Towards the standardisation of adult person-reported outcome domains in diabetes research: A Consensus Statement development panel.

Diabetes is unique among chronic diseases because clinical outcomes are intimately tied to how the person living with diabetes reacts to and implements treatment recommendations. It is further characterised by widespread social stigma, judgement and paternalism. This physical, social and psychological burden collectively influences self-management behaviours. It is widely recognised that the individual's perspective about the impact of trying to manage the disease and the burden that self-management confers must be addressed to achieve optimal health outcomes. Standardised, rigorous assessment of mental and behavioural health status, in interaction with physical health outcomes is crucial to aid understanding of person-reported outcomes (PROs). Whilst tempting to conceptualise PROs as an issue of perceived quality of life (QoL), in fact health-related QoL is multi-dimensional and covers indicators of physical or functional health status, psychological and social well-being. This complexity is illuminated by the large number of person reported outcome measures (PROMs) that have been developed across multiple psychosocial domains. Often measures are used inappropriately or because they have been used in the scientific literature rather than based on methodological or outcome assessment rigour. Given the broad nature of psychosocial functioning/mental health, it is important to broadly define PROs that are evaluated in the context of therapeutic interventions, real-life and observational studies. This report summarises the central themes and lessons derived in the assessment and use of PROMs amongst adults with diabetes. Effective assessment of PROMs routinely in clinical research is crucial to understanding the true impact of any intervention. Selecting appropriate measures, relevant to the specific factors of PROs important in the research study will provide valuable data alongside physical health data.

A Novel Mental Health Curriculum Pilot for Pediatric Cardiology Fellows: Preparing the Subspecialist to Expand the Team.

Mental health (MH) is an important, yet understudied area of care for patients with congenital heart disease (CHD). Pediatric subspecialty fellows believe MH should be within their scope of practice, but few feel confident in their ability to appropriately screen, evaluate, manage, and make treatment referrals for youth with CHD and concurrent MH concerns. A 6-session, didactic-based curriculum was designed by an interprofessional team of experts. It was administered to pediatric cardiology fellows over 9 months during two academic years. Topics included the following: Introduction to MH and CHD, MH Screening and Clinic-Based Interventions, Psychopharmacology, Delirium, Trauma-Informed Care, and Adult CHD and Transitional Care. An investigator-designed survey was developed to assess fellow comfort with MH knowledge, screening, and treatment recommendation domains. Twenty-three fellows participated with 14 completing the pre-post survey (58% participation, 11/17 in year 1, 3/6 in year 2). Most participants were in their first year of training (9/14, 57%). Overall, fellow comfort with MH topics increased significantly (mean score 2.89 ± 0.46 vs. 3.4 ± 0.4, p = 0.0005), with improved comfort in the MH knowledge (p = 0.003) and treatment recommendation domains (p = 0.001). A didactic-based MH curriculum improves the comfort of pediatric cardiology fellows to address the MH concerns of their patients. The topics in this curriculum will continue to be refined over time and could be generalized to training programs, both nationally and across pediatric specialties, to improve MH care for high-risk populations.

Psychosocial Staffing and Implementation of the International Society for Pediatric and Adolescent Diabetes Psychological Care Guidelines in U.S. Pediatric Diabetes Clinics.

Background: Few studies have examined the implementation of the International Society for Pediatric and Adolescent Diabetes (ISPAD) Clinical Practice Consensus Guidelines for the Psychological Care of Children and Adolescents with Type 1 Diabetes. Objective: To collect benchmark data on psychosocial staffing and implementation of the ISPAD guidelines across U.S. pediatric diabetes clinics. Methods: Medical (n = 95; 77 endocrinologists and 18 advance practice providers) and psychosocial (n = 86; 43 social workers and 43 psychologists) providers from 98 of 115 contacted clinics completed an online survey (85% response rate). Providers reported the number of psychosocial staff and rated the adequacy of psychosocial staffing, quality of psychosocial care, and adherence to the ISPAD guidelines in their clinics. χ2 Tests and ANOVA were used to examine differences across clinic size and across medical and psychosocial providers. Results: Clinics averaged a total of ∼4 hours per week of psychosocial provider time per 100 patients with type 1 diabetes. Only 27% of providers agreed that psychosocial staffing was adequate, and 35% described their psychosocial care as comprehensive. Implementation of the ISPAD guidelines varied across clinics, with minimal differences across clinic size. Medical providers reported that evidence-based psychological assessment and interventions were delivered consistently by <55% of clinics. Psychosocial, compared with medical, providers were more likely to report frequent implementation of psychosocial assessment and intervention guidelines. Conclusion: Psychological care in U.S. pediatric type 1 diabetes clinics does not consistently meet the ISPAD guidelines, and many clinics lack adequate psychosocial staff. These benchmark data are a foundational step to improve psychosocial care for pediatric patients with type 1 diabetes.

