The B1 H + -ATPase ( Atp6v1b1 ) Subunit in Non-Type A Intercalated Cells is Required for Driving Pendrin Activity and the Renal Defense Against Alkalosis.

SIGNIFICANCE STATEMENT: In the kidney, the B1 H + -ATPase subunit is mostly expressed in intercalated cells (IC). Its importance in acid-secreting type A ICs is evident in patients with inborn distal renal tubular acidosis and ATP6V1B1 mutations. However, the protein is also highly expressed in alkali-secreting non-type A ICs where its function is incompletely understood. We demonstrate in Atp6v1b1 knock out mice that the B1 subunit is critical for the renal response to defend against alkalosis during an alkali load or chronic furosemide treatment. These findings highlight the importance of non-type A ICs in maintaining acid-base balance in response to metabolic challenges or commonly used diuretics. BACKGROUND: Non-type A ICs in the collecting duct system express the luminal Cl - /HCO 3- exchanger pendrin and apical and/or basolateral H + -ATPases containing the B1 subunit isoform. Non-type A ICs excrete bicarbonate during metabolic alkalosis. Mutations in the B1 subunit (ATP6V1B1) cause distal renal tubular acidosis due to its role in acid secretory type A ICs. The function of B1 in non-type A ICs has remained elusive. METHODS: We examined the responses of Atp6v1b1-/- and Atp6v1b1+/+ mice to an alkali load and to chronic treatment with furosemide. RESULTS: An alkali load or 1 week of furosemide resulted in a more pronounced hypokalemic alkalosis in male ATP6v1b1-/- versus Atp6v1b1+/+ mice that could not be compensated by respiration. Total pendrin expression and activity in non-type A ICs of ex vivo microperfused cortical collecting ducts were reduced, and ß2 -adrenergic stimulation of pendrin activity was blunted in ATP6v1b1-/- mice. Basolateral H + -ATPase activity was strongly reduced, although the basolateral expression of the B2 isoform was increased. Ligation assays for H + -ATPase subunits indicated impaired assembly of V 0 and V 1 H + -ATPase domains. During chronic furosemide treatment, ATP6v1b1-/- mice also showed polyuria and hyperchloremia versus Atp6v1b1+/+ . The expression of pendrin, the water channel AQP2, and subunits of the epithelial sodium channel ENaC were reduced. CONCLUSIONS: Our data demonstrate a critical role of H + -ATPases in non-type A ICs function protecting against alkalosis and reveal a hitherto unrecognized need of basolateral B1 isoform for a proper H + -ATPase complexes assembly and ability to be stimulated.

Dysfunction of Oskyddad causes Harlequin-type ichthyosis-like defects in Drosophila melanogaster.

Prevention of desiccation is a constant challenge for terrestrial organisms. Land insects have an extracellular coat, the cuticle, that plays a major role in protection against exaggerated water loss. Here, we report that the ABC transporter Oskyddad (Osy)-a human ABCA12 paralog-contributes to the waterproof barrier function of the cuticle in the fruit fly Drosophila melanogaster. We show that the reduction or elimination of Osy function provokes rapid desiccation. Osy is also involved in defining the inward barrier against xenobiotics penetration. Consistently, the amounts of cuticular hydrocarbons that are involved in cuticle impermeability decrease markedly when Osy activity is reduced. GFP-tagged Osy localises to membrane nano-protrusions within the cuticle, likely pore canals. This suggests that Osy is mediating the transport of cuticular hydrocarbons (CHC) through the pore canals to the cuticle surface. The envelope, which is the outermost cuticle layer constituting the main barrier, is unaffected in osy mutant larvae. This contrasts with the function of Snu, another ABC transporter needed for the construction of the cuticular inward and outward barriers, that nevertheless is implicated in CHC deposition. Hence, Osy and Snu have overlapping and independent roles to establish cuticular resistance against transpiration and xenobiotic penetration. The osy deficient phenotype parallels the phenotype of Harlequin ichthyosis caused by mutations in the human abca12 gene. Thus, it seems that the cellular and molecular mechanisms of lipid barrier assembly in the skin are conserved during evolution.

Severe obesity and global developmental delay in preschool children: Findings from a Canadian Paediatric Surveillance Program study.

