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Background Phenylalanine hydroxylase (PAH) deficiency is one of 31 targeted inherited metabolic diseases (IMD) for the Canadian Inherited Metabolic Diseases Research Network (CIMDRN). Early diagnosis and initiation of treatment through newborn screening has gradually shifted treatment goals from the prevention of disabling complications to the optimization of long term outcomes. However, clinical evidence demonstrates that subtle suboptimal neurocognitive outcomes are present in the early and continuously diet-treated population with PAH deficiency. This may be attributed to variation in blood phenylalanine levels to outside treatment range and this, in turn, is possibly due to a combination of factors; disease severity, dietary noncompliance and differences in practice related to the management of PAH deficiency. One of CIMDRN’s goals is to understand current practices in the diagnosis and management of PAH deficiency in the pediatric population, from the perspective of both health care providers and patients/families. Objectives We investigated Canadian metabolic dietitians’ perspectives on the nutritional management of children with PAH deficiency, awareness of recently published North American treatment and nutritional guidelines in relation to PAH deficiency, and nutritional care practices within and outside these guidelines. Methods We invited 33 dietitians to participate in a survey, to ascertain their use of recently published guidelines and their practices in relation to the nutritional care of pediatric patients with PAH deficiency. Results We received 19 responses (59% response rate). All participants reported awareness of published guidelines for managing PAH deficiency. To classify disease severity, 89% of dietitians reported using pre-treatment blood phenylalanine (Phe) levels, alone or in combination with other factors. 74% of dietitians reported using blood Phe levels ≥360 μmol/L (6 mg/dL) as the criterion for initiating a Phe-restricted diet. All respondents considered 120-360 μmol/L (2–6 mg/dL) as the optimal treatment range for blood Phe in children 0–9 years old, but there was less agreement on blood Phe targets for older children. Most dietitians reported similar approaches to diet assessment and counseling: monitoring growth trends, use of 3 day diet records for intake analysis, individualization of diet goals, counseling patients to count grams of dietary natural protein or milligrams of dietary Phe, and monitoring blood Phe, tyrosine and ferritin. Conclusion While Canadian dietitians’ practices in managing pediatric PAH deficiency are generally aligned with those of the American College of Medical Genetics and Genomics (ACMG), and with the associated treatment and nutritional guidelines from Genetic Metabolic Dietitians International (GMDI), variation in many aspects of care reflects ongoing uncertainty and a need for robust evidence.

Children with inherited metabolic diseases (IMDs) often have high care needs that require extensive involvement of family caregivers. This study aimed to describe caregiver experiences, including management of children's needs at home, and the impacts of that management on family time, finances, and caregiver and child health-related quality of life (HRQoL). In this sub-study within a larger cohort study, participants were family caregivers of children ≤ 12 years old diagnosed with an IMD, from across Canada. We collected cross-sectional data using an online questionnaire consisting of validated measures and team-developed questions, and analyzed data descriptively. Seventy-one caregivers participated and reported using a range of supports and interventions to care for their children with IMDs, with dietary supports being most common (77.1%). Twenty-seven participants (45%) reported spending ≥ 4 extra hours per week assisting their child with care supports at home and 28 reported ≥ 6 missed days of work by caregivers in the past year for IMD care. All participants reported fulfillment from caregiving tasks, although 82% reported mental struggles related to caregiving. Based on caregiver reports, children with IMDs had lower HRQoL relative to population normative data. We observed lower median scores for several HRQoL subscales among children with IMDs classified as progressive with multi-system involvement relative to other IMDs. We identified important impacts of IMD care for family caregivers. Relief from high levels of caregiving responsibility and time should be a priority for the development of healthcare policies and interventions, to improve health and well-being for both children and their caregivers.

