"Another thing to live for": Supporting HCV treatment and cure among Indigenous people impacted by substance use in Canadian cities.

BACKGROUND: Colonization and colonial systems have led to the overrepresentation of Indigenous people impacted by substance use and HCV infection in Canada. It is critical to ensure Indigenous people's equitable access to new direct acting antiviral HCV treatments (DAAs). Identifying culturally-safe, healing-centered approaches that support the wellbeing of Indigenous people living with HCV is an essential step toward this goal. We listened to the stories and perspectives of HCV-affected Indigenous people and HCV treatment providers with the aim of providing pragmatic recommendations for decolonizing HCV care. METHODS: Forty-five semi-structured interviews were carried out with Indigenous participants affected by HCV from the Cedar Project (n = 20, British Columbia (BC)) and the Canadian Coinfection Cohort (n = 25, BC; Ontario (ON); Saskatchewan (SK)). In addition, 10 HCV treatment providers were interviewed (n = 4 BC, n = 4 ON, n = 2 SK). Interpretive description identified themes to inform clinical approaches and public health HCV care. Themes and related recommendations were validated by Indigenous health experts and Indigenous participants prior to coding and re-contextualization. RESULTS: Taken together, participants' stories and perceptions were interpreted to coalesce into three overarching and interdependent themes representing their recommendations. First: treatment providers must understand and accept colonization as a determinant of health and wellness among HCV-affected Indigenous people, including ongoing cycles of child apprehension and discrimination within the healthcare system. Second: consistently safe attitudes and actions create trust within HCV treatment provider-patient relationships and open opportunities for engagement into care. Third: treatment providers who identify, build, and strengthen circles of care will have greater success engaging HCV-affected Indigenous people who have used drugs into care. CONCLUSION: There are several pragmatic ways to integrate Truth and Reconciliation as well as Indigenous concepts of whole-person wellness into the HCV cascade of care. By doing so, HCV treatment providers have an opportunity to create greater equity and support long-term wellness of Indigenous patients.

Ribonuclease inhibitor 1 regulates erythropoiesis by controlling GATA1 translation.

Ribosomal proteins (RP) regulate specific gene expression by selectively translating subsets of mRNAs. Indeed, in Diamond-Blackfan anemia and 5q- syndrome, mutations in RP genes lead to a specific defect in erythroid gene translation and cause anemia. Little is known about the molecular mechanisms of selective mRNA translation and involvement of ribosomal-associated factors in this process. Ribonuclease inhibitor 1 (RNH1) is a ubiquitously expressed protein that binds to and inhibits pancreatic-type ribonucleases. Here, we report that RNH1 binds to ribosomes and regulates erythropoiesis by controlling translation of the erythroid transcription factor GATA1. Rnh1-deficient mice die between embryonic days E8.5 and E10 due to impaired production of mature erythroid cells from progenitor cells. In Rnh1-deficient embryos, mRNA levels of Gata1 are normal, but GATA1 protein levels are decreased. At the molecular level, we found that RNH1 binds to the 40S subunit of ribosomes and facilitates polysome formation on Gata1 mRNA to confer transcript-specific translation. Further, RNH1 knockdown in human CD34+ progenitor cells decreased erythroid differentiation without affecting myelopoiesis. Our results reveal an unsuspected role for RNH1 in the control of GATA1 mRNA translation and erythropoiesis.

Specific retinal phenotype in early IQCB1-related disease.

PurposeTo describe the ocular and systemic phenotype in IQCB1-related disease.MethodsFour cases (3 males, 1 female) with molecularly confirmed IQCB1-related disease underwent ophthalmological examination including best-corrected visual acuity (BCVA) measurement, fundus evaluation, electroretinography (ERG), and spectral-domain optical coherence tomography (SD-OCT). Systemic evaluation including abdominal ultrasound was performed in all cases.ResultsBCVA ranged from perception of light (Case-2; 1 year) to 20/125 (Case-1; 9 years). Fundus evaluation showed whitish or silvery reflex outside the vascular arcades in all cases; the reflex was circumferential, irregular and covered at-least 6 clock hours at younger ages (3 cases; 1-4 years). The reflex was less conspicuous with increasing age (Case-1 (9 years) and Case-4 (20 years)). The peripheral retinal SD-OCT scans showed evidence of extensive deposition at the level of retinal pigment epithelium with complete absence of overlying photoreceptor outer segments and myoid zone. The ERG was non-detectable in all cases. All cases harbored biallelic nonsense (p.R364*, p. R455*) or frameshifting (p.M370Yfs*49, p.C253Afs*9) mutations in IQCB1. Case-1 additionally had developmental delay, hemi-hyperplasia, toe syndactyly, and kidney cysts.ConclusionIQCB1-related syndromic or non-syndromic Leber congenital amaurosis (LCA) carries unique retinal characteristics which helps differentiate IQCB1-retinopathy from other genetic forms of LCA in childhood.