Background: The co-presentation of severe obesity (SO) and global developmental delay (GDD) in Canadian preschool children has not been examined. However, SO and GDD may require syndromic diagnoses and unique management considerations. Objectives: To determine (1) minimum incidence; (2) age of onset and risk factors; and (3) health care utilization for co-presenting SO and GDD. Methods: Through the Canadian Paediatric Surveillance Program (CPSP), a monthly form was distributed to participants from February 2018 to January 2020 asking for reports of new cases of SO and GDD among children ≤5 years of age. We performed descriptive statistics for quantitative questions and qualitative content analysis for open-ended questions. Results: Forty-seven cases (64% male; 51% white; mean age: 3.5 ± 1.2 years) were included. Age of first weight concern was 2.5 ± 1.3 years and age of GDD diagnosis was 2.7 ± 1.4 years. Minimum incidence of SO and GDD was 3.3 cases per 100,000 for ≤5 years of age per year. Identified problems included school and/or behavioural problems (n = 17; 36%), snoring (n = 14; 30%), and asthma/recurrent wheeze (n = 10; 21%). Mothers of 32% of cases (n = 15) had obesity and 21% of cases (n = 10) received neonatal intensive care. Microarray was ordered for 57% (n = 27) of children. A variety of clinicians and services were accessed. As reported by CPSP participants, challenges faced by families and health service access were barriers to care. Conclusion: Children with SO and GDD have multiple comorbidities, and require early identification and referral to appropriate services. These cases may also benefit from additional testing to rule out known genetic obesity syndromes.

Systemic Jak1 activation causes extrarenal calcitriol production and skeletal alterations provoking stunted growth.

Mineral homeostasis is regulated by a complex network involving endocrine actions by calcitriol, parathyroid hormone (PTH), and FGF23 on several organs including kidney, intestine, and bone. Alterations of mineral homeostasis are found in chronic kidney disease and other systemic disorders. The interplay between the immune system and the skeletal system is not fully understood, but cytokines play a major role in modulating calcitriol production and function. One of the main cellular signaling pathways mediating cytokine function is the Janus kinase (JAK)--signal transducer and activator of transcription (STAT) pathway. Here, we used a mouse model (Jak1S645P+/- ) that resembles a constitutive activating mutation of the Jak1/Stat3 signaling pathway in humans, and shows altered mineral metabolism, with higher fibroblast growth factor 23 (FGF23) levels, lower PTH levels, and higher calcitriol levels. The higher calcitriol levels are probably due to extrarenal calcitriol production. Furthermore, systemic Jak1/Stat3 activation led to growth impairment and skeletal alterations. The growth plate in long bones showed decreased chondrocyte proliferation rates and reduced height of terminal chondrocytes. Furthermore, we demonstrate that Jak1 is also involved in bone remodeling early in life. Jak1S645P+/- animals have decreased bone and cortical volume, imbalanced bone remodeling, reduced MAP kinase signaling, and local inflammation. In conclusion, Jak1 plays a major role in bone health probably both, directly and systemically by regulating mineral homeostasis. Understanding the role of this signaling pathway will contribute to a better knowledge in bone growth and in mineral physiology, and to the development of selective Jak inhibitors as osteoprotective agents.

Systemic Jak1 activation provokes hepatic inflammation and imbalanced FGF23 production and cleavage.

Fibroblast growth factor 23 (FGF23) is a main regulator of mineral homeostasis. Low and high circulating FGF23 levels are associated with bone, renal, cardiovascular diseases, and increased mortality. Understanding the factors and signaling pathways affecting FGF23 levels is crucial for the management of these diseases and their complications. Here, we show that activation of the Jak1/Stat3 signaling pathway leads to inflammation in liver and to an increase in hepatic FGF23 synthesis, a key hormone in mineral metabolism. This increased synthesis leads to massive C-terminal FGF23 circulating levels, the inactive C-terminal fragment, and increased intact FGF23 levels, the active form, resulting in imbalanced production and cleavage. Liver inflammation does not lead to activation of the calcineurin-NFAT pathway, and no signs of systemic inflammation could be observed. Despite the increase of active intact FGF23, excessive C-terminal FGF23 levels block the phosphaturic activity of FGF23. Therefore, kidney function and renal αKlotho expression are normal and no activation of the MAPK pathway was detected. In addition, activation of the Jak1/Stat3 signaling pathway leads to high calcitriol levels and low parathyroid hormone production. Thus, JAK1 is a central regulator of mineral homeostasis. Moreover, this study also shows that in order to assess the impact of high FGF23 levels on disease and kidney function, the source and the balance in FGF23 production and cleavage are critical.

Resilin is needed for wing posture in Drosophila suzukii.

Resilin is a protein matrix in movable regions of the cuticle conferring resistance to fatigue. The main component of Resilin is Pro-Rresilin that polymerises via covalent di- and tri-tyrosine bounds (DT). Loss of Pro-Resilin is nonlethal and causes a held-down wing phenotype (hdw) in the fruit fly Drosophila melanogaster. To test whether this mild phenotype is recurrent in other insect species, we analysed resilin in the spotted-wing fruit fly Drosophila suzukii. As quantified by DT autofluorescence by microscopy, DT intensities in the trochanter and the wing hinge are higher in D. suzukii than in D. melanogaster, while in the proboscis the DT signal is stronger in D. melanogaster compared to D. suzukii. To study the function of Pro-Resilin in D. suzukii, we generated a mutation in the proresilin gene applying the Crispr/Cas9 technique. D. suzukii pro-resilin mutant flies are flight-less and show a hdw phenotype resembling respective D. melanogaster mutants. DT signal intensity at the wing hinge is reduced but not eliminated in D. suzukii hdw flies. Either residual Pro-Resilin accounts for the remaining DT signal or, as proposed for the hdw phenotype in D. melanogaster, other DT forming proteins might be present in Resilin matrices. Interestingly, DT signal intensity reduction rates in D. suzukii and D. melanogaster are somehow different. Taken together, in general, the function of Pro-Resilin seems to be conserved in the Drosophila genus; small differences in DT quantity, however, allow us to hypothesise that Resilin matrices might be modulated during evolution probably to accommodate the species-specific lifestyle.

Social service providers' perspectives on caring for structurally vulnerable hospital patients who use drugs: a qualitative study.

BACKGROUND: People who use drugs and are structurally vulnerable (e.g., experiencing unstable and/or lack of housing) frequently access acute care. However, acute care systems and providers may not be able to effectively address social needs during hospitalization. Our objectives were to: 1) explore social service providers' perspectives on addressing social needs for this patient population; and 2) identify what possible strategies social service providers suggest for improving patient care. METHODS: We completed 18 semi-structured interviews with social service providers (e.g., social workers, transition coordinators, peer support workers) at a large, urban acute care hospital in Western Canada between August 8, 2018 and January 24, 2019. Interviews explored staff experiences providing social services to structurally vulnerable patients who use drugs, as well as continuity between hospital and community social services. We conducted latent content analysis and organized our findings in relation to the socioecological model. RESULTS: Tensions emerged on how participants viewed patient-level barriers to addressing social needs. Some providers blamed poor outcomes on perceived patient deficits, while others emphasized structural factors that impede patients' ability to secure social services. Within the hospital, some participants felt that acute care was not an appropriate location to address social needs, but most felt that hospitalization affords a unique opportunity to build relationships with structurally vulnerable patients. Participants described how a lack of housing and financial supports for people who use drugs in the community limited successful social service provision in acute care. They identified potential policy solutions, such as establishing housing supports that concurrently address medical, income, and substance use needs. CONCLUSIONS: Broad policy changes are required to improve care for structurally vulnerable patients who use drugs, including: 1) ending acute care's ambivalence towards social services; 2) addressing multi-level gaps in housing and financial support; 3) implementing hospital-based Housing First teams; and, 4) offering sub-acute care with integrated substance use management.

A chronic high phosphate intake in mice is detrimental for bone health without major renal alterations.

BACKGROUND: Phosphate intake has increased in the last decades due to a higher consumption of processed foods. This higher intake is detrimental for patients with chronic kidney disease, increasing mortality and cardiovascular disease risk and accelerating kidney dysfunction. Whether a chronic high phosphate diet is also detrimental for the healthy population is still under debate. METHODS: We fed healthy mature adult mice over a period of one year with either a high (1.2% w/w) or a standard (0.6% w/w) phosphate diet, and investigated the impact of a high phosphate diet on mineral homeostasis, kidney function and bone health. RESULTS: The high phosphate diet increased plasma phosphate, parathyroid hormone (PTH) and calcitriol levels, with no change in fibroblast growth factor 23 levels. Urinary phosphate, calcium and ammonium excretion were increased. Measured glomerular filtration rate was apparently unaffected, while blood urea was lower and urea clearance was higher in animals fed the high phosphate diet. No change was observed in plasma creatinine levels. Blood and urinary pH were more acidic paralleled by higher bone resorption observed in animals fed a high phosphate diet. Total and cortical bone mineral density was lower in animals fed a high phosphate diet and this effect is independent of the higher PTH levels observed. CONCLUSIONS: A chronic high phosphate intake did not cause major renal alterations, but affected negatively bone health, increasing bone resorption and decreasing bone mineral density.