Introduction Children with chronic conditions have greater health care needs than the general paediatric population but may not receive care that centres their needs and preferences as identified by their families. Clinicians and researchers are interested in developing interventions to improve family‐centred care need information about the characteristics of existing interventions, their development and the domains of family‐centred care that they address. We conducted a scoping review that aimed to identify and characterize recent family‐centred interventions designed to improve experiences with care for children with chronic conditions. Methods We searched Medline, Embase, PsycInfo and Cochrane databases, and grey literature sources for relevant articles or documents published between 1 January 2019 and 11 August 2020 (databases) or 7–20 October 2020 (grey literature). Primary studies with ≥10 participants, clinical practice guidelines and theoretical articles describing family‐centred interventions that aimed to improve experiences with care for children with chronic conditions were eligible. Following citation and full‐text screening by two reviewers working independently, we charted data covering study characteristics and interventions from eligible reports and synthesized interventions by domains of family‐centred care. Results Our search identified 2882 citations, from which 63 articles describing 61 unique interventions met the eligibility criteria and were included in this review. The most common study designs were quasiexperimental studies (n = 18), randomized controlled trials (n = 11) and qualitative and mixed‐methods studies (n = 9 each). The most frequently addressed domains of family‐centred care were communication and information provision (n = 45), family involvement in care (n = 37) and access to care (n = 30). Conclusion This review, which identified 61 unique interventions aimed at improving family‐centred care for children with chronic conditions across a range of settings, is a concrete resource for researchers, health care providers and administrators interested in improving care for this high‐needs population. Patient or Public Contribution This study was co‐developed with three patient partner co‐investigators, all of whom are individuals with lived experiences of rare chronic diseases as parents and/or patients and have prior experience in patient engagement in research (I. J., N. P., M. S.). These patient partner co‐investigators contributed to this study at all stages, from conceptualization to dissemination.

Background Generating rigorous evidence to inform care for rare diseases requires reliable, sustainable, and longitudinal measurement of priority outcomes. Having developed a core outcome set for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, we aimed to assess the feasibility of prospective measurement of these core outcomes during routine metabolic clinic visits. Methods We used existing cohort data abstracted from charts of 124 children diagnosed with MCAD deficiency who participated in a Canadian study which collected data from birth to a maximum of 11 years of age to investigate the frequency of clinic visits and quality of metabolic chart data for selected outcomes. We recorded all opportunities to collect outcomes from the medical chart as a function of visit rate to the metabolic clinic, by treatment centre and by child age. We applied a data quality framework to evaluate data based on completeness, conformance, and plausibility for four core MCAD outcomes: emergency department use, fasting time, metabolic decompensation, and death. Results The frequency of metabolic clinic visits decreased with increasing age, from a rate of 2.8 visits per child per year (95% confidence interval, 2.3–3.3) among infants 2 to 6 months, to 1.0 visit per child per year (95% confidence interval, 0.9–1.2) among those ≥ 5 years of age. Rates of emergency department visits followed anticipated trends by child age. Supplemental findings suggested that some emergency visits occur outside of the metabolic care treatment centre but are not captured. Recommended fasting times were updated relatively infrequently in patients’ metabolic charts. Episodes of metabolic decompensation were identifiable but required an operational definition based on acute manifestations most commonly recorded in the metabolic chart. Deaths occurred rarely in these patients and quality of mortality data was not evaluated. Conclusions Opportunities to record core outcomes at the metabolic clinic occur at least annually for children with MCAD deficiency. Methods to comprehensively capture emergency care received at outside institutions are needed. To reduce substantial heterogeneous recording of core outcome across treatment centres, improved documentation standards are required for recording of recommended fasting times and a consensus definition for metabolic decompensations needs to be developed and implemented.

Background The Canadian Inherited Metabolic Diseases Research Network (CIMDRN) is a pan-Canadian practice-based research network of 14 Hereditary Metabolic Disease Treatment Centres and over 50 investigators. CIMDRN aims to develop evidence to improve health outcomes for children with inherited metabolic diseases (IMD). We describe the development of our clinical data collection platform, discuss our data quality management plan, and present the findings to date from our data quality assessment, highlighting key lessons that can serve as a resource for future clinical research initiatives relating to rare diseases. Methods At participating centres, children born from 2006 to 2015 who were diagnosed with one of 31 targeted IMD were eligible to participate in CIMDRN’s clinical research stream. For all participants, we collected a minimum data set that includes information about demographics and diagnosis. For children with five prioritized IMD, we collected longitudinal data including interventions, clinical outcomes, and indicators of disease management. The data quality management plan included: design of user-friendly and intuitive clinical data collection forms; validation measures at point of data entry, designed to minimize data entry errors; regular communications with each CIMDRN site; and routine review of aggregate data. Results As of June 2019, CIMDRN has enrolled 798 participants of whom 764 (96%) have complete minimum data set information. Results from our data quality assessment revealed that potential data quality issues were related to interpretation of definitions of some variables, participants who transferred care across institutions, and the organization of information within the patient charts (e.g., neuropsychological test results). Little information was missing regarding disease ascertainment and diagnosis (e.g., ascertainment method – 0% missing). Discussion Using several data quality management strategies, we have established a comprehensive clinical database that provides information about care and outcomes for Canadian children affected by IMD. We describe quality issues and lessons for consideration in future clinical research initiatives for rare diseases, including accurately accommodating different clinic workflows and balancing comprehensiveness of data collection with available resources. Integrating data collection within clinical care, leveraging electronic medical records, and implementing core outcome sets will be essential for achieving sustainability.