Arthroscopic surgery for degenerative knee arthritis and meniscal tears: a clinical practice guideline

The role of arthroscopic surgery in degenerative knee disease was evaluated in this guideline.

Longevity of daily oral vitamin D3 supplementation: differences in 25OHD and 24,25(OH)2D observed 2 years after cessation of a 1-year randomised controlled trial (VICtORy RECALL).

To determine how long vitamin D lasts after supplementation ceases, the marker of status was measured 2 and 3 years after a 1-year trial. Compared to placebo, the proportion of vitamin D-deficient women was still lower, if they had taken daily vitamin D3, after 2 years, indicating its longevity. INTRODUCTION: The purpose of this study was to determine longevity of vitamin D status following cessation of vitamin D3 supplementation, 2 and 3 years after a 1-year randomised, double-blind placebo controlled trial and to investigate possible predictive factors. METHODS: Caucasian non-smoking postmenopausal women randomised to ViCtORY (2009-2010), who had not taken vitamin D supplements since the trial ended, were invited to attend follow-up visits. Total 25-hydroxyvitamin D (25OHD) and 24,25-dihydroxyvitamin D (24,25OH2D) were measured by dual tandem mass spectrometry of serum samples following removal of protein and de-lipidation; the original randomised controlled trial (RCT) samples were re-analysed simultaneously. Vitamin D-binding protein (VDBP) was measured by monoclonal immunoassay. RESULTS: In March 2012 and March 2013, 159 women (mean (SD) age 67.6 (2.1) years) re-attended, equally distributed between the original treatment groups: daily vitamin D3 (400 IU, 1000 IU) and placebo. One month after the RCT ended (March 2010), the proportion of women in placebo, 400 IU and 1000 IU vitamin D3 groups, respectively, with 25OHD < 25 nmol/L was 15, 0 and 0 (chi-square p < 0.001, n = 46, 44, 54). After 2 years (March 2012), it was 22, 4 and 4% (p = 0.002, n = 50, 48, 57); after 3 years, it was 23, 13 and 15% (p = 0.429, n = 48, 45, 52). The respective proportions of women with 24,25OH2D < 2.2 nmol/L were 50, 2 and 2% (1 month, p < 0.001, n = 46, 44, 54); 42, 33 and 12% (2 years, p = 0.002, n = 50, 48, 57); and 45, 27 and 29% (3 years, p = 0.138, n = 47, 45, 51). VDBP was a predictor of circulating 25OHD longevity (beta for VDBP in µg/mL 0.736; 95% CI 0.216-1.255, p = 0.006) but not 24,25OH2D. CONCLUSION: Four hundred international units or 1000 IU of daily vitamin D3 showed benefits over placebo 2 years after supplementation ceased in keeping 25OHD > 25 nmol/L.

Does parental support influence children's active school travel?

Today's 'backseat generation' of children is more often driven to school. Active school travel (AST) can contribute up to 30% of recommended daily physical activity. Although governed by a complex set of factors, parents are considered 'gatekeepers' of children's travel mode decisions. Therefore, we investigate the relationship between parental support and children's AST. Data were from Active Streets, Active People-Junior (British Columbia, Canada). Children self-reported travel mode to/from school for 1 week (10 trips). We assessed parental perceived neighborhood traffic and crime safety (Neighborhood Environmental Walkability Scale-Youth) and frequency of parental support for AST (0-5 ×/week). We investigated the association between daily AST behaviour and parental support using logistic regression (controlling for age, sex, distance to school and perceived neighborhood safety). In our sample (n = 179, 11.0 ± 1.0 years, 59% girls), 57% reported daily AST and 63% of parents provided daily support. Bivariate analyses showed AST behaviour was significantly associated with parental support frequency and parents' perceived safety. In adjusted analysis, daily parental support remained significantly associated with daily AST (OR 9.0, 95% CI 4.2, 19.7). The relationship between parental support and AST was independent of noted correlates of AST. Thus, interventions that focus solely on changes to the built environment may not be enough to encourage AST. Therefore, interventions that aim to increase AST should involve parents and children in the planning process.

