Impairments in Hemodynamic Responses to Orthostasis Associated with Frailty: Results from TILDA

Background: Dysregulated homeostatic response to stressors may underlie frailty in older adults. Orthostatic hypotension results from impairments in cardiovascular homeostasis and is implicated in falls and other adverse outcomes. This study aimed to characterise the relationships between orthostatic BP and heart rate recovery and frailty in an older population. Design: Cross-sectional study. Setting: Two health centres in the Republic of Ireland. Participants: 4334 adults aged 50 and older enrolled in The Irish Longitudinal Study on Ageing. Measurements: Continuous non-invasive blood pressure (BP) responses during active standing were captured by Finometer®. Frailty was assessed using the Cardiovascular Health Study criteria. Linear mixed models (random intercept) with piecewise splines were used to model differences in the rate of BP and heart rate recovery. Results: 93 (2.2%) participants were frail and 1366 (31.5%) were prefrail. Adjusting for age and sex, frailty was associated with a reduced rate of systolic BP recovery between 10-20 seconds post stand (frailty*time = -4.12 95%CI: -5.53 - -2.72) and with subsequent deficits in BP between 20-50 seconds. Similar results were seen for diastolic BP and heart rate. Further adjustment for health behaviours, morbidities, and medications reduced, but did not attenuate these associations. Of the 5 frailty criteria, only slow gait speed was consistently related to impaired BP and heart rate responses in the full models. Conclusions: Frailty, and particularly slow gait speed, was associated with reduced rate of recovery in BP and heart rate recovery following active standing. Impaired BP recovery may represent a marker of physiological frailty

Global, regional, and national trends in haemoglobin concentration and prevalence of total and severe anaemia in children and pregnant and non-pregnant women for 1995–2011: a systematic analysis of population-representative data

Background Low haemoglobin concentrations and anaemia are important risk factors for the health and development of women and children. We estimated trends in the distributions of haemoglobin concentration and in the prevalence of anaemia and severe anaemia in young children and pregnant and non-pregnant women between 1995 and 2011. Methods We obtained data about haemoglobin and anaemia for children aged 6–59 months and women of childbearing age (15–49 years) from 257 population-representative data sources from 107 countries worldwide. We used health, nutrition, and household surveys; summary statistics from WHO’s Vitamin and Mineral Nutrition Information System; and summary statistics reported by other national and international agencies. We used a Bayesian hierarchical mixture model to estimate haemoglobin distributions and systematically addressed missing data, non-linear time trends, and representativeness of data sources. We quantifi ed the uncertainty of our estimates. Findings Global mean haemoglobin improved slightly between 1995 and 2011, from 125 g/L (95% credibility interval 123–126) to 126 g/L (124–128) in non-pregnant women, from 112 g/L (111–113) to 114 g/L (112–116) in pregnant women, and from 109 g/L (107–111) to 111 g/L (110–113) in children. Anaemia prevalence decreased from 33% (29–37) to 29% (24–35) in non-pregnant women, from 43% (39–47) to 38% (34–43) in pregnant women, and from 47% (43–51) to 43% (38–47) in children. These prevalences translated to 496 million (409–595 million) non-pregnant women, 32 million (28–36 million) pregnant women, and 273 million (242–304 million) children with anaemia in 2011. In 2011, concentrations of mean haemoglobin were lowest and anaemia prevalence was highest in south Asia and central and west Africa. Interpretation Children’s and women’s haemoglobin statuses improved in some regions where concentrations had been low in the 1990s, leading to a modest global increase in mean haemoglobin and a reduction in anaemia prevalence. Further improvements are needed in some regions, particularly south Asia and central and west Africa, to improve the health of women and children and achieve global targets for reducing anaemia. Funding Bill & Melinda Gates Foundation, Grand Challenges Canada, and the UK Medical Research Council

Reliability of orthostatic beat-to-beat blood pressure tests: implications for population and clinical studies

