Outcome measures for young people with adolescent idiopathic scoliosis: A qualitative exploration of healthcare professionals' perceptions and practices.

BACKGROUND: Limited knowledge exists on current use of patient reported outcome measures (PROMs) and performance measures for adolescents with idiopathic scoliosis (AIS), as well as health care professionals' (HCPs) perceived barriers and facilitators towards their use. This study's objectives were: 1) to explore current practice of HCPs when assessing outcomes for AIS 2) to understand perceived barriers and facilitators of HCPs to use PROMs 3) to understand perceived barriers and facilitators of HCPs to use performance measures. METHODS: A qualitative study recruited a purposive sample of HCPs from a tertiary hospital in the United Kingdom. Mean years of experience managing individuals with AIS was 11.8 years; and included surgeons, physiotherapists and nurses, educated at Bachelor, Masters and Doctoral level. Consent to participate and demographic information were collected in advance of the interviews. In-depth, virtual semi-structured interviews were informed by a topic guide based on current evidence. Interviews of approximately 45 minutes were audio and video recorded and transcribed verbatim alongside written field notes. Data were coded and analysed using inductive thematic analysis, involving researchers with topic and methodological expertise and input from a patient representative. RESULTS: Two themes emerged regarding current practice of using PROMs routine practice and personal evaluations. Four themes emerged as barriers to using PROMs for individuals with AIS: priority and support (e.g., HCPs focus on providing care), practical challenges (e.g., inadequate PROMs), patient-related challenges (e.g., patient preferences) and knowledge, education, and perceived value. Two themes emerged as facilitators: quality existing measure (e.g., sufficient psychometric properties), and priority and support (e.g., research department/culture). Themes for barriers to use performance measures were practicality (e.g., need physical space) and perceived value and knowledge (e.g., PROMs are more important), while the one theme for facilitators was practical consideration (e.g., acceptability). CONCLUSIONS: Although HCPs perceived the value of using outcome measures, current practice indicates limited use for individuals with AIS. The findings revealed different barriers and facilitators to implement PROMs in practice. Adopting performance measure are limited due to lack of knowledge and perceived value alongside the practicality, while considering practical factors can improve the use of these measures in practice.

Biliary disease progression in childhood onset autoimmune liver disease: A 30-year follow-up into adulthood.

Background & Aims: Long-term follow-up studies of paediatric onset autoimmune liver disease (AILD) are invaluable in helping better understand the clinical course of disease. In day-to-day practice clinicians struggle with disease definitions whilst patients and parents lack clear prognostic information. Methods: The clinical progression of 159 patients with childhood onset AILD between June 1990 and December 2013 was reviewed, capturing data up to adulthood (ending May 2021). Results: Presentation with autoimmune hepatitis (AIH) was dominant (n = 119); biliary presentations accounted for 25%. During follow up, biliary disease progression confirmed by cholangiography and/or liver histology was observed frequently: 19.8% (20/101) patients with childhood onset AIH type 1 (AIH-1) developed biliary features by adulthood and of these 50% phenotypically transitioned to primary sclerosing cholangitis (PSC); the remaining transitioned to an overlap disease phenotype. No patients with AIH type 2 developed biliary progression. Two-thirds of patients with overlap features (14/21) in childhood had phenotypically progressed to PSC by adulthood. Approximately 43% (6/14) of AIH-1 patients requiring a liver transplant in adulthood had explant evidence of biliary disease compared with 11% (1/9) in childhood, whereas 35.7% (5/14) of patients had histology diagnostic of PSC in their explant liver and 7.1% (1/14) had overlap features. All patients with biliary phenotypes (PSC, autoimmune sclerosing cholangitis, overlap) who required a transplant (n = 18) were found to have explant histology consistent with PSC. Twelve of 14 patients with biliary progression developed ulcerative colitis during follow-up with 92% progressing to PSC. Conclusions: Three decades of follow-up demonstrated how children presenting with AILD had a significant risk of clinical transformation to PSC. Biliary progression was significantly associated with the development of inflammatory bowel disease. Impact and implications: Childhood onset autoimmune liver disease remains very impactful for patients and families. Disease nomenclature can however be confusing. Long-term follow up studies as children become adults is important to help understand how and why disease behaves over time. Understanding more about the long-term course of childhood autoimmune liver disease will help patients, families and doctors striving to improve care and reduce poor clinical outcomes. We followed over 150 patients with childhood onset autoimmune liver diseases into adulthood. We found that amongst patients with classical autoimmune hepatitis, 1 in 5 developed biliary disease over time, mostly consisting of primary sclerosing cholangitis. This was associated with developing inflammatory bowel disease. Our study design was retrospective and has relevant limitations. Defining phenotypes of autoimmune liver diseases is difficult and there is insufficient consensus, especially between adult and childhood physicians. Our data confirms the critical importance of careful long-term follow-up of patients, including safe transition to adult care, as well as robustly demonstrates, using real-world data, how disease nature can change over time. Our study affirms the need for investment in prospective cohort studies.

Cascade testing for hereditary cancer: comprehensive multigene panels identify unexpected actionable findings in relatives.

Current guidelines recommend single variant testing in relatives of patients with known pathogenic or likely pathogenic germline variants in cancer predisposition genes. This approach may preclude the use of risk-reducing strategies in family members who have pathogenic or likely pathogenic germline variants in other cancer predisposition genes. Cascade testing using multigene panels was performed in 3696 relatives of 7433 probands. Unexpected pathogenic or likely pathogenic germline variants were identified in 230 (6.2%) relatives, including 144 who were negative for the familial pathogenic or likely pathogenic variant but positive for a pathogenic or likely pathogenic variant in a different gene than the proband and 74 who tested positive for the familial pathogenic or likely pathogenic variant and had an additional pathogenic or likely pathogenic variant in a different gene than the proband. Of the relatives with unexpected pathogenic or likely pathogenic germline variants, 36.3% would have qualified for different or additional cancer screening recommendations. Limiting cascade testing to only the familial pathogenic or likely pathogenic variant would have resulted in missed, actionable findings for a subset of relatives.