The relationship between vitamin D status and muscle strength in young healthy adults from sunny climate countries currently living in the northeast of Scotland.

The current study examined the relationship between vitamin D status and muscle strength in young healthy adults: residents (>6 months) and newcomers (0-3 months), originally from sunny climate countries but currently living in the northeast of Scotland. Our longitudinal data found a positive, albeit small, relationship between vitamin D status and knee extensor isometric strength. INTRODUCTION: Vitamin D has been suggested to play a role in muscle health and function, but studies so far have been primarily in older populations for falls prevention and subsequent risk of fractures. METHODS: Vitamin D status was assessed in a healthy young adults from sunny climate countries (n = 71, aged 19-42 years) with 56% seen within 3 months of arriving in Aberdeen [newcomers; median (range) time living in the UK = 2 months (9-105 days)] and the remainder resident for >6 months [residents; 23 months (6-121 months)]. Participants attended visits every 3 months for 15 months. At each visit, fasted blood samples were collected for analysis of serum 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), carboxy-terminal collagen crosslinks (CTX) and N-terminal propeptide of type I collagen (P1NP). Maximal voluntary contractions (MVC) were performed for grip strength (both arms) and for maximal isometric strength of the knee extensors (right knee). RESULTS: There were small seasonal variations in 25(OH)D concentrations within the newcomers and residents, but no seasonal variation in bone turnover markers. There was a positive, albeit small, association between 25(OH)D and knee extensor maximal isometric strength. Mixed modelling predicted that for each 1 nmol/L increase in 25(OH)D, peak torque would increase by 1 Nm (p = 0.04). CONCLUSIONS: This study suggests that vitamin D may be important for muscle health in young adults migrating from sunnier climates to high latitudes, yet the potential effect is small.

Reference data for jumping mechanography in Canadian children, adolescents and young adults.

OBJECTIVES: To provide age- and sex-specific reference data for mechanography-derived parameters of muscle function in Canadian children and youth using the single two-legged jump (S2LJ) with hands-on-waist. METHODS: Our sample included 2017 observations from 715 participants (9-21 years; 338 girls). Participants performed three S2LJ with hands-on-waist on a force platform (Leonardo Mechanograph, Novotec). Outcomes were maximum peak power (Pmax), Pmax/mass, peak force/body weight (Fmax/BW), force efficiency, maximum jump height (Hmax), and velocity (Vmax). We used the LMS method to construct age- and sex-specific percentile curves and mixed effects models to examine sex and ethnic differences. RESULTS: With the exception of Efficiency, mechanography outcomes were greater in girls (4-40%, p<0.05) than boys at age 9. Boys' advantage in mechanography parameters emerged in adolescence (age 11-13 years; 3-65%, p<0.05) and persisted into young adulthood, except for Fmax/BW which was not greater in boys until age 17 (4-10%, p<0.05). Mechanography outcomes were 3-9% (p<0.05) greater in Asian compared with white participants. CONCLUSIONS: We provide the first reference data for the S2LJ using the hands-on-waist protocol in children, youth and young adults. These data support previous findings using freely moving arms and can be used when evaluating muscle function in pediatric studies.

Developing HSCs become Notch independent by the end of maturation in the AGM region.

The first definitive hematopoietic stem cells (dHSCs) in the mouse emerge in the dorsal aorta of the embryonic day (E) 10.5 to 11 aorta-gonad-mesonephros (AGM) region. Notch signaling is essential for early HSC development but is dispensable for the maintenance of adult bone marrow HSCs. How Notch signaling regulates HSC formation in the embryo is poorly understood. We demonstrate here that Notch signaling is active in E10.5 HSC precursors and involves both Notch1 and Notch2 receptors, but is gradually downregulated while they progress toward dHSCs at E11.5. This downregulation is accompanied by gradual functional loss of Notch dependency. Thus, as early as at final steps in the AGM region, HSCs begin acquiring the Notch independency characteristic of adult bone marrow HSCs as part of the maturation program. Our data indicate that fine stage-dependent tuning of Notch signaling may be required for the generation of definitive HSCs from pluripotent cells.

