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Advanced imaging techniques are enhancing research capacity focussed on the developmental origins of adult health and disease (DOHaD) hypothesis, and consequently increasing awareness of future health risks across various subareas of DOHaD research themes. Understanding how these advanced imaging techniques in animal models and human population studies can be both additively and synergistically used alongside traditional techniques in DOHaD-focussed laboratories is therefore of great interest. Global experts in advanced imaging techniques congregated at the advanced imaging workshop at the 2019 DOHaD World Congress in Melbourne, Australia. This review summarizes the presentations of new imaging modalities and novel applications to DOHaD research and discussions had by DOHaD researchers that are currently utilizing advanced imaging techniques including MRI, hyperpolarized MRI, ultrasound, and synchrotron-based techniques to aid their DOHaD research focus.
Antidepressant use has risen x3-5 in Western countries since the early 1990s, outstripping changes in depression incidence or prevalence. This represents a major public health challenge.
Nationally-collected antidepressant data were used to assess the impact of "Doing Well", (DW) a novel depression care programme operating in Renfrewshire, Scotland. "Doing Well" implemented a model of “stepped collaborative care”, practitioner education and significant service redesign. Prescribing was compared for three groups: "DW" (76,000 population; clinical and educational intervention), "DW neighbours” (101,000 population; educational interventions only), and Scotland (no specific intervention).
A national rise in antidepressant prescriptions was stabilised for the "DW" group (graph). Antidepressant cost/item fell by 42% and 40% in both “DW” and “DW neighbours” groups but rose by 8% nationally.
Access to clinical interventions are required to reduce antidepressant prescriptions, but cost savings may be made with educational interventions alone.
Autism spectrum disorder (ASD) and schizophrenia (SCZ) are separate neurodevelopmental disorders that are both characterized by difficulties in social cognition and social functioning. Due to methodological confounds, the degree of similarity in social cognitive impairments across these two disorders is currently unknown. This study therefore conducted a comprehensive comparison of social cognitive ability in ASD and SCZ to aid efforts to develop optimized treatment programs.
In total, 101 individuals with ASD, 92 individuals with SCZ or schizoaffective disorder, and 101 typically developing (TD) controls, all with measured intelligence in the normal range and a mean age of 25.47 years, completed a large battery of psychometrically validated social cognitive assessments spanning the domains of emotion recognition, social perception, mental state attribution, and attributional style.
Both ASD and SCZ performed worse than TD controls, and very few differences were evident between the two clinical groups, with effect sizes (Cohen's d) ranging from 0.01 to 0.34. For those effects that did reach statistical significance, such as greater hostility in the SCZ group, controlling for symptom severity rendered them non-significant, suggesting that clinical distinctions may underlie these social cognitive differences. Additionally, the strength of the relationship between neurocognitive and social cognitive performance was of similar, moderate size for ASD and SCZ.
Findings largely suggest comparable levels of social cognitive impairment in ASD and SCZ, which may support the use of existing social cognitive interventions across disorders. However, future work is needed to determine whether the mechanisms underlying these shared impairments are also similar or if these common behavioral profiles may emerge via different pathways.
Currently no national guidelines exist for the management of scabies outbreaks in residential or nursing care homes for the elderly in the United Kingdom. In this setting, diagnosis and treatment of scabies outbreaks is often delayed and optimal drug treatment, environmental control measures and even outcome measures are unclear. We undertook a systematic review to establish the efficacy of outbreak management interventions and determine evidence-based recommendations. Four electronic databases were searched for relevant studies, which were assessed using a quality assessment tool drawing on STROBE guidelines to describe the quality of observational data. Nineteen outbreak reports were identified, describing both drug treatment and environmental management measures. The quality of data was poor; none reported all outcome measures and only four described symptom relief measures. We were unable to make definitive evidence-based recommendations. We draw on the results to propose a framework for data collection in future observational studies of scabies outbreaks. While high-quality randomised controlled trials are needed to determine optimal drug treatment, evidence on environmental measures will need augmentation through other literature studies. The quality assessment tool designed is a useful resource for reporting of outcome measures including patient-reported measures in future outbreaks.
