Unraveling the architecture of the dorsal raphe synaptic neuropil using high-resolution neuroanatomy

The dorsal raphe nucleus (DRN), representing the main source of brain’s serotonin, is implicated in the pathophysiology and therapeutics of several mental disorders that can be debilitating and life-long including depression, anxiety and autism. The activity of DRN neurons is precisely regulated, both phasically and tonically, by excitatory glutamate and inhibitory GABAergic axons arising from extra-raphe areas as well as from local sources within the nucleus. Changes in serotonin neurotransmission associated with pathophysiology may be encoded by alterations within this network of regulatory afferents. However, the complex organization of the DRN circuitry remains still poorly understood. Using a recently developed high-resolution immunofluorescence technique called array tomography (AT) we quantitatively analyzed the relative contribution of different populations of glutamate axons originating from different brain regions to the excitatory drive of the DRN. Additionally, we examined the presence of GABA axons within the DRN and their possible association with glutamate axons. In this review, we summarize our findings on the architecture of the rodent DRN synaptic neuropil using high-resolution neuroanatomy, and discuss possible functional implications for the nucleus. Understanding of the synaptic architecture of neural circuits at high resolution will pave the way to understand how neural structure and function may be perturbed in pathological states

Comparing, contrasting, and integrating dissemination and implementation outcomes included in the RE-AIM and Implementation Outcomes Frameworks

As the field of dissemination and implementation science matures, there are a myriad of outcomes, identified in numerous frameworks, that can be considered across individual, organizational, and population levels. This can lead to difficulty in summarizing literature, comparing across studies, and advancing translational science. This manuscript sought to (1) compare, contrast, and integrate the outcomes included in the RE-AIM and Implementation Outcomes Frameworks (IOF) and (2) expand RE-AIM indicators to include relevant IOF dissemination and implementation outcomes. Cross tabular comparisons were made between the constitutive definitions of each construct, across frameworks, to reconcile apparent discrepancies between approaches and to distinguish between implementation outcomes and implementation antecedents. A great deal of consistency was identified across approaches, including adoption (the intention, initial decision, or action to employ an evidence-based intervention), fidelity/implementation (the degree to which an intervention was delivered as intended), organizational maintenance/sustainability (extent to which a newly implemented treatment is maintained or institutionalized), and cost. The IOF construct of penetration was defined as a higher-order construct that may encompass the reach, adoption, and organizational maintenance outcomes within RE-AIM. Within the IOF approach acceptability, appropriateness, and feasibility did not match constitutive definitions of dissemination or implementation but rather reflected theoretical antecedents of implementation outcomes. Integration of the IOF approach across RE-AIM indicators was successfully achieved by expanding the operational definitions of RE-AIM to include antecedents to reach, adoption, implementation, and organizational maintenance. Additional combined metrics were also introduced including penetration, individual level utility, service provider utility, organizational utility, and systemic utility. The expanded RE-AIM indicators move beyond the current approaches described within both the REAIM framework and IOF and provides additional planning and evaluation targets that can contribute to the scientific field and increase the translation of evidence into practice

Risk factors for eating disorder symptoms at 12 years of age: A 6-year longitudinal cohort study

Eating disorders pose risks to health and wellbeing in young adolescents, but prospective studies of risk factors are scarce and this has impeded prevention efforts. This longitudinal study aimed to examine risk factors for eating disorder symptoms in a population-based birth cohort of young adolescents at 12 years. Participants from the Gateshead Millennium Study birth cohort (n = 516; 262 girls and 254 boys) completed self-report questionnaire measures of eating disorder symptoms and putative risk factors at age 7 years, 9 years and 12 years, including dietary restraint, depressive symptoms and body dissatisfaction. Body mass index (BMI) was also measured at each age. Within-time correlates of eating disorder symptoms at 12 years of age were greater body dissatisfaction for both sexes and, for girls only, higher depressive symptoms. For both sexes, higher eating disorder symptoms at 9 years old significantly predicted higher eating disorder symptoms at 12 years old. Dietary restraint at 7 years old predicted boys' eating disorder symptoms at age 12, but not girls'. Factors that did not predict eating disorder symptoms at 12 years of age were BMI (any age), girls’ dietary restraint at 7 years and body dissatisfaction at 7 and 9 years of age for both sexes. In this population-based study, different patterns of predictors and correlates of eating disorder symptoms were found for girls and boys. Body dissatisfaction, a purported risk factor for eating disorder symptoms in young adolescents, developed concurrently with eating disorder symptoms rather than preceding them. However, restraint at age 7 and eating disorder symptoms at age 9 years did predict 12-year eating disorder symptoms. Overall, our findings suggest that efforts to prevent disordered eating might beneficially focus on preadolescent populations