Notch Signaling Regulates the Homeostasis of Tissue-Restricted Innate-like T Cells.

Although Notch signaling plays important roles in lineage commitment and differentiation of multiple cell types including conventional T cells, nothing is currently known concerning Notch function in innate-like T cells. We have found that the homeostasis of several well-characterized populations of innate-like T cells including invariant NKT cells (iNKT), CD8ααTCRαß small intestinal intraepithelial lymphocytes, and innate memory phenotype CD8 T cells is controlled by Notch. Notch selectively regulates hepatic iNKT cell survival via tissue-restricted control of B cell lymphoma 2 and IL-7Rα expression. More generally, Notch regulation of innate-like T cell homeostasis involves both cell-intrinsic and -extrinsic mechanisms and relies upon context-dependent interactions with Notch ligand-expressing fibroblastic stromal cells. Collectively, using conditional ablation of Notch receptors on peripheral T cells or Notch ligands on putative fibroblastic stromal cells, we show that Notch signaling is indispensable for the homeostasis of three tissue-restricted populations of innate-like T cells: hepatic iNKT, CD8ααTCRαß small intestinal intraepithelial lymphocytes, and innate memory phenotype CD8 T cells, thus supporting a generalized role for Notch in innate T cell homeostasis.

Vitamin E homologues α- and γ-tocopherol are not associated with bone turnover markers or bone mineral density in peri-menopausal and post-menopausal women.

UNLABELLED: In a large cohort of older women, we investigated the relationships that different forms of vitamin E may have with bone turnover markers and bone mineral density (BMD). We found a suggestive positive association between serum alpha-tocopherol and BMD at the femoral neck, but no other clinically relevant observations. INTRODUCTION: Vitamin E has anti-oxidant and anti-inflammatory properties hypothesized to benefit bone, but limited studies exist regarding its homologues. We examined circulating and dietary α- and γ-tocopherols with bone turnover markers (BTMs) and bone mineral density (BMD), and the role of inflammation in this relationship. METHODS: We performed two cross-sectional analyses from two visits (V2, 1997-1999, n = 3883; V3, 2007-2011, n = 2130) of the Aberdeen Prospective Osteoporosis Screening Study. Dietary and supplement intakes by food frequency questionnaire were assessed at both visits. V2 BTMs (urinary free pyridinoline and deoxypyridinoline, serum N-terminal propeptide of type 1 collagen) and V3 serum α- and γ-tocopherols, inflammatory markers (interleukin-6 [IL-6], serum amyloid A [SAA], high-sensitivity C-reactive protein [hs-CRP], E-selectin) and dual X-ray absorptiometry BMD at the femoral neck and lumbar spine were collected. Food sources of tocopherol homologues and diet-serum correlations were determined. The relationships between dietary tocopherols and BTMs (V2), and dietary and serum tocopherols with BMD (V3) were examined by multivariable regression (adjusting for age, cholesterol, inflammatory markers, carotenoids, body mass index, physical activity level, alcohol intake, smoking status and national deprivation category). RESULTS: Serum γ-tocopherol was associated with increasing concentrations of hs-CRP, SAA and E-selectin (P-trend all <0.0001), while α-tocopherol was associated with decreasing concentrations of IL-6 and hs-CRP (P-trend all <0.001). Controlling for covariates, serum α-tocopherol was positively associated with BMD at the femoral neck (ß = 0.002, P = 0.04) among those not reporting vitamin E supplementation. CONCLUSION: We did not find biologically meaningful results between dietary and tocopherol homologues with BTMs or BMD.

[Better Reporting of Interventions: Template for Intervention Description and Replication (TIDieR) Checklist and Guide]. / Die TIDieR Checkliste und Anleitung - ein Instrument für eine verbesserte Interventionsbeschreibung und Replikation.

