Gene-Environment Interactions in Attention Deficit Hyperactivity Disorder

The overall goal of this project is to advance our understanding of the multifactorial etiology of Attention Deficit Hyperactivity Disorder (ADHD) by testing a diathesis-stress model of gene x environment (g x e) interactions. Although the literature increasingly supports g x e interactions in the manifestation of ADHD, few studies have investigated multiple genetic and environmental risk factors, included direct tests of gene - environment correlations (rG-Es), explored the specificity of interactions to symptom dimensions, or attempted to minimize comparisons. Therefore, utilizing both within-family (FBAT/PBAT) and case-control methodology, this study sought to (1) explore main effects of polymorphisms in the DRD2, DRD4, DRD5, DAT1, 5HTT, ADRA2C and DBH genes on ADHD symptoms in a community sample, (2) explore main effects of environmental risk factors on ADHD symptoms (including direct tests of gene - environment correlation), (3) test for g x e interaction effects between those environmental and genetic risk factors substantiated by main effects, and (4) investigate whether results were specific to particular symptom dimensions of ADHD. Analyses demonstrated a robust main effect of the DRD4 4-repeat allele (DRD4*4R) on ADHD symptoms rather than the DRD4 7-repeat allele (DRD4*7R), that had previously been implicated in ADHD. Analyses also revealed main effects of maternal smoking, prenatal alcohol exposure, season of birth, parental education, and television viewing habits on ADHD symptoms. After considering rG-Es, results demonstrated significant diathesis-stress g x e interactions between DRD4*4R and season of birth, maternal smoking, and parental education that selectively exacerbated hyperactive-impulsive (HI) symptoms. Exploratory analyses demonstrated a main effect of the DAT1 10-repeat allele (DAT1*10R) on ADHD-Combined Type and HI symptoms, and revealed significant interactions between DAT1*10R and parental education and season of birth on HI behaviors. Taken together, these data are consistent with a diathesis-stress model for g x e interactions in ADHD, suggest a possible alternate risk factor in linkage disequilibrium with DRD4*4R and DRD4*7R that may be the true risk allele, provide evidence that DAT1*10R may play into a subtype-specific etiology for ADHD-C, and support the idea that polymorphisms in dopaminergic genes interact with parental education and season of birth to selectively exacerbate HI symptoms

Topoclimate effects on growing season length and montane conifer growth in complex terrain

Spatial variability in the topoclimate-driven linkage between forest phenology and tree growth in complex terrain is poorly understood, limiting our understanding of how ecosystems function as a whole. To characterize the influence of topoclimate on phenology and growth, we determined the start, end, and length of the growing season (GS(start), GS(end), and GSL, respectively) using the correlation between transpiration and evaporative demand, measured with sapflow. We then compared these metrics with stem relative basal area increment (relative BAI) at seven sites among elevation and aspects in a Colorado montane forest. As elevation increased, we found shorter GSL (-50 d km(-1)) due to later GS(start) (40 d km(-1)) and earlier GS(end) (-10 d km(-1)). North-facing sites had a 21 d shorter GSL than south-facing sites at similar elevations (i.e. equal to 200 m elevation difference on a given aspect). Growing season length was positively correlated with relative BAI, explaining 83% of the variance. This study shows that topography exerts strong environmental controls on GSL and thus forest growth. Given the climate-related dependencies of these controls, the results presented here have important implications for ecosystem responses to changes in climate and highlight the need for improved phenology representation in complex terrain

Ecohydrologic separation of water between trees and streams in a Mediterranean climate

Water movement in upland humid watersheds from the soil surface to the stream is often described using the concept of translatory flow 1,2 , which assumes that water entering the soil as precipitation displaces the water that was present previously, pushing it deeper into the soil and eventually into the stream 2 . Within this framework, water at any soil depth is well mixed and plants extract the same water that eventually enters the stream. Here we present water-isotope data from various pools throughout a small watershed in the Cascade Mountains, Oregon, USA. Our data imply that a pool of tightly bound water that is retained in the soil and used by trees does not participate in translatory flow, mix with mobile water or enter the stream. Instead, water from initial rainfall events after rainless summers is locked into small pores with low matric potential until transpiration empties these pores during following dry summers. Winter rainfall does not displace this tightly bound water. As transpiration and stormflow are out of phase in the Mediterranean climate of our study site, two separate sets of water bodies with different isotopic characteristics exist in trees and streams. We conclude that complete mixing of water within the soil cannot be assumed for similar hydroclimatic regimes as has been done in the past 3,4 . Links between plant water-use (transpiration) and hydrology have been examined quantitatively since the paired-watershed studies in 1921 (ref. 5). These watershed-scale experiments clearly demonstrated links between vegetation and streamflow. However, the paired-watershed approach can only infer the mechanisms behind these vegetation-streamflow interaction

Controls on the diurnal streamflow cycles in two subbasins of an alpine headwater catchment

In high-altitude alpine catchments, diurnal streamflow cycles are typically dominated by snowmelt or ice melt. Evapotranspiration-induced diurnal streamflow cycles are less observed in these catchments but might happen simultaneously. During a field campaign in the summer 2012 in an alpine catchment in the Swiss Alps (Val Ferret catchment, 20.4 km2, glaciarized area: 2%), we observed a transition in the early season from a snowmelt to an evapotranspiration-induced diurnal streamflow cycle in one of two monitored subbasins. The two different cycles were of comparable amplitudes and the transition happened within a time span of several days. In the second monitored subbasin, we observed an ice melt-dominated diurnal cycle during the entire season due to the presence of a small glacier. Comparisons between ice melt and evapotranspiration cycles showed that the two processes were happening at the same times of day but with a different sign and a different shape. The amplitude of the ice melt cycle decreased exponentially during the season and was larger than the amplitude of the evapotranspiration cycle which was relatively constant during the season. Our study suggests that an evapotranspiration-dominated diurnal streamflow cycle could damp the ice melt-dominated diurnal streamflow cycle. The two types of diurnal streamflow cycles were separated using a method based on the identification of the active riparian area and measurement of evapotranspiration