Objective: To assess the test–retest reliability of orthostatic beat-to-beat blood pressure responses to active standing and related clinical definitions of orthostatic hypotension. Methods: A random sample of community-dwelling older adults from the pan-European Survey of Health, Ageing and Retirement in Europe, Ireland underwent a health assessment that mimicked that of the Irish Longitudinal Study on Ageing. An active stand test was performed using continuous blood pressure measurements. Participants attended a repeat assessment 4–12 weeks after the initial measurement. A mixed-effects regression model estimated the reliability and minimum detectable change while controlling for fixed observer and time of day effects. Results: A total of 125 individuals underwent repeat assessment (mean age 66.2 ± 7.5 years; 55.6% female). Mean time between visits was 84.3 ± 23.3 days. There was no significant mean difference in heart rate or blood pressure recovery variables between the first and repeat assessments. Minimum detectable change was noted for changes from resting values in systolic blood pressure (26.4 mmHg) and diastolic blood pressure (13.7 mmHg) at 110 s and for changes in heart rate (10.9 bpm) from resting values at 30 s after standing. Intra-class correlation values ranged from 0.47 for nadir values to 0.80 for heart rate and systolic blood pressure values measured 110 s after standing. Conclusion: Continuous orthostatic beat-to-beat blood pressure and related clinical definitions show low to moderate reliability and substantial natural variation over a 4–12-week period. Understanding variation in measures is essential for study design or estimating the effects of orthostatic hypotension, while clinically it can be used when evaluating longer term treatment effects

Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores

Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R(2) increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase

Partitioning heritability by functional annotation using genome-wide association summary statistics

Recent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here we analyze a broad set of functional elements, including cell type-specific elements, to estimate their polygenic contributions to heritability in genome-wide association studies (GWAS) of 17 complex diseases and traits with an average sample size of 73,599. To enable this analysis, we introduce a new method, stratified LD score regression, for partitioning heritability from GWAS summary statistics while accounting for linked markers. This new method is computationally tractable at very large sample sizes and leverages genome-wide information. Our findings include a large enrichment of heritability in conserved regions across many traits, a very large immunological disease-specific enrichment of heritability in FANTOM5 enhancers and many cell type-specific enrichments, including significant enrichment of central nervous system cell types in the heritability of body mass index, age at menarche, educational attainment and smoking behavior

Impact of FTO genotypes on BMI and weight in polycystic ovary syndrome : a systematic review and meta-analysis

Aims/hypothesis FTO gene single nucleotide polymorphisms (SNPs) have been shown to be associated with obesity-related traits and type 2 diabetes. Several small studies have suggested a greater than expected effect of the FTO rs9939609 SNP on weight in polycystic ovary syndrome (PCOS). We therefore aimed to examine the impact of FTO genotype on BMI and weight in PCOS. Methods A systematic search of medical databases (PubMed, EMBASE and Cochrane CENTRAL) was conducted up to the end of April 2011. Seven studies describing eight distinct PCOS cohorts were retrieved; seven were genotyped for SNP rs9939609 and one for SNP rs1421085. The per allele effect on BMI and body weight increase was calculated and subjected to meta-analysis. Results A total of 2,548 women with PCOS were included in the study; 762 were TT homozygotes, 1,253 had an AT/CT genotype, and 533 were AA/CC homozygotes. Each additional copy of the effect allele (A/C) increased the BMI by a mean of 0.19 z score units (95% CI 0.13, 0.24; p = 2.26 × 10−11) and body weight by a mean of 0.20 z score units (95% CI 0.14, 0.26; p = 1.02 × 10−10). This translated into an approximately 3.3 kg/m2 increase in BMI and an approximately 9.6 kg gain in body weight between TT and AA/CC homozygotes. The association between FTO genotypes and BMI was stronger in the cohorts with PCOS than in the general female populations from large genome-wide association studies. Deviation from an additive genetic model was observed in heavier populations. Conclusions/interpretation The effect of FTO SNPs on obesity-related traits in PCOS seems to be more than two times greater than the effect found in large population-based studies. This suggests an interaction between FTO and the metabolic context or polygenic background of PCOS

Pandemic (H1N1) 2009 influenza outbreak in Australia : impact on emergency departments