Without a complete published description of interventions, clinicians and patients cannot reliably implement interventions that are shown to be useful, and other researchers cannot replicate or build on research findings. The quality of description of interventions in publications, however, is remarkably poor. To improve the completeness of reporting, and ultimately the replicability, of interventions, an international group of experts and stakeholders developed the Template for Intervention Description and Replication (TIDieR) checklist and guide. The process involved a literature review for relevant checklists and research, a Delphi survey of an international panel of experts to guide item selection, and a face-to-face panel meeting. The resultant 12-item TIDieR checklist (brief name, why, what (materials), what (procedure), who intervened, how, where, when and how much, tailoring, modifications, how well (planned), how well (actually carried out)) is an extension of the CONSORT 2010 statement (item 5) and the SPIRIT 2013 statement (item 11). While the emphasis of the checklist is on trials, the guidance is intended to apply across all evaluative study designs. This paper presents the TIDieR checklist and guide, with a detailed explanation of each item, and examples of good reporting. The TIDieR checklist and guide should improve the reporting of interventions and make it easier for authors to structure the accounts of their interventions, reviewers and editors to assess the descriptions, and readers to use the information.

Single cell tuning of Myc expression by antigen receptor signal strength and interleukin-2 in T lymphocytes.

Myc controls the metabolic reprogramming that supports effector T cell differentiation. The expression of Myc is regulated by the T cell antigen receptor (TCR) and pro-inflammatory cytokines such as interleukin-2 (IL-2). We now show that the TCR is a digital switch for Myc mRNA and protein expression that allows the strength of the antigen stimulus to determine the frequency of T cells that express Myc. IL-2 signalling strength also directs Myc expression but in an analogue process that fine-tunes Myc quantity in individual cells via post-transcriptional control of Myc protein. Fine-tuning Myc matters and is possible as Myc protein has a very short half-life in T cells due to its constant phosphorylation by glycogen synthase kinase 3 (GSK3) and subsequent proteasomal degradation. We show that Myc only accumulates in T cells exhibiting high levels of amino acid uptake allowing T cells to match Myc expression to biosynthetic demands. The combination of digital and analogue processes allows tight control of Myc expression at the population and single cell level during immune responses.

Bone micro-architecture of elite alpine skiers is not reflected by bone mineral density.

UNLABELLED: Bone quality is affected by muscle forces and external forces. We investigated how micro-architecture is influenced in elite alpine skiers who have received high loading levels throughout their adolescent bone development. Bone strength was higher in skiers, likely due to external forces, but muscle forces may also be a significant contributor. INTRODUCTION: Impact loading and muscle forces affect bone quality, but little is known about how they influence 3 dimensional aspects of bone structure. This study investigated bone quality in female and male elite alpine skiers using high-resolution peripheral quantitative computed tomography (HR-pQCT). METHODS: HR-pQCT at the distal radius and tibia, whole-body lean mass, and muscle strength were assessed in 10 female (22.7 ± 3.9 years) and 12 male (25.5 ± 3.3 years) Canadian national alpine team athletes and compared to recreationally active female (N = 10, 23.8 ± 3.2 years) and male (N = 12; 23.7 ± 3.6 years) control subjects. HR-pQCT standard parameters and customized cortical and finite element (FE) analyses were performed and analyzed using one-way ANOVA and Pearson's correlation. RESULTS: Male and female skiers had stronger bones than controls at radius (38-49 %, p < 0.001) and tibia (24-28 %, p < 0.001). This result was not consistently reflected by total bone mineral density (BMD) because higher trabecular BMD occurred in parallel with lower cortical BMD, which was due to a redistribution of mineral leading to a shift of the endocortical margin toward a thicker cortex. The endocortical regional adaptation was likely responsible for the greater strength of the athletes' bones. Lean mass and muscle strength was 29 to 90 % greater (p < 0.001) in athletes compared to controls. Good associations between muscle strength and FE-estimated bone strength were found (r = 0.63 to 0.80; p < 0.001), although micro-architecture was more strongly associated with muscle outcomes in females than males. CONCLUSIONS: Higher bone strength in elite alpine skiers is achieved through micro-architectural adaptation that is not apparent by BMD measurements alone. The improved micro-architecture at radius and tibia suggests that muscle forces may play an important role in bone adaptation.