IntroductionChildren with inherited metabolic diseases (IMDs) often have complex and intensive healthcare needs and their families face challenges in receiving high-quality, family centred health services. Improvement in care requires complex interventions involving multiple components and stakeholders, customised to specific care contexts. This study aims to comprehensively understand the healthcare experiences of children with IMDs and their families across Canada.Methods and analysisA two-stage explanatory sequential mixed methods design will be used. Stage 1: quantitative data on healthcare networks and encounter experiences will be collected from 100 parent/guardians through a care map, 2 baseline questionnaires and 17 weekly diaries over 5–7 months. Care networks will be analysed using social network analysis. Relationships between demographic or clinical variables and ratings of healthcare experiences across a range of family centred care dimensions will be analysed using generalised linear regression. Other quantitative data related to family experiences and healthcare experiences will be summarised descriptively. Ongoing analysis of quantitative data and purposive, maximum variation sampling will inform sample selection for stage 2: a subset of stage 1 participants will participate in one-on-one videoconference interviews to elaborate on the quantitative data regarding care networks and healthcare experiences. Interview data will be analysed thematically. Qualitative and quantitative data will be merged during analysis to arrive at an enhanced understanding of care experiences. Quantitative and qualitative data will be combined and presented narratively using a weaving approach (jointly on a theme-by-theme basis) and visually in a side-by-side joint display.Ethics and disseminationThe study protocol and procedures were approved by the Children’s Hospital of Eastern Ontario’s Research Ethics Board, the University of Ottawa Research Ethics Board and the research ethics boards of each participating study centre. Findings will be published in peer-reviewed journals and presented at scientific conferences.

Background Improvements in health care for children with chronic diseases must be informed by research that emphasizes outcomes of importance to patients and families. To support a program of research in the field of rare inborn errors of metabolism (IEM), we conducted a broad scoping review of primary studies that: (i) focused on chronic pediatric diseases similar to IEM in etiology or manifestations and in complexity of management; (ii) reported patient- and/or family-oriented outcomes; and (iii) measured these outcomes using self-administered tools. Methods We developed a comprehensive review protocol and implemented an electronic search strategy to identify relevant citations in Medline, EMBASE, DARE and Cochrane. Two reviewers applied pre-specified criteria to titles/abstracts using a liberal accelerated approach. Articles eligible for full-text review were screened by two independent reviewers with discrepancies resolved by consensus. One researcher abstracted data on study characteristics, patient- and family-oriented outcomes, and self-administered measures. Data were validated by a second researcher. Results 4,118 citations were screened with 304 articles included. Across all included reports, the most-represented diseases were diabetes (35%), cerebral palsy (23%) and epilepsy (18%). We identified 43 unique patient- and family-oriented outcomes from among five emergent domains, with mental health outcomes appearing most frequently. The studies reported the use of 405 independent self-administered measures of these outcomes. Conclusions Patient- and family-oriented research investigating chronic pediatric diseases emphasizes mental health and appears to be relatively well-developed in the diabetes literature. Future research can build on this foundation while identifying additional outcomes that are priorities for patients and families.

John Harbison's choice of literary material for his vocal repertoire has been diverse, ranging from classic poets such as Johann Wolfgang von Goethe, Emily Dickinson, and Thomas Hardy to modern and even ancient writers, such as Elizabeth Bishop, William Carlos Williams, Czeslaw Milosz, and translations of the fifteenth-century Hindu poet Mirabai. At the same time, Harbison has been drawn to certain poets several times, including Eugenio Montale, Emily Dickinson, William Carlos Williams, and the art historian Michael Fried. Despite the fact that Fried is a lesser-known poet, Harbison has been drawn to set his verse repeatedly. Simple Daylight, however, is the only vocal work of Harbison that relies solely on Fried's texts. This thesis explores the reasons why Harbison was inspired to set Fried's poems so many times. In the program note for Simple Daylight, Harbison wrote that his ordering of Fried's poems made \"a sequence closer in tone to a Bach cantata text than to a nineteenth-century song cycle\" and evoked \"a sub-cutaneous narrative very favorable for musical purposes, but no doubt unintended by the poet.\" This statement begs the question of how the ordering of the texts made the piece more akin to a Bach cantata than a nineteenth-century song cycle. At first glance, Simple Daylight seems to fit the definition of a song cycle. Harbison himself asserted that the ordering of the poems suggested a \"sub-cutaneous narrative\"—a thread that drew the pieces into a whole. Might Harbison have employed other cyclic devices as well, such as common musical motives or a reprise of music within the work? In order to answer these questions, I analyzed Simple Daylight to discover why Harbison believed that the piece was textually more akin to a Bach cantata than a song cycle. This analysis involved researching the primary characteristics of Bach's cantata texts and comparing these to the texts of Simple Daylight. Then I examined the musical treatment of the poetry, and, through the use of set theory, I identified musical and structural devices that unify the piece. These analyses ultimately revealed whether the piece is a true song cycle or merely a set of songs with texts by the same poet that are organized in a cantata-like fashion.