Introduction: Despite significant advances in resuscitation efforts, there are some patients who remain in ventricular fibrillation (VF) after multiple shocks during out-of-hospital cardiac arrest (OHCA). Double sequential external defibrillation (DSED) has been proposed as a treatment option for patients in shock refractory VF. We sought to compare DSED to standard therapy with regards to VF termination and return of spontaneous circulation (ROSC) for patients presenting in shock refractory VF. Methods: We performed a retrospective review of all treated adult OHCA who presented in VF and received a minimum of three successive shocks over a two year period beginning on Jan 1, 2015 in four Canadian EMS agencies. Using ambulance call reports and defibrillator files, we compared VF termination (defined as the absence of VF at the rhythm check following defibrillation and 2 minutes of CPR) and VF termination into a perfusing rhythm with ROSC between patients who received standard therapy (CPR, defibrillation, epinephrine and antiarrhythmics) and those who received DSED (after on-line medical consultation) for shock refractory VF. Cases of traumatic cardiac arrest and those who presented in VF but terminated VF prior to 3 successive shocks were excluded. Results: Among 197 patients who met the study criteria for shock refractory VF, 161 (81.7%) patients received standard therapy and 36 (18.3%) received DSED. For the primary outcome, VF termination was significantly higher for DSED compared to standard therapy (63.9% vs 18.0%; Δ45.9%; 95% CI: 28.3 to 60.5). For the secondary outcome of VF termination into ROSC, DSED was associated with significantly higher ROSC compared to standard care (33.3% vs 13%; Δ20.3%; 95% CI:13.0 to 33.3). The median (IQR) number of failed standard shocks prior to DSED was 8 (6, 10). When DSED terminated VF, it did so with a single DSED shock in 69.6% of cases. Conclusion: Our observational findings suggest improved VF termination and ROSC are associated with DSED compared to standard therapy for shock refractory VF. An appropriately powered randomized controlled trial is required to assess the impact of DSED on patient-important outcomes.
Introduction: 9-1-1 telecommunicators receive minimal education on agonal breathing, often resulting in unrecognized out-of-hospital cardiac arrest (OHCA). We successfully piloted an educational intervention that significantly improved telecommunicators’ OHCA recognition and bystander CPR rates in Ottawa. We sought to better understand the operations of Canadian 9-1-1 communications centers (CC) in preparation for a multi-centre study of this intervention. Methods: We conducted a National survey of all Canadian CCs. Survey domains included information on organizational structure, dispatch system used, education curriculum, and performance monitoring. It was peer-reviewed, translated in French, pilot-tested, and distributed electronically using a modified Dillman method. We designated respondents in each CC before distribution and used targeted follow-up and small incentives to increase response rate. Respondents also described functioning of neighboring CCs if known. Results: We received information from 51/51 provincial and 1/25 territorial CCs, representing 99.7% of the Canadian population. CCs largely utilize the Medical Dispatch Priority System (MPDS) platform (93%), many are Province/Ministry regulated (50%) and most require a High School diploma as minimum entry level education (78%). Telecommunicators receive initial in-class training (median 1.3 months, IQR 0.3-1.9; range 0.1-2.2), often followed by a preceptorship (84.4%) (median 1.0 months, IQR 0.7-1.7; range 0.4-6.0). Educational curriculum includes information on agonal breathing in 41% of CC, without audio examples in 34%. Among responding CCs, over 39,000 suspected OHCA 9-1-1 calls are received annually. Few CCs maintain local performance statistics on OHCA recognition (25%), bystander CPR rates (25%) or survival rates (50%). Most (97%) expressed interest in future research collaborations. Conclusion: Most Canadian telecommunicators receive no or minimal education in recognizing agonal breathing. Further training and improved OHCA monitoring may assist recognition and enhance outcomes.
Early life experiences can affect social behaviour in later life, but opportunities for socio-behavioural development are often overlooked in current husbandry practices. This experiment investigated the effects of rearing piglets in two-stage group lactation (GL) system from 7 or 14 days of age on piglet aggression at weaning. Three lactation housing treatments were applied to a total of 198 piglets from 30 litters of multiparous sows. All dams farrowed in standard farrowing crates (FCs). Group lactation litters were transferred with their dam at 7 (GL7) or 14 days (GL14) postpartum to GL pens (one pen of five sows at 8.4 m2/sow and one pen of seven sows at 8.1 m2/sow, per GL treatment). Farrowing crate litters remained with their dam in a single litter until weaning. At weaning, 10 to 14 piglets from two unfamiliar litters from the same housing treatment were mixed into pens (n=5 pens/treatment) and their behaviour was continuously recorded for 3.5 h. For each pen, the frequency of aggressive bouts (reciprocal and non-reciprocal aggression lasting <5 s), the frequency and duration of fights (reciprocal aggression lasting ⩾5 s) and bullying events (non-reciprocal aggression lasting ⩾5 s) were recorded, along with whether interactions involved familiar or unfamiliar piglets. Aggressive bouts delivered by FC piglets were approximately 1.5 and 3.0 times more frequent than that delivered by GL7 and GL14 piglets, respectively (40.5, 16.7 and 9.9 bouts/pig, respectively; P<0.05). Fighting was more frequent (1.6, 0.3 and 0.4 fights/pig, respectively; P<0.001) and fights were longer (83, 15 and 32 s fight/pig, respectively; P<0.001) between FC piglets than between GL7 or GL14 piglets. Bullying did not differ between housing treatments (P>0.05). GL7 and GL14 piglets engaged in a similar number of fights with unfamiliar as familiar piglets, but FC piglets had almost three times as many fights with unfamiliar than with familiar piglets (P<0.05). This experiment confirms the benefits of GL housing for pig social development. Further investigation is required to determine whether mixing before 14 days postpartum has implications for other indicators of animal welfare and productivity in a two-stage GL housing system.
