differences, these prevalence estimates are consistent with those in the UK and France. However, the percentage of undiagnosed cases amongst adults aged 45+ years appears to be higher in the RoI. Increased efforts to improve early detection and population level interventions to address adverse diet and lifestyle factors are urgently needed

Investigation of the association between the Enferplex bovine tuberculosis antibody test and the future risk of bovine tuberculosis in irish cattle in infected herds: a pilot field study

The Single Intradermal Comparative Tuberculin Test (SICTT) and the interferon-gamma (IFN-γ) assay are the approved diagnostic tests for bovine tuberculosis (bTB) in Ireland. The aim of this pilot study was to explore if there was any added diagnostic benefit from applying the Enferplex bTB test (an antibody test) in severe bTB herd breakdowns after the removal of cattle that had tested positive to the SICTT and the IFN-γ test. In addition to the normal bTB testing and management protocols, the animals in these herds that tested negative to SICTT and the IFN-γ test were followed forward for a period of two years. All animals were tested by Enferplex at enrolment. The time to subsequent bTB detection (diagnosed with SICTT/IFN-γ tests or detection of visible lesions at routine slaughter) for animals that tested positive or negative to the Enferplex bTB test at the start of the study was compared using Kaplan–Meier survival curves and Cox based survival models. Of the 484 enrolled animals (from 11 herds), 171 (35.3%) and 151 (31.1%) initially tested positive in the Enferplex assay under the high sensitivity and high specificity interpretation settings respectively. The results of the survival analysis showed that there was no difference in the survival time to a positive diagnosis with bTB during the follow-up period between animals initially classified as positive and negative by the Enferplex test. Further research is warranted to explore the potential benefit of using the Enferplex test in other scenarios.Department of Agriculture, Food and the MarineOpen Access funding provided by the IReL ConsortiumTo check citing and date details in 6

Exploring diurnal variation using piecewise linear splines:an example using blood pressure

Background: There are many examples of physiological processes that follow a circadian cycle and researchers are interested in alternative methods to illustrate and quantify this diurnal variation. Circadian blood pressure (BP) deserves additional attention given uncertainty relating to the prognostic significance of BP variability in relation to cardiovascular disease. However, the majority of studies exploring variability in ambulatory blood pressure monitoring (ABPM) collapse the data into single readings ignoring the temporal nature of the data. Advanced statistical techniques are required to explore complete variation over 24 h. Methods: We use piecewise linear splines in a mixed-effects model with a constraint to ensure periodicity as a novel application for modelling daily blood pressure. Data from the Mitchelstown Study, a cross-sectional study of Irish adults aged 47–73 years (n = 2047) was utilized. A subsample (1207) underwent 24-h ABPM. We compared patterns between those with and without evidence of subclinical target organ damage (microalbuminuria). Results: We were able to quantify the steepest rise and fall in SBP, which occurred just after waking (2.23 mmHg/30 min) and immediately after falling asleep (−1.93 mmHg/30 min) respectively. The variation about an individual’s trajectory over 24 h was 12.3 mmHg (standard deviation). On average those with microalbuminuria were found to have significantly higher SBP (7.6 mmHg, 95% CI 5.0–10.1) after adjustment for age, sex and BMI. Including an interaction term between each linear spline and microalbuminuria did not improve model fit. Conclusion: We have introduced a practical method for the analysis of ABPM where we can determine the rate of increase or decrease for different periods of the day. This may be particularly useful in examining chronotherapy effects of antihypertensive medication. It offers new measures of short-term BP variability as we can quantify the variation about an individual’s trajectory but also allows examination of the variation in slopes between individuals (random-effects)

Recognition of the Major Histocompatibility Complex (MHC) class Ib molecule H2-Q10 by the natural killer cell receptor Ly49C

Murine natural killer (NK) cells are regulated by the interaction of Ly49 receptors with major histocompatibility complex class I molecules (MHC-I). Although the ligands for inhibitory Ly49 were considered to be restricted to classical MHC (MHC-Ia), we have shown that the non-classical MHC molecule (MHC-Ib) H2-M3 was a ligand for the inhibitory Ly49A. Here we establish that another MHC-Ib, H2-Q10, is a bona fide ligand for the inhibitory Ly49C receptor. H2-Q10 bound to Ly49C with a marginally lower affinity (∼5 μm) than that observed between Ly49C and MHC-Ia (H-2Kb/H-2Dd, both ∼1 μm), and this recognition could be prevented by cis interactions with H-2K in situ. To understand the molecular details underpinning Ly49·MHC-Ib recognition, we determined the crystal structures of H2-Q10 and Ly49C bound H2-Q10. Unliganded H2-Q10 adopted a classical MHC-I fold and possessed a peptide-binding groove that exhibited features similar to those found in MHC-Ia, explaining the diverse peptide binding repertoire of H2-Q10. Ly49C bound to H2-Q10 underneath the peptide binding platform to a region that encompassed residues from the α1, α2, and α3 domains, as well as the associated β2-microglobulin subunit. This docking mode was conserved with that previously observed for Ly49C·H-2Kb. Indeed, structure-guided mutation of Ly49C indicated that Ly49C·H2-Q10 and Ly49C·H-2Kb possess similar energetic footprints focused around residues located within the Ly49C β4-stand and L5 loop, which contact the underside of the peptide-binding platform floor. Our data provide a structural basis for Ly49·MHC-Ib recognition and demonstrate that MHC-Ib represent an extended family of ligands for Ly49 molecules

Design and methods for a cluster randomized trial of the Sunless Study: A skin cancer prevention intervention promoting sunless tanning among beach visitors

<p>Abstract</p> <p>Background</p> <p>Skin cancer is the most prevalent yet most preventable cancer in the US. While protecting oneself from ultraviolet radiation (UVR) can largely reduce risk, rates of unprotected sun exposure remain high. Because the desire to be tan often outweighs health concerns among sunbathers, very few interventions have been successful at reducing sunbathing behavior. Sunless tanning (self-tanners and spray tans), a method of achieving the suntanned look without UVR exposure, might be an effective supplement to prevention interventions.</p> <p>Methods and Design</p> <p>This cluster randomized trial will examine whether a beach-based intervention that promotes sunless tanning as a substitute for sunbathing and includes sun damage imaging and sun safety recommendations is superior to a questionnaire only control group in reducing sunbathing frequency. Female beach visitors (N = 250) will be recruited from 2 public beaches in eastern Massachusetts. Beach site will be the unit of randomization. Follow-up assessment will occur at the end of the summer (1-month following intervention) and 1 year later. The primary outcome is average sunbathing time per week. The study was designed to provide 90% power for detecting a difference of .70 hours between conditions (standard deviation of 2.0) at 1-year with an intra-cluster correlation coefficient of 0.01 and assuming a 25% rate of loss to follow-up. Secondary outcomes include frequency of sunburns, use of sunless tanning products, and sun protection behavior.</p> <p>Discussion</p> <p>Interventions might be improved by promoting behavioral substitutes for sun exposure, such as sunless tanners, that create a tanned look without exposure to UVR.</p> <p>Trial registration</p> <p>NCT00403377</p