Executive summary\ud Objective:\ud The aims of this study were to identify the impact of Pandemic (H1N1) 2009 Influenza on Australian Emergency Departments (EDs) and their staff, and to inform planning, preparedness, and response management arrangements for future pandemics, as well as managing infectious patients presenting to EDs in everyday practice.\ud Methods\ud This study involved three elements:\ud 1. The first element of the study was an examination of published material including published statistics. Standard literature research methods were used to identify relevant published articles. In addition, data about ED demand was obtained from Australian Government Department of Health and Ageing (DoHA) publications, with several state health departments providing more detailed data.\ud 2. The second element of the study was a survey of Directors of Emergency Medicine identified with the assistance of the Australasian College for Emergency Medicine (ACEM). This survey retrieved data about demand for ED services and elicited qualitative comments on the impact of the pandemic on ED management.\ud 3. The third element of the study was a survey of ED staff. A questionnaire was emailed to members of three professional colleges—the ACEM; the Australian College of Emergency Nursing (ACEN); and the College of Emergency Nursing Australasia (CENA). The overall response rate for the survey was 18.4%, with 618 usable responses from 3355 distributed questionnaires. Topics covered by the survey included ED conditions during the (H1N1) 2009 influenza pandemic; information received about Pandemic (H1N1) 2009 Influenza; pandemic plans; the impact of the pandemic on ED staff with respect to stress; illness prevention measures; support received from others in work role; staff and others’ illness during the pandemic; other factors causing ED staff to miss work during the pandemic; and vaccination against Pandemic (H1N1) 2009 Influenza. Both qualitative and quantitative data were collected and analysed.\ud Results:\ud The results obtained from Directors of Emergency Medicine quantifying the impact of the pandemic were too limited for interpretation. Data sourced from health departments and published sources demonstrated an increase in influenza-like illness (ILI) presentations of between one and a half and three times the normal level of presentations of ILIs. Directors of Emergency Medicine reported a reasonable level of preparation for the pandemic, with most reporting the use of pandemic plans that translated into relatively effective operational infection control responses. Directors reported a highly significant impact on EDs and their staff from the pandemic. Growth in demand and related ED congestion were highly significant factors causing distress within the departments. Most (64%) respondents established a ‘flu clinic’ either as part of Pandemic (H1N1) 2009 Influenza Outbreak in Australia: Impact on Emergency Departments.\ud the ED operations or external to it. They did not note a significantly higher rate of sick leave than usual.\ud Responses relating to the impact on staff were proportional to the size of the colleges. Most respondents felt strongly that Pandemic (H1N1) 2009 Influenza had a significant impact on demand in their ED, with most patients having low levels of clinical urgency. Most respondents felt that the pandemic had a negative impact on the care of other patients, and 94% revealed some increase in stress due to lack of space for patients, increased demand, and filling staff deficits. Levels of concern about themselves or their family members contracting the illness were less significant than expected. Nurses displayed significantly higher levels of stress overall, particularly in relation to skill-mix requirements, lack of supplies and equipment, and patient and patients’ family aggression. More than one-third of respondents became ill with an ILI. Whilst respondents themselves reported taking low levels of sick leave, respondents cited difficulties with replacing absent staff. Ranked from highest to lowest, respondents gained useful support from ED colleagues, ED administration, their hospital occupational health department, hospital administration, professional colleges, state health department, and their unions. Respondents were generally positive about the information they received overall; however, the volume of information was considered excessive and sometimes inconsistent. The media was criticised as scaremongering and sensationalist and as being the cause of many unnecessary presentations to EDs. Of concern to the investigators was that a large proportion (43%) of respondents did not know whether a pandemic plan existed for their department or hospital. A small number of staff reported being redeployed from their usual workplace for personal risk factors or operational reasons. As at the time of survey (29 October –18 December 2009), 26% of ED staff reported being vaccinated against Pandemic (H1N1) 2009 Influenza. Of those not vaccinated, half indicated they would ‘definitely’ or ‘probably’ not get vaccinated, with the main reasons being the vaccine was ‘rushed into production’, ‘not properly tested’, ‘came out too late’, or not needed due to prior infection or exposure, or due to the mildness of the disease.\ud Conclusion:\ud Pandemic (H1N1) 2009 Influenza had a significant impact on Australian Emergency Departments. The pandemic exposed problems in existing plans, particularly a lack of guidelines, general information overload, and confusion due to the lack of a single authoritative information source. Of concern was the high proportion of respondents who did not know if their hospital or department had a pandemic plan. Nationally, the pandemic communication strategy needs a detailed review, with more engagement with media networks to encourage responsible and consistent reporting. Also of concern was the low level of immunisation, and the low level of intention to accept vaccination. This is a problem seen in many previous studies relating to seasonal influenza and health care workers. The design of EDs needs to be addressed to better manage infectious patients. Significant workforce issues were confronted in this pandemic, including maintaining appropriate staffing levels; staff exposure to illness; access to, and appropriate use of, personal protective equipment (PPE); and the difficulties associated with working in PPE for prolonged periods. An administrative issue of note was the reporting requirement, which created considerable additional stress for staff within EDs. Peer and local support strategies helped ensure staff felt their needs were provided for, creating resilience, dependability, and stability in the ED workforce. Policies regarding the establishment of flu clinics need to be reviewed. The ability to create surge capacity within EDs by considering staffing, equipment, physical space, and stores is of primary importance for future pandemics