Loose farrowing pens have been considered as alternatives to crates to enhance sow welfare. A major concern with pen systems is often higher piglet pre-weaning mortality, especially due to crushing by the sow. An optimal management of light and mat surface temperature may promote greater piglet use of the creep, which has been associated with reduced piglet crushing. A total of 108 sows and their piglets were studied in sow welfare and piglet protection pens on a commercial piggery, across two replicates. Sows were randomly assigned to pens arranged within two creep treatments (bright creep: 300 lx v. dark creep: 4 lx), considering mat temperature as a covariate. Twelve sows and their litters in each treatment (24 in total) had their behaviour continuously recorded for 72-h postpartum (pp), and four focal piglets per litter were weighed on the first and third days pp. In situ behaviour observations were performed daily (from 0800 to 1700 h) on all sows and their litters, every 15 min over 72-h pp to record piglet time spent in the creep, latency to enter the creep for the first time, latency for the litter to remain in the creep for at least 10 min, and piglet and sow use of pen areas immediately in front of (A2) and farthest from the creep (A3). Piglets with access to bright creeps spent on average 7.2% more time (P<0.01) in the creeps than piglets in pens with Dark creeps. In addition, for each degree increase in mat temperature, piglets spent on average 2.1% more time (P<0.01) in the creep. Piglets in pens with bright creeps spent less time in A2 (P=0.04) and the least time in A3 (P=0.01). Light or mat temperature did not affect sow use of pen areas or piglet weight gain. Piglets with bright creeps tended (P=0.06) to take longer to enter the creep for the first time after birth, but the latency for 30.0% of the litter to remain clustered for 10 min tended (P=0.08) to be shorter in bright compared to dark creeps. Overall, piglet use of the creep increased with warm mat temperatures and brightness, which should be further investigated as potential strategies to promote piglet safety and reduce crushing in pen farrowing systems.
The objective of this study was to investigate the impact of the most commonly cited factors that may have influenced infants’ gut microbiota profiles at one year of age: mode of delivery, breastfeeding duration and antibiotic exposure. Barcoded V3/V4 amplicons of bacterial 16S-rRNA gene were prepared from the stool samples of 52 healthy 1-year-old Australian children and sequenced using the Illumina MiSeq platform. Following the quality checks, the data were processed using the Quantitative Insights Into Microbial Ecology pipeline and analysed using the Calypso package for microbiome data analysis. The stool microbiota profiles of children still breastfed were significantly different from that of children weaned earlier (P<0.05), independent of the age of solid food introduction. Among children still breastfed, Veillonella spp. abundance was higher. Children no longer breastfed possessed a more ‘mature’ microbiota, with notable increases of Firmicutes. The microbiota profiles of the children could not be differentiated by delivery mode or antibiotic exposure. Further analysis based on children’s feeding patterns found children who were breastfed alongside solid food had significantly different microbiota profiles compared to that of children who were receiving both breastmilk and formula milk alongside solid food. This study provided evidence that breastfeeding continues to influence gut microbial community even at late infancy when these children are also consuming table foods. At this age, any impacts from mode of delivery or antibiotic exposure did not appear to be discernible imprints on the microbial community profiles of these healthy children.