Development of sedentary behavior across childhood and adolescence : longitudinal analysis of the Gateshead Millennium Study

Background In many parts of the world policy and research interventions to modify sedentary behavior of children and adolescents are now being developed. However, the evidence to inform these interventions (e.g. how sedentary behavior changes across childhood and adolescence) is limited. This study aimed to assess longitudinal changes in sedentary behavior, and examine the degree of tracking of sedentary behavior from age 7y to 15y. Methods Participants were part of the Gateshead Millennium Study cohort. Measures were made at age 7y (n = 507), 9y (n = 510), 12y (n = 425) and 15y (n = 310). Participants were asked to wear an ActiGraph GT1M and accelerometer epochs were defined as sedentary when recorded counts were ≤25 counts/15 s. Differences in sedentary time and sedentary fragmentation were examined using the Friedman test. Tracking was examined using Spearman’s correlation coefficients and trajectories over time were assessed using multilevel linear spline modelling. Results Median daily sedentary time increased from 51.3 % of waking hours at 7y to 74.2 % at 15y. Sedentary fragmentation decreased from 7y to 15y. The median number of breaks/hour decreased from 8.6 to 4.1 breaks/hour and the median bout duration at 50 % of the cumulative sedentary time increased from 2.4 min to 6.4 min from 7y to 15y. Tracking of sedentary time and sedentary fragmentation was moderate from 7y to 15y however, the rate of change differed with the steepest increases/decreases seen between 9y and 12y. Conclusion In this study, sedentary time was high and increased to almost 75 % of waking hours at 15y. Sedentary behavior became substantially less fragmented as children grew older. The largest changes in sedentary time and sedentary fragmentation occurred between 9y to 12y, a period which spans the transition to secondary school. These results can be used to inform future interventions aiming to change sedentary behavior

Can't play, won't play : longitudinal changes in perceived barriers to participation in sports clubs across the child-adolescent transition

Participation in sports is associated with numerous physical and psychosocial health benefits, however, participation declines with age, and knowledge of perceived barriers to participation in children is lacking. This longitudinal study of children and adolescents aimed to use the ecological model of physical activity to assess changes in barriers to participation in sports clubs to identify age- and weight-specific targets for intervention

Book Review Roundtable: Kathryn E. Stoner’s Russia Resurrected: Its Power and Purpose in a New Global Order and James Reilly’s Orchestration: China’s Economic Statecraft Across Asia and Europe

This double book review roundtable examines the drivers and international influence of Russia and China. It features Kathryn Stoner’s Russia Resurrected: Its Power and Purpose in a New Global Order and James Reilly’s Orchestration: China’s Economic Statecraft Across Asia and Europe

Non-linear longitudinal associations between moderate-to-vigorous physical activity and adiposity across the adiposity distribution during childhood and adolescence : Gateshead Millennium Study

Objective: Insufficient moderate-to-vigorous intensity physical activity (MVPA) is harmful for youth; however, the evidence for differential effects by weight status is limited. The study aimed to examine associations between MVPA and adiposity by weight status across childhood and adolescence. Methods: Participants were from the Gateshead Millennium Study. Physical activity and body composition measures were taken at age 7y (n=502; measures taken between October 2006-December 2007), 9y (n=506; October 2008-September 2009), 12y (n=420; October 2011-September 2012) and 15y (n=306; September 2014-September 2015). Participants wore an ActiGraph GT1M and epochs were classified as MVPA when accelerometer counts were ≥574 counts/15s. Weight and height were measured using standardised methods and fat mass using bioelectrical impedance. Associations between MVPA and changes in BMI and FMI were examined by weight status using quantile regression. Results: Higher MVPA was associated with lower FMI for the 25th, 50th, 75th and 90th percentile and lower BMI at the 50th, 75th and 90th percentile, independent of accelerometer wear time, sex and sedentary time. The association between MVPA and change in adiposity was stronger in the higher than lower FMI and BMI percentiles (e.g. 1hr/day more MVPA was associated with a 1.5 kg/m2 and 2.7 kg/m2 lower FMI at the 50th and 90th FMI percentiles, respectively). Conclusion: The effect of MVPA on adiposity in the higher adiposity percentiles is stronger than reported to date. Given overweight and obese children are the highest risk group for later obesity, targeting MVPA might be a particularly effective obesity prevention strategy

GRADE-ADOLOPMENT process to develop 24-hour movement behavior recommendations and physical activity guidelines for the under 5s in the United Kingdom, 2019

Background: This article summarizes the approach taken to develop UK Chief Medical Officers' physical activity guidelines for the Under 5s, 2019. Methods: The Grading of Recommendations Assessment, Development and Evaluation (GRADE)- Adaptation, Adoption, De Novo Development (ADOLOPMENT) approach was used, based on the guidelines from Canada and Australia, with evidence updated to February 2018. Recommendations were based on the associations between (1) time spent in sleep, sedentary time, physical activity, and 10 health outcomes and (2) time spent in physical activity and sedentary behavior on sleep outcomes (duration and latency). Results: For many outcomes, more time spent in physical activity and sleep (up to a point) was beneficial, as was less time spent in sedentary behavior. The authors present, for the first time, evidence in GRADE format on behavior type-outcome associations for infants, toddlers, and preschoolers. Stakeholders supported all recommendations, but recommendations on sleep and screen time were not accepted by the Chief Medical Officers; UK guidelines will refer only to physical activity. Conclusions: This is the first European use of GRADE-ADOLOPMENT to develop physical activity guidelines. The process is robust, rapid, and inexpensive, but the UK experience illustrates a number of challenges that should help development of physical activity guidelines in future

Plasma sTNFR1 and IL8 for prognostic enrichment in sepsis trials: a prospective cohort study.

BackgroundEnrichment strategies improve therapeutic targeting and trial efficiency, but enrichment factors for sepsis trials are lacking. We determined whether concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1), interleukin-8 (IL8), and angiopoietin-2 (Ang2) could identify sepsis patients at higher mortality risk and serve as prognostic enrichment factors.MethodsIn a multicenter prospective cohort study of 400 critically ill septic patients, we derived and validated thresholds for each marker and expressed prognostic enrichment using risk differences (RD) of 30-day mortality as predictive values. We then used decision curve analysis to simulate the prognostic enrichment of each marker and compare different prognostic enrichment strategies.Measurements and main resultsAn admission sTNFR1 concentration > 8861 pg/ml identified patients with increased mortality in both the derivation (RD 21.6%) and validation (RD 17.8%) populations. Among immunocompetent patients, an IL8 concentration > 94 pg/ml identified patients with increased mortality in both the derivation (RD 17.7%) and validation (RD 27.0%) populations. An Ang2 level > 9761 pg/ml identified patients at 21.3% and 12.3% increased risk of mortality in the derivation and validation populations, respectively. Using sTNFR1 or IL8 to select high-risk patients improved clinical trial power and efficiency compared to selecting patients with septic shock. Ang2 did not outperform septic shock as an enrichment factor.ConclusionsThresholds for sTNFR1 and IL8 consistently identified sepsis patients with higher mortality risk and may have utility for prognostic enrichment in sepsis trials

Endogenous Cholinergic Neurotransmission Contributes to Behavioral Sensitization to Morphine

Neuroplasticity in the mesolimbic dopaminergic system is critical for behavioral adaptations associated with opioid reward and addiction. These processes may be influenced by cholinergic transmission arising from the laterodorsal tegmental nucleus (LDTg), a main source of acetylcholine to mesolimbic dopaminergic neurons. To examine this possibility we asked if chronic systemic morphine administration affects expression of genes in ventral and ventrolateral periaqueductal gray at the level of the LDTg using rtPCR. Specifically, we examined gene expression changes in the area of interest using Neurotransmitters and Receptors PCR array between chronic morphine and saline control groups. Analysis suggested that chronic morphine administration led to changes in expression of genes associated, in part, with cholinergic neurotransmission. Furthermore, using a quantitative immunofluorescent technique, we found that chronic morphine treatment produced a significant increase in immunolabeling of the cholinergic marker (vesicular acetylcholine transporter) in neurons of the LDTg. Finally, systemic administration of the nonselective and noncompetitive neuronal nicotinic antagonist mecamylamine (0.5 or 2 mg/kg) dose-dependently blocked the expression, and to a lesser extent the development, of locomotor sensitization. The same treatment had no effect on acute morphine antinociception, antinociceptive tolerance or dependence to chronic morphine. Taken together, the results suggest that endogenous nicotinic cholinergic neurotransmission selectively contributes to behavioral sensitization to morphine and this process may, in part, involve cholinergic neurons within the LDTg