Jak1/Stat3 Activation Alters Phosphate Metabolism Independently of Sex and Extracellular Phosphate Levels.

INTRODUCTION: Phosphate homeostasis is regulated by a complex network involving the parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and calcitriol acting on several organs including the kidney, intestine, bone, and parathyroid gland. Previously, we showed that activation of the Janus kinase 1 (Jak1)-signal transducer and activator of transcription 3 (Stat3) signaling pathway leads to altered mineral metabolism with higher FGF23 levels, lower PTH, and higher calcitriol levels. Here, we investigated if there are sex differences in the role of Jak1/Stat3 signaling pathway on phosphate metabolism and if this pathway is sensitive to extracellular phosphate alterations. METHODS: We used a mouse model (Jak1S645P+/-) that resembles a constitutive activating mutation of the Jak1/Stat3 signaling pathway in humans and analyzed the impact of sex on mineral metabolism parameters. Furthermore, we challenged Jak1S645P+/- male and female mice with a high (1.2% w/w) and low (0.1% w/w) phosphate diet and a diet with phosphate with organic origin with lower bioavailability. RESULTS: Female mice, as male mice, showed higher intact FGF23 levels but no phosphaturia, and higher calcitriol and lower PTH levels in plasma. A phosphate challenge did not alter the effect of Jak1/Stat3 activation on phosphate metabolism for both genders. However, under a low phosphate diet or a diet with lower phosphate availability, the animals showed a tendency to develop hypophosphatemia. Moreover, male and female mice showed similar phosphate metabolism parameters. The only exception was higher PTH levels in male mice than those in females. DISCUSSION/CONCLUSION: Sex and extracellular phosphate levels do not affect the impact of Jak1/Stat3 activation on phosphate metabolism.

Physician-related predictors of referral for multidisciplinary paediatric obesity management: a population-based study.

BACKGROUND: It is recommended that primary care-based physicians refer children with overweight and obesity to multidisciplinary paediatric obesity management, which can help to improve weight and health. OBJECTIVE: To determine predictors of referral to multidisciplinary paediatric obesity management. METHODS: This retrospective, population-level study included physicians who could refer 2-17 years old with a body mass index ≥85th percentile to one of three multidisciplinary paediatric obesity management clinics in Alberta, Canada. Physician demographic and procedural data were obtained from Practitioner Claims and Provider Registry maintained by Alberta Health from January 2014 to December 2017. Physician characteristics were compared based on whether they did or did not refer children for obesity management. Univariable and multivariable logistic regression models analysed associations between physician characteristics and referral making. RESULTS: Of the 3863 physicians (3468 family physicians, 395 paediatricians; 56% male; 49.3 ± 12.2 years old; 22.3 ± 12.6 years since graduation) practicing during the study period, 1358 (35.2%) referred at least one child for multidisciplinary paediatric obesity management. Multivariable regression revealed that female physicians (versus males) [odds ratio (OR): 1.68, 95% confidence interval (CI): 1.46-1.93; P < 0.0001], paediatricians (versus family physicians) (OR: 4.89, 95% CI: 3.85-6.21; P < 0.0001) and urban-based physicians (versus non-urban-based physicians) (OR: 2.17, 95% CI: 1.79-2.65; P < 0.0001) were more likely to refer children for multidisciplinary paediatric obesity management. CONCLUSIONS: Approximately one-third of family physicians and paediatricians referred children for multidisciplinary paediatric obesity management. Strategies are needed to improve referral practices for managing paediatric obesity, especially among male physicians, family physicians and non-urban-based physicians as they were less likely to refer children.

Paediatric overweight and obesity impact one-third of children in Canada and the USA. It is recommended that physicians refer children with overweight and obesity to paediatric obesity management, which can help to improve their weight and health. While referral practices of US physicians have been well characterized, Canadian evidence remains limited. To address this gap, we examined predictors of referral making for paediatric obesity management. Our study included physicians (family physicians and paediatricians) who could refer 2­17 years old with overweight and obesity to three paediatric weight management clinics in Alberta, Canada between January 2014 and December 2017. Descriptive analyses and regression models were performed. Of the 3863 physicians practicing during the study period, 1358 (35.2%) referred at least one child for paediatric obesity management. Referring physicians were more likely to be female, paediatricians and practicing in urban-based clinics. Additional research is needed to explore physicians' decisions to refer children for obesity management, which can inform interventions to enhance referral, and ultimately, improve the health and well-being of children with obesity.

Establishing a Working Definition of User Experience for eHealth Interventions of Self-reported User Experience Measures With eHealth Researchers and Adolescents: Scoping Review.

BACKGROUND: Across eHealth intervention studies involving children, adolescents, and their parents, researchers have measured user experience to assist with intervention development, refinement, and evaluation. To date, no widely accepted definitions or measures of user experience exist to support a standardized approach for evaluation and comparison within or across interventions. OBJECTIVE: We conduct a scoping review with subsequent Delphi consultation to identify how user experience is defined and measured in eHealth research studies, characterize the measurement tools used, and establish working definitions for domains of user experience that could be used in future eHealth evaluations. METHODS: We systematically searched electronic databases for published and gray literature available from January 1, 2005, to April 11, 2019. We included studies assessing an eHealth intervention that targeted any health condition and was designed for use by children, adolescents, and their parents. eHealth interventions needed to be web-, computer-, or mobile-based, mediated by the internet with some degree of interactivity. We required studies to report the measurement of user experience as first-person experiences, involving cognitive and behavioral factors reported by intervention users. We appraised the quality of user experience measures in included studies using published criteria: well-established, approaching well-established, promising, or not yet established. We conducted a descriptive analysis of how user experience was defined and measured in each study. Review findings subsequently informed the survey questions used in the Delphi consultations with eHealth researchers and adolescent users for how user experience should be defined and measured. RESULTS: Of the 8634 articles screened for eligibility, 129 articles and 1 erratum were included in the review. A total of 30 eHealth researchers and 27 adolescents participated in the Delphi consultations. On the basis of the literature and consultations, we proposed working definitions for 6 main user experience domains: acceptability, satisfaction, credibility, usability, user-reported adherence, and perceived impact. Although most studies incorporated a study-specific measure, we identified 10 well-established measures to quantify 5 of the 6 domains of user experience (all except for self-reported adherence). Our adolescent and researcher participants ranked perceived impact as one of the most important domains of user experience and usability as one of the least important domains. Rankings between adolescents and researchers diverged for other domains. CONCLUSIONS: Findings highlight the various ways in which user experience has been defined and measured across studies and what aspects are most valued by researchers and adolescent users. We propose incorporating the working definitions and available measures of user experience to support consistent evaluation and reporting of outcomes across studies. Future studies can refine the definitions and measurement of user experience, explore how user experience relates to other eHealth outcomes, and inform the design and use of human-centered eHealth interventions.

Resilin matrix distribution, variability and function in Drosophila.

BACKGROUND: Elasticity prevents fatigue of tissues that are extensively and repeatedly deformed. Resilin is a resilient and elastic extracellular protein matrix in joints and hinges of insects. For its mechanical properties, Resilin is extensively analysed and applied in biomaterial and biomedical sciences. However, there is only indirect evidence for Resilin distribution and function in an insect. Commonly, the presence of dityrosines that covalently link Resilin protein monomers (Pro-Resilin), which are responsible for its mechanical properties and fluoresce upon UV excitation, has been considered to reflect Resilin incidence. RESULTS: Using a GFP-tagged Resilin version, we directly identify Resilin in pliable regions of the Drosophila body, some of which were not described before. Interestingly, the amounts of dityrosines are not proportional to the amounts of Resilin in different areas of the fly body, arguing that the mechanical properties of Resilin matrices vary according to their need. For a functional analysis of Resilin matrices, applying the RNA interference and Crispr/Cas9 techniques, we generated flies with reduced or eliminated Resilin function, respectively. We find that these flies are flightless but capable of locomotion and viable suggesting that other proteins may partially compensate for Resilin function. Indeed, localizations of the potentially elastic protein Cpr56F and Resilin occasionally coincide. CONCLUSIONS: Thus, Resilin-matrices are composite in the way that varying amounts of different elastic proteins and dityrosinylation define material properties. Understanding the biology of Resilin will have an impact on Resilin-based biomaterial and biomedical sciences.

To what extent do supervised drug consumption services incorporate non-injection routes of administration? A systematic scoping review documenting existing facilities.

BACKGROUND: Most of the existing research on supervised consumption services (SCS) is focused on injection drug use. Less is known about the applicability of SCS for people who consume drugs orally, intranasally, or through inhalation. This is problematic because people who use drugs through modes other than injection are also at risk of overdose death and other harm, and experience barriers accessing health and social services. We aimed to describe existing SCS models that accommodate these alternate routes of drug consumption, and synthesize available information on characteristics of program participants. METHODS: We conducted a systematic scoping review of 9 peer-reviewed and 13 grey literature databases on SCS that incorporate non-injection routes of consumption. We screened 22,882 titles, and excluded 22,843 (99.8%) articles. We ultimately included 39 (0.2%) full-text articles; 28 (72%) of these articles explicitly identified SCS that permit alternate routes of consumption and 21 (54%) discussed characteristics of participants who consume drugs through non-injection routes. Data on study characteristics, terms and definitions, and site and program participant characteristics were extracted and double-coded. Extracted data were analyzed using descriptive statistics and narrative synthesis. RESULTS: Included articles describe 48 SCS that permit non-injection routes of consumption, most of which were located in Germany. The majority of these SCS were legally sanctioned and had models of care that were largely comparable to supervised injection services. Notable differences included physical infrastructure such as ventilated rooms or outdoor areas to accommodate inhalation, and shorter time limits on non-injection drug consumption episodes. Program participants engaging in non-injection forms of consumption were typically men over the age of 30 and structurally vulnerable (e.g., experiencing homelessness or unstable housing). CONCLUSIONS: Extant academic and grey literature indicates that site characteristics and demographics of program participants of SCS that permit non-injection routes of consumption largely reflect those of supervised injection services. Further research on the range of existing SCS that incorporate non-injection routes of consumption is needed to ensure high quality service provision, and improved health outcomes for people who consume drugs via oral, intranasal, and inhalation routes.

Tumor necrosis factor stimulates fibroblast growth factor 23 levels in chronic kidney disease and non-renal inflammation.

Fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis, and its early rise in patients with chronic kidney disease is independently associated with all-cause mortality. Since inflammation is characteristic of chronic kidney disease and associates with increased plasma FGF23 we examined whether inflammation directly stimulates FGF23. In a population-based cohort, plasma tumor necrosis factor (TNF) was the only inflammatory cytokine that independently and positively correlated with plasma FGF23. Mouse models of chronic kidney disease showed signs of renal inflammation, renal FGF23 expression and elevated systemic FGF23 levels. Renal FGF23 expression coincided with expression of the orphan nuclear receptor Nurr1 regulating FGF23 in other organs. Antibody-mediated neutralization of TNF normalized plasma FGF23 and suppressed ectopic renal Fgf23 expression. Conversely, TNF administration to control mice increased plasma FGF23 without altering plasma phosphate. Moreover, in Il10-deficient mice with inflammatory bowel disease and normal kidney function, plasma FGF23 was elevated and normalized upon TNF neutralization. Thus, the inflammatory cytokine TNF contributes to elevated systemic FGF23 levels and also triggers ectopic renal Fgf23 expression in animal models of chronic kidney disease.

Inhibition of fatty acid desaturation impairs cuticle differentiation in Drosophila melanogaster.

Previously, we showed that inhibition of the activity of fatty acid desaturases (Desat) perturbs signalling of the developmental timing hormone ecdysone in the fruit fly Drosophila melanogaster. To understand the impact of this effect on cuticle differentiation, a process regulated by ecdysone, we analysed the cuticle of D. melanogaster larvae fed with the Desat inhibitor CA10556. In these larvae, the expression of most of the key cuticle genes is normal or slightly elevated at day one of CA10556 feeding. As an exception, expression of twdlM coding for a yet uncharacterised cuticle protein is completely suppressed. The cuticle of these larvae appears to be normal at the morphological level. However, these animals are sensitive to desiccation, a trait that according to our data, among others, may be associated with reduced TwdlM amounts. At day two of CA10556 feeding, expression of most of the cuticle genes tested including twdlM is suppressed. Expression of cpr47Eb coding for a chitin-binding protein is, by contrast, highly elevated suggesting that Cpr47Eb participates at a specific compensation program. Overall, the cuticle of these larvae is thinner than the cuticle of control larvae. Taken together, lipid desaturation is necessary for a coordinated deployment of a normal cuticle differentiation program.