Development and Evaluation of the Pediatric Diabetes Routine Questionnaire for Parents of Young Children with Type 1 Diabetes.

This study describes the development and psychometric evaluation of the Pediatric Diabetes Routines Questionnaire for Parents of Young Children (PDRQ-PYC) with type 1 diabetes, a measure adapted from the school-age and adolescent versions of the PDRQ, to measure diabetes-specific routines in families with children under age 6 years with type 1 diabetes. Participants included 173 parents of young children with type 1 diabetes (YC-T1D) who completed measures of diabetes-specific routines, diabetes adjustment, self-efficacy, benefit finding, depression, child behavior problems, spousal support, and T1D treatment engagement. Exploratory factor analysis supported a one-factor model consisting of a unidimensional PDRQ-PYC total score. The PDRQ-PYC total score demonstrated good internal consistency, convergent validity, and criterion validity. The present study demonstrates that PDRQ-PYC is a valuable and feasible tool for measuring the consistency and regularity with which families of YC-T1D perform T1D management tasks. Along with the school-age and adolescent versions of the PDRQ, the PDRQ-PYC now provides the ability to assess diabetes-specific routines from early childhood through adolescence and findings support the notion that routines are associated with engagement in diabetes tasks.ClinicalTrials.gov Identifier NCT03222180 (first posted July 19, 2017).

A clostripain-like protease plays a major role in generating the secretome of enterotoxigenic Bacteroides fragilis.

Bacteroides fragilis toxin (BFT) is a protein secreted by enterotoxigenic (ETBF) strains of B. fragilis. BFT is synthesized as a proprotein (proBFT) that is predicted to be a lipoprotein and that is cleaved into two discrete fragments by a clostripain-like protease called fragipain (Fpn). In this study, we obtained evidence that Fpn cleaves proBFT following its transport across the outer membrane. Remarkably, we also found that the disruption of the fpn gene led to a strong reduction in the level of >100 other proteins, many of which are predicted to be lipoproteins, in the culture medium of an ETBF strain. Experiments performed with purified Fpn provided direct evidence that the protease releases at least some of these proteins from the cell surface. The observation that wild-type cells outcompeted an fpn- strain in co-cultivation assays also supported the notion that Fpn plays an important role in cell physiology and is not simply dedicated to toxin biogenesis. Finally, we found that purified Fpn altered the adhesive properties of HT29 intestinal epithelial cells. Our results suggest that Fpn is a broad-spectrum protease that not only catalyzes the protein secretion on a wide scale but that also potentially cleaves host cell proteins during colonization.

The association between pediatric mental health disorders and type 1 diabetes-related outcomes.

OBJECTIVE: Transition from pediatric to adult healthcare systems is a difficult process for young adults with Type 1 Diabetes (T1D) and most patients experience a deterioration in disease control. Mental health (MH) disorders are common in individuals with T1D and are believed to play a role in disease control and transition of care. We evaluated the association between the presence of pediatric MH disorder and measures of success in diabetes care in young adults who recently transitioned to adult care. RESEARCH DESIGN AND METHODS: Retrospective cohort study of young adults in a large adult endocrinology system who transitioned from a pediatric hospital system after 2009. MH disorders were diagnosed by clinical pediatric psychologists during routine care at the pediatric hospital. Measurements of Hemoglobin A1c, diabetes-related emergencies, clinic attendance and intervals in transition were assessed and compared between the pediatric and adult hospital systems. RESULTS: 237 young adults were identified and 100 (42%) of these were diagnosed with a MH disorder during pediatric care. Presence of a MH disorder was associated with higher Hemoglobin A1c levels prior to transition and increased rates of diabetes-related hospitalizations during the transition interval. Patients with a MH disorder were less likely to establish a pattern of consistent follow up after transition (p = 0.021). CONCLUSIONS: MH disorders are common and predict greater challenges with diabetes management and less effective transition into the adult endocrinology system. Early recognition of MH disorders may allow for allocation of more proactive and intensive support for affected patients.

Toward an Anti-Maleficent Research Agenda.

Important advances in biomedical and behavioral research ethics have occurred over the past few decades, many of them centered on identifying and eliminating significant harms to human subjects of research. Comprehensive attention has not been paid to the totality of harms experienced by animal subjects, although scientific and moral progress require explicit appraisal of these harms. Science is a public good and the prioritizing within, conduct of, generation of, and application of research must soundly address questions about which research is morally defensible and valuable enough to support through funding, publication, tenure, and promotion. Likewise, educational pathways of re-imagined science are critical.

Psychiatric Evaluation and Management in Pediatric Spinal Cord Injuries: a Review.

PURPOSE OF REVIEW: To summarize current key recommendations in the evaluation and management of mental health disorders associated with spinal cord injuries (SCI) among pediatric patients, based on a review of recent evidence-based literature and clinical experience. RECENT FINDINGS: Anticipating potential mental health risks among youth with SCI and implementing early multidisciplinary management improves physical and mental health outcomes. When caregivers of youth with SCI model healthy coping strategies, it promotes healthy coping strategies in patients themselves. Peer mentor programs can be instrumental in patient adjustment, improve mental health, and aid in recovery. Pediatric SCI is particularly impactful on a child's development and individuation. Early involvement of a mental health team while in the hospital can help with the initial adjustment period and address psychiatric concerns that might interfere with recovery. The transition from the hospital to home is a period of vulnerability for individuals with SCI.

Topical Review: Crowdsourcing as a Novel Approach to Qualitative Research.

OBJECTIVE: To describe a novel, five-phase approach to collecting qualitative data from hard-to-reach populations using crowdsourcing methods. METHODS: Drawing from experiences across recent studies with type 1 diabetes and congenital heart disease stakeholders, we describe five phases of crowdsourcing methodology, an innovative approach to conducting qualitative research within an online environment, and discuss relevant practical and ethical issues. RESULTS: Phases of crowdsourcing methodology are: (I) Preparing; (II) Forming Crowds; (III) Collecting Crowdsourced Data; (IV) Coding and Analyzing Crowdsourced Data; and (V) Generating and Disseminating Findings. Iterative feedback from stakeholders is obtained in all five phases. Practical and ethical issues include accessing diverse stakeholders, emotional engagement of crowd participants, responsiveness and transparency of crowdsourcing methodology, and limited personal contact with crowd participants. CONCLUSIONS: Crowdsourcing is an innovative, efficient, feasible, and timely approach to engaging hard-to-reach populations in qualitative research.

Do Interactions of Vitamin D3 and BMP Signaling Hold Implications in the Pathogenesis of Fibrodysplasia Ossificans Progressiva?

PURPOSE OF REVIEW: Fibrodysplasia ossificans progressiva (FOP) is a debilitating rare disease known for episodic endochondral heterotopic ossification (HO) caused by gain-of-function mutations in ACVR1/ALK2. However, disease severity varies among patients with identical mutations suggesting disease-modifying factors, including diet, may have therapeutic implications. The roles of vitamin D3 in calcium metabolism and chondrogenesis are known, but its effects on BMP signaling and chondrogenesis are less studied. This review attempts to assess the possibility of vitamin D's effects in FOP by exploring relevant intersections of VD3 with mechanisms of FOP flares. RECENT FINDINGS: In vitro and in vivo studies suggest vitamin D suppresses inflammation, while clinical studies suggest that vitamin D3 protects against arteriosclerosis and inversely correlates with non-genetic intramuscular HO. However, the enhancement of chondrogenesis, BMP signaling, and possibly Activin A expression by vitamin D may be more relevant in FOP. There appears to be little potential for vitamin D to reduce HO in FOP, but testing the potential for excess vitamin D to promote HO may be warranted.

Can Clinical Ethics Survive Climate Change?

The Ethics of Environmentally Responsible Health Care (2004) argued that the obligation to protect nature must be a core principle of bioethics and that the environmental harm of health-care practices should be taken seriously. In the two decades since, the accelerating pace of climate change and environmental decline has strengthened the moral case for reducing the environmental costs of health care. Nevertheless, mainstream bioethics has until recently neglected these vital issues. In response, a field of clinical environmental bioethics is emerging that applies concepts and measures of sustainability to such key clinical ethical issues as humanizing technology, setting limits, caring for the dying, respecting patient wishes, and allocating resources justly. Bioethical analysis of these and other issues can support just and humane health-care adaptation to climate change. Health-care adaptation in turn plays an important role in helping communities and nations adapt to the inevitable forward march of climate change. This essay offers two recommendations: (1) establish a climate transition commission for health-care adaptation to climate change with bioethics participation, and (2) strengthen advocacy for health-care reform by uniting it with climate activism.

Feasibility of Implementing a Pediatric Diabetes Clinic via Telehealth.

OBJECTIVE: In response to the coronavirus disease 2019 (COVID-19) pandemic and social distancing guidelines, our pediatric diabetes team rapidly changed the format of conducting diabetes clinic from in person to telehealth. We compared the actual number and rate of completed, canceled, and no-show visits between an 8-week period in 2019, when we exclusively conducted visits in person and the same 8-week period in 2020, during the COVID-19 quarantine, when we exclusively conducted visits via telehealth. METHODS: We used electronic health record data for all patients, as well as Dexcom continuous glucose monitoring data collected for a subset of youths during the COVID-19 quarantine and the immediate pre-COVID-19 period. RESULTS: Although there was a difference in the absolute number of in-person versus telehealth visits canceled during these two time periods, there was no difference in the rates of completed, canceled, and no-show visits completed in person or via telehealth. This finding suggests that, despite a rapid shift to a completely new health care delivery model, our providers completed a similar rate of patient care via telehealth during the COVID-19 quarantine and that telehealth may be a feasible method for providing diabetes care. However, our results also suggested that youths' glucose management was less optimal during the quarantine period. CONCLUSION: COVID-19 presented an opportunity to adopt and test the feasibility of using a telehealth delivery model for routine diabetes care. Yet, to make telehealth a viable treatment delivery alternative will likely involve the uptake of new clinic procedures, investment in institutional infrastructure, and team-based flexibility.

Erratum: Feasibility of Implementing a Pediatric Diabetes Clinic via Telehealth. Diabetes Spectrum 2021;34:190-197 (https://doi.org/10.2337/ds20-0060).

[This corrects the article on p. 190 in vol. 34, PMID: 34149260.].

Validation of the Healthcare Transition Outcomes Inventory for Young Adults With Type 1 Diabetes.

OBJECTIVE: We recently developed and content validated the Healthcare Transition Outcomes Inventory (HCTOI), a stakeholder vetted, multidimensional measure of the outcomes of the transition from pediatric to adult healthcare for young adults (YA) with type 1 diabetes (T1D). In this study, we aimed to evaluate the psychometric properties of the HCTOI. METHODS: We collected and analyzed cross-sectional data from 128 YA (18-25 years old) with T1D to evaluate the psychometric properties of the HCTOI. We conducted confirmatory factor analysis (CFA), item analysis, and examined reliability and validity in relation to measures of quality of life, diabetes distress, regimen adherence, and glycemic control. RESULTS: CFA supported a five-factor solution: integration of T1D into emerging adult roles, balance of parental support with T1D autonomy, establishing and maintaining continuity of care, forming a collaborative patient-provider relationship, and ownership of T1D. We reduced the HCTOI from 54 to 34 items. The HCTOI demonstrated adequate internal consistency (α's = 0.62-0.87) and significant correlations demonstrated construct (quality of life, diabetes distress) and criterion validity (adherence, glycemic control). CONCLUSIONS: The HCTOI demonstrated promising initial psychometric properties. As the first measure of the multiple dimensions of healthcare transition outcomes, the HCTOI provides a means to examine longitudinal relations between transition readiness and outcomes and to assess the efficacy or effectiveness of interventions and programs designed to improve the transition process for YA with T1D.

Development and Validation of the Parent-Preschoolers Diabetes Adjustment Scale (PP-DAS).

OBJECTIVE: This article extends work on a social-ecological model of caregiver adjustment and describes the: (a) development and (b) validation of the Parent-Preschoolers Diabetes Adjustment Scale (PP-DAS), a broad measure of caregiver adjustment. METHODS: Participants were caregivers (nstudy1 = 51; nstudy2 = 177) of very young children (<6 years old) with Type 1 diabetes (T1D). In study 1, researchers and stakeholders collaborated to develop 92 items using the 5 domains of a social-ecological model of caregiver adjustment to the challenges of raising a very young child with T1D, and parents and researchers provided feedback on these items. In study 2, confirmatory factor analysis (CFA) and exploratory factor analysis (EFA) were used to examine the factor structure of the PP-DAS. Reliability and validity were also examined. RESULTS: After review by parents and researchers, 52 items were removed resulting in the 40-item version used in study 2. The CFA demonstrated poor fit with the five proposed domains of the social-ecological model, so an EFA was conducted and supported a different five-factor solution. Twenty items were removed due to low factor loadings or communalities, resulting in a final 20-item measure. The PP-DAS demonstrated adequate internal consistency (α's = .73-.84), convergent validity with parent psychological functioning and self-efficacy in T1D management, and criterion validity with hemoglobin A1c and adherence. CONCLUSIONS: The PP-DAS is a valid and reliable measure of adjustment in caregivers of very young children with T1D. The PP-DAS may help identify caregivers who are having adjustment difficulties and would benefit from additional support.

Inhibition of Osteocyte Membrane Repair Activity via Dietary Vitamin E Deprivation Impairs Osteocyte Survival.

Osteocytes experience plasma membrane disruptions (PMD) that initiate mechanotransduction both in vitro and in vivo in response to mechanical loading, suggesting that osteocytes use PMD to sense and adapt to mechanical stimuli. PMD repair is crucial for cell survival; antioxidants (e.g., alpha-tocopherol, also known as Vitamin E) promote repair while reactive oxygen species (ROS), which can accumulate during exercise, inhibit repair. The goal of this study was to determine whether depleting Vitamin E in the diet would impact osteocyte survival and bone adaptation with loading. Male CD-1 mice (3 weeks old) were fed either a regular diet (RD) or Vitamin E-deficient diet (VEDD) for up to 11 weeks. Mice from each dietary group either served as sedentary controls with normal cage activity, or were subjected to treadmill exercise (one bout of exercise or daily exercise for 5 weeks). VEDD-fed mice showed more PMD-affected osteocytes (+ 50%) after a single exercise bout suggesting impaired PMD repair following Vitamin E deprivation. After 5 weeks of daily exercise, VEDD mice failed to show an exercise-induced increase in osteocyte PMD formation, and showed signs of increased osteocytic oxidative stress and impaired osteocyte survival. Surprisingly, exercise-induced increases in cortical bone formation rate were only significant for VEDD-fed mice. This result may be consistent with previous studies in skeletal muscle, where myocyte PMD repair failure (e.g., with muscular dystrophy) initially triggers hypertrophy but later leads to widespread degeneration. In vitro, mechanically wounded MLO-Y4 cells displayed increased post-wounding necrosis (+ 40-fold) in the presence of H2O2, which could be prevented by Vitamin E pre-treatment. Taken together, our data support the idea that antioxidant-influenced osteocyte membrane repair is a vital aspect of bone mechanosensation in the osteocytic control of PMD-driven bone adaptation.

Benefit finding among parents of young children with type 1 diabetes.

Benefit finding, perceived positive effects of adversity, has been associated with psychological well-being in people with chronic illnesses and with better adherence for adolescents with type 1 diabetes (T1D). Our qualitative research with parents of young children (< 6 years old) with T1D indicated that benefit finding (BF) is a common parental coping mechanism, but no tools exist to measure BF in parents. We determined psychometric properties of the Diabetes Benefit Finding Scale for Parents (DBFS-P), a 16-item questionnaire adapted from the validated adolescent version. Parents of young children with T1D (n = 172) were participants in a randomized trial of an online intervention. We examined the DBFS-P factor structure through principal component analysis (PCA); internal consistency through Cronbach's alpha; convergent validity via bivariate correlations between the DBFS-P and measures of parental depression, anxiety, T1D self-efficacy, and hypoglycemia fear; and discriminant validity via bivariate correlations between the DBFS-P and measures of parental somatization and child behavior problems. PCA revealed one factor (56.47% variance) with Cronbach's α = 0.95. Convergent validity of the DBFS-P was supported by significant correlations with parental depression (r = -0.35, P < 0.001), anxiety (r = -0.20, P = 0.008), T1D self-efficacy (r = 0.36, P < 0.001), and hypoglycemia fear (r = 0.27, P < 0.001). Non-significant correlations with parental somatization (r = -0.06, P = 0.42) and child behavior problems (r = -0.12, P = 0.14) support its discriminant validity. The DBFS-P demonstrated good psychometric properties as a tool for assessing BF among caregivers.

Development and Validation of the Pediatric Diabetes Routines Questionnaire for Adolescents.

This study describes the development and psychometric evaluation of an adolescent self-report version of the Pediatric Diabetes Routines Questionnaire (PDRQ:A), a measure of diabetes-specific routines for youth with type 1 diabetes, and further validation of the parent-version (PDRQ:P) in an adolescent sample. Participants included 120 parent-adolescent dyads (ages 12-17) and an additional 24 parents who completed measures of diabetes-specific adolescent routines, general adolescent routines, diabetes self-care, and family support of youth diabetes care. The PDRQ:P/A demonstrated good internal consistency, test-retest reliability, and parent-child agreement, and adequate validity coefficients. Confirmatory factor analysis supported a one-factor model. Promising results were obtained. The PDRQ:P/A is a clinically feasible parent- and self-report measure that can provide valuable information regarding how frequently adolescents engage in their diabetes management tasks in a consistent manner. Addition of an adolescent report format will enhance the utility of the measure for clinical and research use.

Loss of Hdac3 in osteoprogenitors increases bone expression of osteoprotegerin, improving systemic insulin sensitivity.

Type 2 diabetes is an emerging global health epidemic. Foundations for new therapies are arising from understanding interactions between body systems. Bone-derived factors that reduce RANKL (receptor activator of NF-kappa B ligand) signaling in the liver may prevent insulin resistance and the onset of type 2 diabetes. Here we demonstrate that deletion of the epigenetic regulator, Hdac3, in Osx1-expressing osteoprogenitors prevents insulin resistance induced by high fat diet by increasing serum and skeletal gene expression levels of osteoprotegerin (Opg), a natural inhibitor of RANKL signaling. Removal of one Opg allele in mice lacking Hdac3 in Osx1+ osteoprogenitors increases the insulin resistance of the Hdac3-deficient mice on a high fat diet. Thus, Hdac3-depletion in osteoblasts increases expression of Opg, subsequently preserving insulin sensitivity. The Hdac inhibitor vorinostat also increased Opg transcription and histone acetylation of the Opg locus. These results define a new mechanism by which bone regulates systemic insulin sensitivity.

Mutation-Driven Parallel Evolution during Viral Adaptation.

Convergent evolution has been demonstrated across all levels of biological organization, from parallel nucleotide substitutions to convergent evolution of complex phenotypes, but whether instances of convergence are the result of selection repeatedly finding the same optimal solution to a recurring problem or are the product of mutational biases remains unsettled. We generated 20 replicate lineages allowed to fix a single mutation from each of four bacteriophage genotypes under identical selective regimes to test for parallel changes within and across genotypes at the levels of mutational effect distributions and gene, protein, amino acid, and nucleotide changes. All four genotypes shared a distribution of beneficial mutational effects best approximated by a distribution with a finite upper bound. Parallel adaptation was high at the protein, gene, amino acid, and nucleotide levels, both within and among phage genotypes, with the most common first-step mutation in each background fixing on an average in 7 of 20 replicates and half of the substitutions in two of the four genotypes occurring at shared sites. Remarkably, the mutation of largest beneficial effect that fixed for each genotype was never the most common, as would be expected if parallelism were driven by selection. In fact, the mutation of smallest benefit for each genotype fixed in a total of 7 of 80 lineages, equally as often as the mutation of largest benefit, leading us to conclude that adaptation was largely mutation-driven, such that mutational biases led to frequent parallel fixation of mutations of suboptimal effect.