Bayesian Routes and Unit Roots: de rebus prioribus semper est disputandum

This paper provides detailed responses to the following 8 discussants of my paper “To Criticize the Critics: An Objective Bayesian Analysis of Stochastic Trends”: Gary Koop and Mark Steel; Edward Leamer; In-Moo Kim and G. S. Maddala Dale J. Poirier; Peter C. Schotman and Herman K. van Dijk; James H. Stock; David Dejong and Charles H. Whiteman; and Christopher Sims. This reply puts new emphasis on the call made in the earlier paper for objective Bayesian analysis in time series; it underlines the need for a new approach, especially with regard to posterior odds testing; and it draws attention to a new methodology of Bayesian analysis developed in a recent paper by Phillips-Ploberger (1991). Some new simulations that shed light on certain comments of the discussants are proven; new empirical evidence is reported with the extended Nelson-Plosser data supplied by Schotman and van Dijk; and the new Phillips-Ploberger posterior odds test is given a brief empirical illustration

Information-sharing with respite care services for older adults:a qualitative exploration of carers’ experiences

This study was financially supported by the Queen’s Nursing Institute Scotland (QNIS Project ELCRI01), Edinburgh, Scotland.Respite services play an important role in supporting older adults and their carers. When an older person is unable to fully represent themselves, provision of respite care relies on effective information-sharing between carers and respite staff. This study aimed to explore, from carers’ perspectives, the scope, quality and fit of information-sharing between carers, older people and respite services. An explorative, cross-sectional qualitative study involving a purposive sample of 24 carers, recruited via carer support groups and community groups in voluntary organisations, was undertaken in North East Scotland. Data were collected from August 2013 to September 2014, with participants taking part in a focus group or individual interview. Data were analysed systematically using the Framework Approach. The multiple accounts elicited from carers identified how barriers and facilitators to information-sharing with respite services changed over time across three temporal phases: ‘Reaching a point’, ‘Trying it out’ and ‘Settled in’. Proactive information-sharing about accessibility and eligibility for respite care, and assessment of carers’ needs in their own right, were initially important; as carers and older people moved on to try services out, time and space to develop mutual understandings and negotiate care arrangements came to the fore; then, once shared expectations had been established, carers’ chief concerns were around continuity of care and maintaining good interpersonal relationships. The three temporal phases also impacted on which modes of information-sharing were available to, and worked best for, carers as well as on carers’ perceptions of how information and communication technologies should be utilised. This study highlights the need for respite staff to take proactive, flexible approaches to working with carers and to make ongoing efforts to engage with carers, and older people, throughout the months and years of them utilising respite services. Information and communication technologies have potential to enhance information-sharing but traditional approaches will remain important.PostprintPeer reviewe

“Having diabetes shouldn’t stop them”: healthcare professionals’ perceptions of physical activity in children with Type 1 diabetes

Background Healthcare professionals (HCP) working with children who have Type 1 Diabetes Mellitus (T1DM) have an important role in advising about and supporting the control of blood glucose level in relation to physical activity. Regular physical activity has known benefits for children with T1DM, but children with chronic conditions may face barriers to participation. The perceptions of HCPs were explored in an effort to understand what influences physical activity in children with T1DM and to inform the practice of those working with children who have T1DM. Methods Semi-structured interviews with 11 HCPs involved in the care of children with T1DM in the UK were conducted. Interviews were recorded, transcribed verbatim and data were analysed using thematic analysis. Results The factors perceived to influence participation in physical activity are presented as five major themes and eleven sub-themes. Themes included the positive influence of social support, the child’s motivation to be active, the potential for formal organisations such as school and diabetes clinic to support physical activity, the challenges faced by those who have T1DM and the perceived barriers to HCPs fulfilling their role of promoting physical activity. Conclusions Healthcare professionals recognised their role in helping children with T1DM and their parents to incorporate physical activity into diabetes management and everyday life, but perceived barriers to the successful fulfilment of this role. The findings highlight the potential for clinical and non-clinical supportive systems to be sensitive to these challenges and facilitate children’s regular participation in physical activity

Workplace wellness using online learning tools in a healthcare setting

The aim was to develop and evaluate an online learning tool for use with UK healthcare employees, healthcare educators and healthcare students, to increase knowledge of workplace wellness as an important public health issue. A ‘Workplace Wellness’ e-learning tool was developed and peer-reviewed by 14 topic experts. This focused on six key areas relating to workplace wellness: work-related stress, musculoskeletal disorders, diet and nutrition, physical activity, smoking and alcohol consumption. Each key area provided current evidence-based information on causes and consequences, access to UK government reports and national statistics, and guidance on actions that could be taken to improve health within a workplace setting. 188 users (93.1% female, age 18–60) completed online knowledge questionnaires before (n = 188) and after (n = 88) exposure to the online learning tool. Baseline knowledge of workplace wellness was poor (n = 188; mean accuracy 47.6%, s.d. 11.94). Knowledge significantly improved from baseline to post-intervention (mean accuracy = 77.5%, s.d. 13.71) (t(75) = −14.801, p < 0.0005) with knowledge increases evident for all included topics areas. Usability evaluation showed that participants perceived the tool to be useful (96.4%), engaging (73.8%) and would recommend it to others (86.9%). Healthcare professionals, healthcare educators and pre-registered healthcare students held positive attitudes towards online learning, indicating scope for development of further online packages relating to other important health parameters

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication