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AIM To describe how generic preference-based health-related quality of life (HRQoL) instruments have been used in research involving children with neurodevelopmental disorders (NDD). METHOD A systematic search of nine databases identified studies that used generic preference-based HRQoL instruments in children with NDD. Data extracted following the Preferred Reporting Items for Systematic Review and Meta-Analyses extension for Scoping Review guidelines included type of NDD, instrument used, respondent type, justification, and critical appraisal for these selections. RESULTS Thirty-six studies were identified: four cost-utility analyses; 15 HRQoL assessments; five economic burden studies; three intervention studies; and nine 'other'. The Health Utilities Index (Mark 2 and Mark 3) and EuroQoL 5D (EQ-5D; three-level EQ-5D, five-level EQ-5D, and the youth version of the EQ-5D) instruments were most frequently used (44% and 31% respectively). The relatively low use of these instruments overall may be due to a lack of psychometric evidence, inconsistency in justification for and lack of clarity on appropriate respondent type and age, and geographical challenges in applying preference weights. INTERPRETATION This study highlights the dearth of studies using generic preference-based HRQoL instruments in children with NDD. The use of cost-utility analysis in this field is limited and validation of these instruments for children with NDD is needed. The quality of data should be considered before guiding policy and care decisions. WHAT THIS PAPER ADDS Limited use of generic preference-based health-related quality of life (HRQoL) instruments in studies on children with neurodevelopmental disorders. Only 11% of studies were cost-utility analyses. Inconsistencies in justification for choosing generic preference-based HRQoL instruments and respondent types.

For new technology and innovation such as precision medicine to become part of the solution for the fiscal sustainability of Canadian Medicare, decision-makers need to change how services are priced rather than trying to restrain emerging technologies like precision medicine for short-term cost savings. If provincial public payers shift their thinking to be public purchasers, value considerations would direct reform of the reimbursement system to have prices that adjust with technologically driven productivity gains. This strategic shift in thinking is necessary if Canadians are to benefit from the promised benefits of innovations like precision medicine.

BackgroundPregnancy is a critical time for fetal development, and education of women regarding healthy lifestyle choices is an important function for prenatal care providers, those that provide care to women during pregnancy. Within Canada, women choose to receive pregnancy care from one of a variety of publicly funded care providers. This study examines the association between the type of care provider(s) seen during pregnancy and the provision of advice related to nutrition, weight management and substance abuse.MethodsUsing data from the Alberta-based All Our Families prospective pregnancy cohort, we conducted bivariate and multivariate analyses to determine the likelihood of receiving advice related to nutrition, weight management, and substance abuse across provider(s) seen.ResultsOf 3341 women in our sample, 38% saw a single provider during pregnancy and 56% received care from multiple providers. Advice on nutrition was more likely to be provided across all providers, while weight management and substance abuse was less frequently and less consistently discussed. Relative to doctors in low-risk maternity clinics, midwives were most likely to provide nutrition (OR: 3.09, 95% CI: 1.19-8.01) and weight management (OR: 1.99, 95% CI: 1.13-3.50) advice to women.ConclusionFindings suggest that the type of prenatal advice received by women depends on the provider(s) seen during pregnancy. Substance abuse was least likely to be discussed across providers, suggesting important implications given recent cannabis legalization.

BACKGROUND: Escalating health care spending is a concern in Western countries, given the lack of evidence of a direct connection between spending and improvements in health. We aimed to determine the association between spending on health care and social programs and health outcomes in Canada. METHODS: We used retrospective data from Canadian provincial expenditure reports, for the period 1981 to 2011, to model the effects of social and health spending (as a ratio, social/health) on potentially avoidable mortality, infant mortality and life expectancy. We used linear regressions, accounting for provincial fixed effects and time, and controlling for confounding variables at the provincial level. RESULTS: A 1-cent increase in social spending per dollar spent on health was associated with a 0.1% (95% confidence interval [CI] 0.04% to 0.16%) decrease in potentially avoidable mortality and a 0.01% (95% CI 0.01% to 0.02%) increase in life expectancy. The ratio had a statistically nonsignificant relationship with infant mortality (p = 0.2). INTERPRETATION: Population-level health outcomes could benefit from a reallocation of government dollars from health to social spending, even if total government spending were left unchanged. This result is consistent with other findings from Canada and the United States.

Background Early detection of neurodevelopmental disorders (NDDs) enables access to early interventions for children. We assess the Ages and Stages Questionnaire (ASQ)’s ability to identify children with a NDD in population data. Method Children 4 to 5 years old in the National Longitudinal Survey of Children and Youth (NLSCY) from cycles 5 to 8 were included. The sensitivity, specificity, positive and negative predictive values were calculated for the ASQ at 24, 27, 30, 33, 36 and 42 months. Fixed effects regression analyses assessed longitudinal associations between domain scores and child age. Results Specificity for the ASQ was high with 1SD or 2SD cutoffs, indicating good accuracy in detecting children who will not develop a NDD, however the sensitivity varied over time points and cut-offs. Sensitivity for the 1 SD cutoff at 24 months was above the recommended value of 70% for screening. Differences in ASQ domains scores between children with and without NDD increases with age. Conclusions The high specificity and negative predictive values of the ASQ support its use in identifying children who are not at the risk of developing a NDD. The capacity of the ASQ to identify children with a NDD in the general population is limited except for the ASQ-24 months with 1SD and can be used to identify children at risk of NDD. Electronic supplementary material The online version of this article (10.1186/s12887-018-1105-z) contains supplementary material, which is available to authorized users.

In terrestrial mammals, the oxygen storage capacity of the CNS is limited, and neuronal function is rapidly impaired if oxygen supply is interrupted even for a short period of time. However, oxygen tension monitored by the peripheral (arterial) chemoreceptors is not sensitive to regional CNS differences in partial pressure of oxygen (PO2 ) that reflect variable levels of neuronal activity or local tissue hypoxia, pointing to the necessity of a functional brain oxygen sensor. This experimental animal (rats and mice) study shows that astrocytes, the most numerous brain glial cells, are sensitive to physiological changes in PO2 . Astrocytes respond to decreases in PO2 a few millimeters of mercury below normal brain oxygenation with elevations in intracellular calcium ([Ca(2+)]i). The hypoxia sensor of astrocytes resides in the mitochondria in which oxygen is consumed. Physiological decrease in PO2 inhibits astroglial mitochondrial respiration, leading to mitochondrial depolarization, production of free radicals, lipid peroxidation, activation of phospholipase C, IP3 receptors, and release of Ca(2+) from the intracellular stores. Hypoxia-induced [Ca(2+)]i increases in astrocytes trigger fusion of vesicular compartments containing ATP. Blockade of astrocytic signaling by overexpression of ATP-degrading enzymes or targeted astrocyte-specific expression of tetanus toxin light chain (to interfere with vesicular release mechanisms) within the brainstem respiratory rhythm-generating circuits reveals the fundamental physiological role of astroglial oxygen sensitivity; in low-oxygen conditions (environmental hypoxia), this mechanism increases breathing activity even in the absence of peripheral chemoreceptor oxygen sensing. These results demonstrate that astrocytes are functionally specialized CNS oxygen sensors tuned for rapid detection of physiological changes in brain oxygenation. Significance statement: Most, if not all, animal cells possess mechanisms that allow them to detect decreases in oxygen availability leading to slow-timescale, adaptive changes in gene expression and cell physiology. To date, only two types of mammalian cells have been demonstrated to be specialized for rapid functional oxygen sensing: glomus cells of the carotid body (peripheral respiratory chemoreceptors) that stimulate breathing when oxygenation of the arterial blood decreases; and pulmonary arterial smooth muscle cells responsible for hypoxic pulmonary vasoconstriction to limit perfusion of poorly ventilated regions of the lungs. Results of the present study suggest that there is another specialized oxygen-sensitive cell type in the body, the astrocyte, that is tuned for rapid detection of physiological changes in brain oxygenation.

The employment rate among persons with autism spectrum disorder has been noted as unacceptably low. Employment-support services are increasingly linked to the potential for favorable job outcomes, yet little is known about employment-support practices and the outcome of these interventions. This mixed-methods study examined employment-support resources for persons with autism spectrum disorder. An online survey was completed by 137 senior clinicians or administrators in employment-support programs in Canada. Additionally, 122 follow-up interviews were conducted with individuals with autism spectrum disorder (n = 71) and their parents/caregivers (n = 51). Findings indicate that the quality and beneficial impact of employment-support services for adults with autism spectrum disorder may be more favorably perceived by employment-support personnel than by individuals with autism spectrum disorder and their families. Furthermore, employment-support personnel were more disparaging about autism spectrum disorder vocational support capacity within their community, compared to their own programs. Individuals with autism spectrum disorder and their families seek services that support both accessing and retaining employment. Capacity-building in employment support for youth and adults with autism spectrum disorder is recommended, based on a reported insufficiency of, and a lack of evidence guiding, existing services. Program recommendations and an emerging model for integrated vocational support in autism spectrum disorder are offered.

KEY POINTS: The ventilatory response to reduced oxygen (hypoxia) is biphasic, comprising an initial increase in ventilation followed by a secondary depression. Our findings indicate that, during hypoxia, astrocytes in the pre‐Bötzinger complex (preBötC), a critical site of inspiratory rhythm generation, release a gliotransmitter that acts via P2Y(1) receptors to stimulate ventilation and reduce the secondary depression. In vitro analyses reveal that ATP excitation of the preBötC involves P2Y(1) receptor‐mediated release of Ca(2+) from intracellular stores. By identifying a role for gliotransmission and the sites, P2 receptor subtype, and signalling mechanisms via which ATP modulates breathing during hypoxia, these data advance our understanding of the mechanisms underlying the hypoxic ventilatory response and highlight the significance of purinergic signalling and gliotransmission in homeostatic control. Clinically, these findings are relevant to conditions in which hypoxia and respiratory depression are implicated, including apnoea of prematurity, sleep disordered breathing and congestive heart failure. ABSTRACT: The hypoxic ventilatory response (HVR) is biphasic, consisting of a phase I increase in ventilation followed by a secondary depression (to a steady‐state phase II) that can be life‐threatening in premature infants who suffer from frequent apnoeas and respiratory depression. ATP released in the ventrolateral medulla oblongata during hypoxia attenuates the secondary depression. We explored a working hypothesis that vesicular release of ATP by astrocytes in the pre‐Bötzinger Complex (preBötC) inspiratory rhythm‐generating network acts via P2Y(1) receptors to mediate this effect. Blockade of vesicular exocytosis in preBötC astrocytes bilaterally (using an adenoviral vector to specifically express tetanus toxin light chain in astrocytes) reduced the HVR in anaesthetized rats, indicating that exocytotic release of a gliotransmitter within the preBötC contributes to the hypoxia‐induced increases in ventilation. Unilateral blockade of P2Y(1) receptors in the preBötC via local antagonist injection enhanced the secondary respiratory depression, suggesting that a significant component of the phase II increase in ventilation is mediated by ATP acting at P2Y(1) receptors. In vitro responses of the preBötC inspiratory network, preBötC inspiratory neurons and cultured preBötC glia to purinergic agents demonstrated that the P2Y(1) receptor‐mediated increase in fictive inspiratory frequency involves Ca(2+) recruitment from intracellular stores leading to increases in intracellular Ca(2+) ([Ca(2+)](i)) in inspiratory neurons and glia. These data suggest that ATP is released by preBötC astrocytes during hypoxia and acts via P2Y(1) receptors on inspiratory neurons (and/or glia) to evoke Ca(2+) release from intracellular stores and an increase in ventilation that counteracts the hypoxic respiratory depression.

Purpose A growing number of cancer survivors suffer high levels of distress, depression and stress, as well as sleep disturbance, pain and fatigue. Two different mind-body interventions helpful for treating these problems are Mindfulness-Based Cancer Recovery (MBCR) and Tai Chi/Qigong (TCQ). However, while both interventions show efficacy compared to usual care, they have never been evaluated in the same study or directly compared. This study will be the first to incorporate innovative design features including patient choice while evaluating two interventions to treat distressed cancer survivors. It will also allow for secondary analyses of which program best targets specific symptoms in particular groups of survivors, based on preferences and baseline characteristics. Methods and significance The design is a preference-based multi-site randomized comparative effectiveness trial. Participants (N = 600) with a preference for either MBCR or TCQ will receive their preferred intervention; while those without a preference will be randomized into either intervention. Further, within the preference and non-preference groups, participants will be randomized into immediate intervention or wait-list control. Total mood disturbance on the Profile of mood states (POMS) post-intervention is the primary outcome. Other measures taken pre- and post-intervention and at 6-month follow-up include quality of life, psychological functioning, cancer-related symptoms and physical functioning. Exploratory analyses investigate biomarkers (cortisol, cytokines, blood pressure/Heart Rate Variability, telomere length, gene expression), which may uncover potentially important effects on key biological regulatory and antineoplastic functions. Health economic measures will determine potential savings to the health system.

BACKGROUND: Maternal age at pregnancy has shown right shift, increasing in recent decades. Advanced maternal age is associated with increased obstetrical and perinatal complications. The impact of maternal age on neurodevelopmental (ND) outcomes of preterm infants remains unknown.

There is a concern that the allocation of autism spectrum disorder (ASD) research funding may be misallocating resources, overemphasizing basic science at the expense of translational and clinical research. Anthony Bailey has proposed that an economic evaluation of autism research funding allocations could be beneficial for funding agencies by identifying under- or overfunded areas of research. In response to Bailey, we illustrate why economics cannot provide an objective, technical solution for identifying the "best" allocation of research resources. Economic evaluation has its greatest power as a late-stage research tool for interventions with identified objectives, outcomes, and data. This is not the case for evaluating whether research areas are over- or underfunded. Without an understanding of how research funding influences the likelihood and value of a discovery, or without a statement of the societal objectives for ASD research and level of risk aversion, economic analysis cannot provide a useful normative evaluation of ASD research.

Background As a signatory to the UN Convention on the Rights of Persons with Disabilities, Canada has committed to protect the rights and dignity of persons with developmental disabilities (DD), which means that labour markets, education, and training opportunities should be inclusive and accessible. Purpose Describe the unmet employment, education and daily needs of adults with DD, with a sub analysis of persons with autism spectrum disorder (ASD) and cerebral palsy (CP) in Canada, to inform efficient and equitable policy development. Methods and procedures Secondary analysis of 2012 Canadian Survey on Disability was used to study a sample including working age (15–64 years old) individuals with self-reported DD, CP and ASD. Persons with DD reported on their met and unmet needs in term of activities of daily living, education and employment. Outcomes and results Labour force participation is the lowest for those with DD compared to any other disability. Individuals with CP and ASD report a high level of unmet needs that differ in terms of educational, vocational and daily living supports. Conclusions and implications Improving labour force participation to be inclusive and accessible requires policy that considers the range of unmet needs that exist for persons with DD.

ATP signalling in the CNS is mediated by a three-part system comprising the actions of ATP (and ADP) at P2 receptors (P2Rs), adenosine (ADO) at P1 receptors (P1Rs), and ectonucleotidases that degrade ATP into ADO. ATP excites preBotzinger complex (preBotC) inspiratory rhythm-generating networks where its release attenuates the hypoxic depression of breathing. Its metabolite, ADO, inhibits breathing through unknown mechanisms that may involve the preBotC. Our objective is to understand the dynamics of this signalling system and its influence on preBotC networks. We show that the preBotC of mouse and rat is sensitive to P2Y(1) purinoceptor (P2Y(1)R) activation, responding with a >2-fold increase in frequency. Remarkably, the mouse preBotC is insensitive to ATP. Only after block of A(1) ADORs is the ATP-evoked, P2Y(1)R-mediated frequency increase observed. This demonstrates that ATP is rapidly degraded to ADO, which activates inhibitory A(1)Rs, counteracting the P2Y(1)R-mediated excitation. ADO sensitivity of mouse preBotC was confirmed by a frequency decrease that was absent in rat. Differential ectonucleotidase activities are likely to contribute to the negligible ATP sensitivity of mouse preBotC. Real-time PCR analysis of ectonucleotidase isoforms in preBotC punches revealed TNAP (degrades ATP to ADO) or ENTPDase2 (favours production of excitatory ADP) as the primary constituent in mouse and rat, respectively. These data further establish the sensitivity of this vital network to P2Y(1)R-mediated excitation, emphasizing that individual components of the three-part signalling system dramatically alter network responses to ATP. Data also suggest therapeutic potential may derive from methods that alter the ATP-ADO balance to favour the excitatory actions of ATP.

The hypoxic ventilatory response (HVR) comprises an initial increase in ventilation followed by a secondary depression. We tested the hypothesis that the exocytotic release of ATP by astrocytes in ...

Opioids activate glia in the central nervous system in part by activating the toll-like receptor 4 (TLR4)/myeloid differentiation 2 (MD2) complex. TLR4/MD2-mediated activation of glia by opioids compromises their analgesic actions. Glial activation is also hypothesized as pivotal in opioid-mediated reward and tolerance and as a contributor to opioid-mediated respiratory depression. We tested the contribution of TLR4 to opioid-induced respiratory depression using rhythmically active medullary slices that contain the pre-Bötzinger Complex (preBötC, an important site of respiratory rhythm generation) and adult rats in vivo. Injection with DAMGO (μ-opioid receptor agonist; 50 μM) or bath application of DAMGO (500 nM) or fentanyl (1 μM) slowed frequency recorded from XII nerves to 40%, 40%, or 50% of control, respectively. This DAMGO-mediated frequency inhibition was unaffected by preapplication of lipopolysaccharides from Rhodobacter sphaeroides (a TLR4 antagonist, 2,000 ng/ml) or (+)naloxone (1–10 μM, a TLR4-antagonist). Bath application of (−)naloxone (500 nM; a TLR4 and μ-opioid antagonist), however, rapidly reversed the opioid-mediated frequency decrease. We also compared the opioid-induced respiratory depression in slices in vitro in the absence and presence of bath-applied minocycline (an inhibitor of microglial activation) and in slices prepared from mice injected (ip) 18 h earlier with minocycline or saline. Minocycline had no effect on respiratory depression in vitro. Finally, the respiratory depression evoked in anesthetized rats by tail vein infusion of fentanyl was unaffected by subsequent injection of (+)naloxone, but completely reversed by (−)naloxone. These data indicate that neither activation of microglia in preBötC nor TLR4/MD2-activation contribute to opioid-induced respiratory depression.