NLRC5 exclusively transactivates MHC class I and related genes through a distinctive SXY module.

MHC class II (MHCII) genes are transactivated by the NOD-like receptor (NLR) family member CIITA, which is recruited to SXY enhancers of MHCII promoters via a DNA-binding "enhanceosome" complex. NLRC5, another NLR protein, was recently found to control transcription of MHC class I (MHCI) genes. However, detailed understanding of NLRC5's target gene specificity and mechanism of action remained lacking. We performed ChIP-sequencing experiments to gain comprehensive information on NLRC5-regulated genes. In addition to classical MHCI genes, we exclusively identified novel targets encoding non-classical MHCI molecules having important functions in immunity and tolerance. ChIP-sequencing performed with Rfx5(-/-) cells, which lack the pivotal enhanceosome factor RFX5, demonstrated its strict requirement for NLRC5 recruitment. Accordingly, Rfx5-knockout mice phenocopy Nlrc5 deficiency with respect to defective MHCI expression. Analysis of B cell lines lacking RFX5, RFXAP, or RFXANK further corroborated the importance of the enhanceosome for MHCI expression. Although recruited by common DNA-binding factors, CIITA and NLRC5 exhibit non-redundant functions, shown here using double-deficient Nlrc5(-/-)CIIta(-/-) mice. These paradoxical findings were resolved by using a "de novo" motif-discovery approach showing that the SXY consensus sequence occupied by NLRC5 in vivo diverges significantly from that occupied by CIITA. These sequence differences were sufficient to determine preferential occupation and transactivation by NLRC5 or CIITA, respectively, and the S box was found to be the essential feature conferring NLRC5 specificity. These results broaden our knowledge on the transcriptional activities of NLRC5 and CIITA, revealing their dependence on shared enhanceosome factors but their recruitment to distinct enhancer motifs in vivo. Furthermore, we demonstrated selectivity of NLRC5 for genes encoding MHCI or related proteins, rendering it an attractive target for therapeutic intervention. NLRC5 and CIITA thus emerge as paradigms for a novel class of transcriptional regulators dedicated for transactivating extremely few, phylogenetically related genes.

Deficits in distal radius bone strength, density and microstructure are associated with forearm fractures in girls: an HR-pQCT study.

UNLABELLED: Forearm fractures are common during growth. We studied bone strength in youth with a recent forearm fracture. In girls, suboptimal bone strength was associated with fractures. In boys, poor balance and physical inactivity may lead to fractures. Prospective studies will confirm these relationships and identify targets for prevention strategies. INTRODUCTION: The etiology of pediatric forearm fractures is unclear. Thus, we examined distal radius bone strength, microstructure, and density in children and adolescents with a recent low- or moderate-energy forearm fracture and those without forearm fractures. METHODS: We assessed the non-dominant (controls) and non-fractured (cases) distal radius (7% site) using high-resolution peripheral quantitative computed tomography (HR-pQCT) (Scanco Medical AG) in 270 participants (girls: cases n = 47, controls n = 61 and boys: cases n = 88, controls n = 74) aged 8-16 years. We assessed standard anthropometry, maturity, body composition (dual energy X-ray absorptiometry (DXA), Hologic QDR 4500 W) physical activity, and balance. We fit sex-specific logistic regression models for each bone outcome adjusting for maturity, ethnicity, height, and percent body fat. RESULTS: In girls, impaired bone strength (failure load, ultimate stress) and a high load-to-strength ratio were associated with low-energy fractures (odds ratios (OR) 2.8-4.3). Low total bone mineral density (Tt.BMD), bone volume ratio, trabecular thickness, and cortical BMD and thickness were also associated with low-energy fractures (ORs 2.0-7.0). In boys, low Tt.BMD, but not bone strength, was associated with low-energy fractures (OR = 1.8). Boys with low-energy fractures had poor balance and higher percent body fat compared with controls (p < 0.05). Boys with fractures (both types) were less active than controls (p < 0.05). CONCLUSIONS: Forearm fracture etiology appears to be sex-specific. In girls, deficits in bone strength are associated with fractures. In boys, a combination of poor balance, excess body fat, and low physical activity may lead to fractures. Prospective studies are needed to confirm these relationships and clarify targets for prevention strategies.