Internal gravity wave energy contributes significantly to the energy budget of the oceans, affecting mixing and the thermohaline circulation. Hence it is important to determine the internal wave energy flux
is the pressure perturbation field and
is the velocity perturbation field. However, the pressure perturbation field is not directly accessible in laboratory or field observations. Previously, a Green’s function based method was developed to calculate the instantaneous energy flux field from a measured density perturbation field
, given a constant buoyancy frequency
. Here we present methods for computing the instantaneous energy flux
for an internal wave field with vertically varying background
, as in the oceans where
typically decreases by two orders of magnitude from the pycnocline to the deep ocean. Analytic methods are presented for computing
from a density perturbation field for
varying linearly with
. To generalize this approach to arbitrary
, we present a computational method for obtaining
. The results for
for the different cases agree well with results from direct numerical simulations of the Navier–Stokes equations. Our computational method can be applied to any density perturbation data using the MATLAB graphical user interface ‘EnergyFlux’.
The extensive heterogeneity both between and within the medulloblastoma (MB) subgroups underscores a critical need for variant-specific biomarkers and therapeutic strategies. We previously identified a role for the CD271/p75 neurotrophin receptor (p75NTR) in regulating stem/progenitor cells in the SHH MB subgroup. Here, we demonstrate the utility of CD271 as a novel diagnostic and prognostic marker for SHH MB using immunohistochemical analysis as well as transcriptome data across 763 primary tumors. Characterization of CD271+ and CD271- cells by RNA sequencing revealed that these two subpopulations are molecularly distinct, co-existing cellular subsets both in vitro and in vivo. MAPK/ERK signaling is upregulated in the CD271+ population and inhibiting this pathway reduced CD271 levels, stem/progenitor cell proliferation and cell survival as well as cell migration in vitro. Importantly, the MEK inhibitor selumetinib extends survival and reduces CD271 levels in vivo. Our study demonstrates the clinical utility of CD271 as both a diagnostic and prognostic tool for SHH MB tumors and reveals a novel role for MEK inhibitors in targeting CD271+ SHH MB cells.
Introduction: Medical journals are an essential venue for knowledge translation. Skilled reviewers and editors are required to ensure quality standards in research publications and yet postgraduate programs rarely include this training in their curricula. Imparting appropriate skills and developing capacity in journalship has thus proved challenging. The Canadian Journal of Emergency Medicine (CJEM) is the national journal for Emergency Medicine (EM) in Canada. The CJEM editorial board recently decided to provide longitudinal mentorship for junior academic faculty members and trainees through an editorial internship. The internship had three goals for participants: (1) introduce and develop the responsibilities and skills of a good editor; (2) enhance a career in academic EM; and, (3) galvanize future participation as a reviewer or editor in scientific publications. Methods: The senior editorial board of CJEM and the inaugural intern developed a one-year Editorial Internship that was launched in June 2017. The curricular framework was designed by current and prior CJEM senior editors from four Canadian universities, and was informed by similar programs in the United States. The curriculum was refined iteratively based on feedback and discussion between the senior editors and intern. The internship was designed for a single individual in the Canadian EM community, including residents, pediatric fellows and practicing emergency physicians. Results: To develop the responsibilities and skills of being a good editor, the intern performed six mentored reviews of manuscripts either under current review at CJEM or previous submissions identified as difficult peer review decisions. In addition, the intern learned about CJEM values and norms by participating in monthly videoconference meetings and quarterly editorial board meetings. To enhance an academic career, the intern was assigned two writing projects under the guidance of senior editors for publication in CJEM, and completed an online critical appraisal course. Conclusion: The inaugural editorial intern gained experience as an editor and produced scholarly work. We feel the internship met its first two goals, and CJEM has committed to continue the internship annually. The ultimate determination of whether the internship achieved its third goal will only be known after longitudinal tracking of participants career involvement in academic publishing and editing.
An outbreak of mumps within a student population in Scotland was investigated to assess the effect of previous vaccination on infection and clinical presentation, and any genotypic variation. Of the 341 cases, 79% were aged 18–24. Vaccination status was available for 278 cases of whom 84% had received at least one dose of mumps containing vaccine and 62% had received two. The complication rate was 5·3% (mainly orchitis), and 1·2% were admitted to hospital. Genetic sequencing of mumps virus isolated from cases across Scotland classified 97% of the samples as genotype G. Two distinct clusters of genotype G were identified, one circulating before the outbreak and the other thereafter, suggesting the virus that caused this outbreak was genetically different from the previously circulating virus. Whilst the poor vaccine effectiveness we found may be due to waning immunity over time, a contributing factor may be that the current mumps vaccine is less effective against some genotypes. Although the general benefits of the measles–mumps–rubella (MMR) vaccine should continue to be promoted, there may be value in reassessing the UK vaccination schedule and the current mumps component of the MMR vaccine.