To decarbonise the built environment, it is widely assumed that ‘fabric-first’ building upgrades are essential. An alternative, people-first approach is proposed that could deliver energy and carbon reductions at scale and speed. The approach begins by re-examining some rarely questioned assumptions around historical practices and building science. Physics and thermal physiology can inform a reassessment of the causes of thermal discomfort, and show why using air temperature alone as a measure of the thermal environment is inherently problematic. Historical sources reveal the forgotten ways people were made more comfortable in the days before space-conditioning. Together, these encourage a deeper examination of how buildings were constructed, maintained and operated prior to the Industrial Revolution. These insights can be harnessed to develop a practical new trajectory for building operation and retrofit. Preliminary results are reported from two ongoing UK field studies. Co-creation workshops and simple environmental monitoring are being used to encourage occupants to learn to ‘sail’ (i.e. passively manage) their own buildings more effectively to support their own needs. It is not yet possible to put numbers on the energy and carbon saved, but these early experiments may encourage professionals and policymakers to give much greater consideration to ‘people-first’ climate action. Policy relevance A common approach to decarbonising buildings is a focus on ‘fabric-first’ retrofits, which tend to be disruptive, carbon-intensive, expensive and will take decades to convert the stock. Feedback is also exposing disappointing savings, and risks to both building fabric and occupant health. This approach often seeks to update buildings to ‘modern’ standards, using models that have proved problematic, and frequently ignoring in-use performance. Conversely, a ‘people-first’ approach can empower occupants to identify what might improve things, trial simple interventions, and make rapid, low-risk alterations to improve their health and thermal comfort. This can draw on and adapt proven, low-cost historical methods. This alternative ‘soft’ approach uses facilitators to help occupants ‘learn to sail’ (i.e. effectively operate) buildings more effectively and sustainably. The insights will also enable any capital measures to be more precisely targeted.

Acute polymicrobial sepsis is a life-threatening emergency caused by the body's immune response to bloodstream infection by two or more microbes. Early detection and management of sepsis have been the focus of global survey programs, driven by its association with hospital readmissions and long-term adverse health outcomes. Animal models are essential tools for studying mechanisms of sepsis pathogenesis and the only way to empirically dissect the acute phase of disease. With this in mind, the goal of the current study was two-fold: to demonstrate the feasibility of performing multiplexed longitudinal assessment of acute sepsis pathogenesis and to emphasize the granularity with which acute sepsis can be studied using this method. Using the fecal suspension test (FST) model of acute polymicrobial sepsis in C57BL/6 mice we simultaneously characterize hematological, immunological, and microbiological aspects of acute sepsis induction. Our data shows that high dimensional flow cytometry paired with flow-based plasma cytokine measurements captures the dynamic shift from pro-inflammatory to anti-inflammatory immune responses during an acute septic event; highlighting the role of emergency myelopoiesis in this process. Additionally, myeloid cell heterogeneity is characterized and strongly implicates the emergence of myeloid derived suppressor like cells (MDSC-like cells) as central to this switch. Furthermore, we demonstrate a 16S-based method for studying the blood biome that allows for discrimination between endogenous (bacterial DNAemia) and exogenous (actively growing bacteria in blood) sources of microbial DNA. Using this approach, we demonstrate that polymicrobial sepsis in our model is due to outgrowth of and ; two genera of bacterial pathobionts commonly observed in human sepsis patients. Finally, using several assessments of disease severity, we demonstrate stratification of septic mice into survivors and non-survivors and show how pre-septic immune assessment can be used to identify potential biomarkers of sepsis risk. Collectively, the approach we describe simultaneously reduces research animal use, strengthens scientific rigor, provides a pre-clinical platform for biomarker discovery and the study of therapeutic interventions, and most importantly advances our ability to study the acute phase of sepsis that carries a high mortality rate and is difficult to prospectively study in humans.