Unlike vitamin D recommendations by the Institute of Medicine, the Clinical Practice Guidelines by the Endocrine Society acknowledge body weight differentials and recommend obese subjects be given two to three times more vitamin D to satisfy their body's vitamin D requirement. However, the Endocrine Society also acknowledges that there are no good studies that clearly justify this. In this study we examined the combined effect of vitamin D supplementation and body weight on serum 25-hydroxyvitamin (25(OH)D) and serum calcium in healthy volunteers. We analyzed 22,214 recordings of vitamin D supplement use and serum 25(OH)D from 17,614 healthy adult volunteers participating in a preventive health program. This program encourages the use of vitamin D supplementation and monitors its use and serum 25(OH)D and serum calcium levels. Participants reported vitamin D supplementation ranging from 0 to 55,000 IU per day and had serum 25(OH)D levels ranging from 10.1 to 394 nmol/L. The dose response relationship between vitamin D supplementation and serum 25(OH)D followed an exponential curve. On average, serum 25(OH)D increased by 12.0 nmol/L per 1,000 IU in the supplementation interval of 0 to 1,000 IU per day and by 1.1 nmol/L per 1,000 IU in the supplementation interval of 15,000 to 20,000 IU per day. BMI, relative to absolute body weight, was found to be the better determinant of 25(OH)D. Relative to normal weight subjects, obese and overweight participants had serum 25(OH)D that were on average 19.8 nmol/L and 8.0 nmol/L lower, respectively (P

ATP released during hypoxia from the ventrolateral medulla activates purinergic receptors (P2Rs) to attenuate the secondary hypoxic depression of breathing by a mechanism that likely involves a P2Y1R-mediated excitation of preBötzinger complex (preBötC) inspiratory rhythm-generating networks. In this study, we used rhythmically activein vitropreparations from embryonic and postnatal rats and ATP microinjection into the rostral ventral respiratory group (rVRG)/preBötC to reveal that these networks are sensitive to ATP when rhythm emerges at embryonic day 17 (E17). The peak frequency elicited by ATP at E19 and postnatally was the same (∼45 bursts/min), but relative sensitivity was threefold greater at E19, reflecting a lower baseline frequency (5.6 ± 0.9 vs 19.0 ± 1.3 bursts/min). Combining microinjection techniques with ATP biosensors revealed that ATP concentration in the rVRG/preBötC falls rapidly as a result of active processes and closely correlates with inspiratory frequency. A phosphate assay established that preBötC-containing tissue punches degrade ATP at rates that increase perinatally. Thus, the agonist profile [ATP/ADP/adenosine (ADO)] produced after ATP release in the rVRG/preBötC will change perinatally. Electrophysiology further established that the ATP metabolite ADP is excitatory and that, in fetal but not postnatal animals, ADO at A1receptors exerts a tonic depressive action on rhythm, whereas A1antagonists extend the excitatory action of ATP on inspiratory rhythm. These data demonstrate that ATP is a potent excitatory modulator of the rVRG/preBötC inspiratory network from the time it becomes active and that ATP actions are determined by a dynamic interaction between the actions of ATP at P2 receptors, ectonucleotidases that degrade ATP, and ATP metabolites on P2Y and P1 receptors.

Poor interlaboratory precision for the determination of nitrogen adsorption specific area initiated a study of the parameters involved. Degassing conditions were standarized following the investigation of temperature- time relationships of various alumina types which may be present in smelter-grade alumina. Complete isotherms were obtained, single versus triple points were compared, and attempts were made to use carbon as a standard. A standard degassing procedure has resulted in improved precision for two laboratories having different equipment. There are some unanswered questions regarding desensitization of surface during analysis and the applicability of the BET equation.