Cardiometabolic diseases exhibit changes in lipid biology, which is important as lipids have critical roles in membrane architecture, signalling, hormone synthesis, homoeostasis and metabolism. However, Developmental Origins of Health and Disease studies of cardiometabolic disease rarely include analysis of lipids. This short review highlights some examples of lipid pathology and then explores the technology available for analysing lipids, focussing on the need to develop imaging modalities for intracellular lipids. Analytical methods for studying interactions between the complex endocrine and intracellular signalling pathways that regulate lipid metabolism have been critical in expanding our understanding of how cardiometabolic diseases develop in association with obesity and dietary factors. Biochemical methods can be used to generate detailed lipid profiles to establish links between lifestyle factors and metabolic signalling pathways and determine how changes in specific lipid subtypes in plasma and homogenized tissue are associated with disease progression. New imaging modalities enable the specific visualization of intracellular lipid traffic and distribution in situ. These techniques provide a dynamic picture of the interactions between lipid storage, mobilization and signalling, which operate during normal cell function and are altered in many important diseases. The development of methods for imaging intracellular lipids can provide a dynamic real-time picture of how lipids are involved in complex signalling and other cell biology pathways; and how they ultimately regulate metabolic function/homoeostasis during early development. Some imaging modalities have the potential to be adapted for in vivo applications, and may enable the direct visualization of progression of pathogenesis of cardiometabolic disease after poor growth in early life.
The Vlasov–Maxwell equations possess a Hamiltonian structure expressed in terms of a Hamiltonian functional and a functional bracket. In the present paper, the transformation (‘lift’) of the Vlasov–Maxwell bracket induced by the dynamical reduction of single-particle dynamics is investigated when the reduction is carried out by Lie-transform perturbation methods. The ultimate goal of this work is to provide an explicit pathway to the Hamiltonian formulations for the guiding-centre and gyrokinetic Vlasov–Maxwell equations, which have found important applications in our understanding of turbulent magnetized plasmas. Here, it is shown that the general form of the reduced Vlasov–Maxwell equations possesses a Hamiltonian structure defined in terms of a reduced Hamiltonian functional and a reduced bracket that automatically satisfies the standard bracket properties.
Epidemiology formed the basis of ‘the Barker hypothesis’, the concept of ‘developmental programming’ and today’s discipline of the Developmental Origins of Health and Disease (DOHaD). Animal experimentation provided proof of the underlying concepts, and continues to generate knowledge of underlying mechanisms. Interventions in humans, based on DOHaD principles, will be informed by experiments in animals. As knowledge in this discipline has accumulated, from studies of humans and other animals, the complexity of interactions between genome, environment and epigenetics, has been revealed. The vast nature of programming stimuli and breadth of effects is becoming known. As a result of our accumulating knowledge we now appreciate the impact of many variables that contribute to programmed outcomes. To guide further animal research in this field, the Australia and New Zealand DOHaD society (ANZ DOHaD) Animals Models of DOHaD Research Working Group convened at the 2nd Annual ANZ DOHaD Congress in Melbourne, Australia in April 2015. This review summarizes the contributions of animal research to the understanding of DOHaD, and makes recommendations for the design and conduct of animal experiments to maximize relevance, reproducibility and translation of knowledge into improving health and well-being.
Prenatal and early-life environmental exposures play a key role in the development of atopy and allergic disease. The Family Atherosclerosis Monitoring In earLY life Study is a general, population-based Canadian birth cohort that prospectively evaluated prenatal and early-life traits and their association with atopy and/or allergic disease. The study population included 901 babies, 857 mothers and 530 fathers. Prenatal and postnatal risk factors were evaluated through questionnaires collected during the antenatal period and at 1 year. The end points of atopy and allergic diseases in infants were evaluated through questionnaires and skin prick testing. Key outcomes included atopy (24.5%), food allergy (17.5%), cow’s milk allergy (4.8%), wheezing (18.6%) and eczema (16%). The association between infant antibiotic exposure [odds ratio (OR): 2.04, 95% confidence interval (CI): 1.45–2.88] and increased atopy was noted in the multivariate analysis, whereas prenatal maternal exposure to dogs (OR: 0.60, 95% CI: 0.42–0.84) and acetaminophen (OR: 0.68, 95% CI: 0.51–0.92) was associated with decreased atopy. This population-based birth cohort in Canada demonstrated high rates of atopy, food allergy, wheezing and eczema. Several previously reported and some novel prenatal and postnatal exposures were associated with atopy and allergic diseases at 1 year of age.