The elevation of circulating fibroblast growth factor 23 without kidney disease does not increase cardiovascular disease risk.

High circulating fibroblast growth factor 23 (FGF23) levels are probably a major risk factor for cardiovascular disease in chronic kidney disease. FGF23 interacts with the receptor FGFR4 in cardiomyocytes inducing left ventricular hypertrophy. Moreover, in the liver FGF23 via FGFR4 increases the risk of inflammation which is also found in chronic kidney disease. In contrast, X-linked hypophosphatemia is characterized by high FGF23 circulating levels due to loss of function mutations of the phosphate-regulating gene with homologies to an endopeptidase on the X chromosome (PHEX), but is not characterized by high cardiovascular morbidity. Here we used a novel murine X-linked hypophosphatemia model, the PhexC733RMhda mouse line, bearing an amino acid substitution (p.Cys733Arg) to test whether high circulating FGF23 in the absence of renal injury would trigger cardiovascular disease. As X-linked hypophosphatemia patient mimics, these mice show high FGF23 levels, hypophosphatemia, normocalcemia, and low/normal vitamin D levels. Moreover, these mice show hyperparathyroidism and low circulating soluble αKlotho levels. At the age of 27 weeks we found no left ventricular hypertrophy and no alteration of cardiac function as assessed by echocardiography. These mice also showed no activation of the calcineurin/NFAT pathway in heart and liver and no tissue and systemic signs of inflammation. Importantly, blood pressure, glomerular filtration rate and urea clearance were similar between genotypes. Thus, the presence of high circulating FGF23 levels alone in the absence of renal impairment and normal/high phosphate levels is not sufficient to cause cardiovascular disease.

Families' perceived benefits of home visits for managing paediatric obesity outweigh the potential costs and barriers.

AIM: Home visits have successfully been used to deliver various health services, but what role could they play in paediatric weight management? Low treatment initiation and high attrition prompted our multidisciplinary paediatric weight management clinic to investigate how families perceived the benefits and barriers of home visits. METHODS: We focused on children with obesity aged 2-17 who were enrolled in our tertiary-level clinic in Alberta, Canada. None had received a home visit. The families were interviewed face-to-face from October 2015 to October 2016, and we used a qualitative description methodological framework and manifest content analysis. The parents were the main interviewees. RESULTS: Of the 56 families, 89% were interested in a home visit, 82% wanted support from a dietician and 54% from an exercise specialist. The perceived benefits of home visits included comprehensive assessment (95%), convenience (86%), tailored care (29%) and family involvement (13%), while the costs and barriers included clinicians' potential judgmental attitudes (30%), loss of privacy (19%) and distractions (10%). Some thought clinicians would find home visits inconvenient (25%), with bureaucratic challenges (14%) and sustainability issues (5%). CONCLUSION: Families felt home visits were a convenient option for managing paediatric obesity and identified important benefits and barriers that could guide such interventions.

Substance Use Among Homeless Individuals With Schizophrenia and Bipolar Disorder.

Mental illness and substance use are overrepresented within urban homeless populations. This paper compared substance use patterns between homeless individuals diagnosed with schizophrenia spectrum (SS) and bipolar disorders (BD) using the Mini-International Neuropsychiatric Interview. From a sample of 497 subjects drawn from Vancouver, Canada who participated in the At Home/Chez Soi study, 146 and 94 homeless individuals were identified as BD and SS, respectively. In the previous 12 months, a greater proportion of BD homeless reported greater use of cocaine (χ = 20.0, p = 0.000), amphetamines (χ = 13,8, p = 0.000), opiates (χ = 24.6, p = 0.000), hallucinogens (χ = 11.7, p = 0.000), cannabinoids (χ = 5.05, p = 0.034), and tranquilizers (χ = 7.95, p = 0.004) compared to SS. Cocaine and opiates were significantly associated with BD homeless (χ = 39.06, df = 2, p < 0.000). The present study illustrates the relationship between substance use and BD in a vulnerable urban population of homeless, affected by adverse psychosocial factors and severe psychiatric conditions.

The readiness and motivation interview for families (RMI-Family) managing pediatric obesity: study protocol.

BACKGROUND: Experts recommend that clinicians assess motivational factors before initiating care for pediatric obesity. Currently, there are no well-established clinical tools available for assessing motivation in youth with obesity or their families. This represents an important gap in knowledge since motivation-related information may shed light on which patients might fail to complete treatment programs. Our study was designed to evaluate the measurement properties and utility of the Readiness and Motivational Interview for Families (RMI-Family), a structured interview that utilizes a motivational interviewing approach to (i) assess motivational factors in youth and their parents, and (ii) examine the degree to which motivation and motivation-related concordance between youth and parents are related to making changes to lifestyle habits for managing obesity in youth. METHODS: From 2016 to 2020, this prospective study will include youth with obesity (body mass index [BMI] ≥97th percentile; 13-17 years old; n = 250) and their parents (n = 250). The study will be conducted at two primary-level, multidisciplinary obesity management clinics based at children's hospitals in Alberta, Canada. Participants will be recruited and enrolled after referral to these clinics, but prior to initiating clinical care. Each youth and their parent will complete the RMI-Family (~1.5 h) at baseline, and 6- and 12-months post-baseline. Individual (i.e., youth or parent) and family-level (i.e., across youth and parent) responses to interview questions will be scored, as will aspects of interview administration (e.g., fidelity to motivational interviewing tenets). The RMI-Family will also be examined for test-retest reliability. Youth data collected at each time point will include demography, anthropometry, lifestyle habits, psychosocial functioning, and health services utilization. Cross-sectional and longitudinal associations between individual and family-level interview scores on the RMI-Family and these clinical measures will be examined. DISCUSSION: As a measurement tool drawing on family-centered care and motivational interviewing, the RMI-Family was designed to increase understanding of the role of motivational factors in pediatric obesity management, allowing healthcare providers and policymakers to manage pediatric obesity more effectively and efficiently. Findings will help to create an innovative, tailored model of health care delivery that uses resources judiciously and is designed to best meet families' needs.

Implementation of eMental Health care: viewpoints from key informants from organizations and agencies with eHealth mandates.

BACKGROUND: The use of technology such as computers, tablets, and smartphones to improve access to and the delivery of mental health care (eMental Health care) is growing worldwide. However, despite the rapidly expanding evidence base demonstrating the efficacy of eMental Health care, its implementation in clinical practice and health care systems remains fragmented. To date, no peer-reviewed, key-informant studies have reported on the perspectives of decision-makers concerned with whether and how to implement eMental Health care. METHODS: From September to November 2015, we conducted 31 interviews with key informants responsible for leadership, policy, research, and/ or information technology in organizations influential in the adoption of technology for eMental Health care. Deductive and inductive thematic analyses of transcripts were conducted using the Behavior Change Wheel as an organizing framework. Frequency and intensity effect sizes were calculated for emerging themes to further explore patterns within the data. RESULTS: Key informant responses (n = 31) representing 6 developed countries and multiple organizations showed consensus on common factors impacting implementation: individual and organizational capacities (e.g., computer literacy skills [patients and providers], knowledge gaps about cyber security, limited knowledge of available services); motivational drivers of technology-based care (e.g., extending care, data analytics); and opportunities for health systems to advance eMental Health care implementation (e.g., intersectoral research, rapid testing cycles, sustainable funding). Frequency effect sizes showed strong associations between implementation and credibility, knowledge, workflow, patient empowerment, electronic medical record (EMR) integration, sustained funding and intersectoral networks. Intensity effect sizes showed the highest concentration of statements (>10% of all comments) related to funding, credibility, knowledge gaps, and patient empowerment. CONCLUSION: This study provides previously unavailable information about key informant perspectives on eMental Health care implementation. The themes that emerged, namely the need to intensify intersectoral research, measure/monitor readiness to implement, define cost-utility benchmarks, raise awareness about available technologies, and test assumptions that 'proven' technologies will be easily integrated can inform the design and evaluation of eMental Health care implementation models.