Clinical and Functional Analyses of an African-ancestry Gain-of-function HOXB13 Variant Implicated in Aggressive Prostate Cancer.

BACKGROUND: Recent reports have uncovered a HOXB13 variant (X285K) predisposing to prostate cancer in men of West African ancestry. The clinical relevance and protein function associated with this inherited variant are unknown. OBJECTIVE: To determine the clinical relevance of HOXB13 (X285K) in comparison with HOXB13 (G84E) and BRCA2 pathogenic/likely pathogenic (P/LP) variants, and to elucidate the oncogenic mechanisms of the X285K protein. DESIGN, SETTING, AND PARTICIPANTS: Real-world data were collected from 21,393 men with prostate cancer undergoing genetic testing from 2019 to 2022, and in vitro cell-line models were established for the evaluation of oncogenic functions associated with the X285K protein. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Genetic testing results were compared among patient groups according to self-reported race/ethnicity, Gleason scores, and American Joint Committee on Cancer stages using the exact test. Oncogenic functions of X285K were evaluated by RNA sequencing, chromatin immunoprecipitation sequencing, and Western blot analyses. RESULTS AND LIMITATIONS: HOXB13 (X285K) was significantly enriched in self-reported Black (1.01%) versus White (0.01%) patients. We observed a trend of more aggressive disease in the HOXB13 (X285K) and BRCA2 P/LP carriers than in the HOXB13 (G84E) carriers. Replacement of the wild-type HOXB13 protein with the X285K protein resulted in a gain of an E2F/MYC signature, validated by the elevated expression of cyclin B1 and c-Myc, without affecting the androgen response signature. Elevated expression of cyclin B1 and c-Myc was explained by enhanced binding of the X285K protein to the promoters and enhancers of these genes. The limitations of the study are the lack of complete clinical outcome data for all patients studied and the use of a single cell line in the functional analysis. CONCLUSIONS: HOXB13 (X285K) is significantly enriched in self-reported Black patients, and X285K carriers detected in the real-world clinical setting have aggressive prostate cancer features similar to the BRCA2 carriers. Functional studies revealed a unique gain-of-function oncogenic mechanism of X285K protein in regulating E2F/MYC signatures. PATIENT SUMMARY: The HOXB13 (X285K) variant is clinically and functionally linked to aggressive prostate cancer, supporting genetic testing for X285K in Black men and early disease screening of carriers of this variant.

Sustained in vivo perfusion of a re-endothelialized tissue engineered kidney graft in a human-scale animal model.

Introduction: Despite progress in whole-organ decellularization and recellularization, maintaining long-term perfusion in vivo remains a hurdle to realizing clinical translation of bioengineered kidney grafts. The objectives for the present study were to define a threshold glucose consumption rate (GCR) that could be used to predict in vivo graft hemocompatibility and utilize this threshold to assess the in vivo performance of clinically relevant decellularized porcine kidney grafts recellularized with human umbilical vein endothelial cells (HUVECs). Materials and methods: Twenty-two porcine kidneys were decellularized and 19 were re-endothelialized using HUVECs. Functional revascularization of control decellularized (n = 3) and re-endothelialized porcine kidneys (n = 16) was tested using an ex vivo porcine blood flow model to define an appropriate metabolic glucose consumption rate (GCR) threshold above which would sustain patent blood flow. Re-endothelialized grafts (n = 9) were then transplanted into immunosuppressed pigs with perfusion measured using angiography post-implant and on days 3 and 7 with 3 native kidneys used as controls. Patent recellularized kidney grafts underwent histological analysis following explant. Results: The glucose consumption rate of recellularized kidney grafts reached a peak of 39.9 ± 9.7 mg/h at 21 ± 5 days, at which point the grafts were determined to have sufficient histological vascular coverage with endothelial cells. Based on these results, a minimum glucose consumption rate threshold of 20 mg/h was set. The revascularized kidneys had a mean perfusion percentage of 87.7% ± 10.3%, 80.9% ± 33.1%, and 68.5% ± 38.6% post-reperfusion on Days 0, 3 and 7, respectively. The 3 native kidneys had a mean post-perfusion percentage of 98.4% ± 1.6%. These results were not statistically significant. Conclusion: This study is the first to demonstrate that human-scale bioengineered porcine kidney grafts developed via perfusion decellularization and subsequent re-endothelialization using HUVEC can maintain patency with consistent blood flow for up to 7 days in vivo. These results lay the foundation for future research to produce human-scale recellularized kidney grafts for transplantation.

Content validity of the Scoliosis Research Society questionnaire (SRS-22r): A qualitative concept elicitation study.

INTRODUCTION: Scoliosis Research Society-22 revised (SRS-22r) is the common questionnaire used to evaluate health related quality of life (HRQOL) for young people with adolescent idiopathic scoliosis (AIS). The aim of this study is to evaluate its content validity for this population. METHODS: In-depth semi-structured interviews were conducted with a purposive sample of young people with AIS (Cobb angle ≥25˚, aged 10-18 years). Concept elicitation was used to evaluate the influence of AIS on participants' HRQOL. Participant information sheets and consent/assent forms were age relevant. Topic guide was informed by the SRS-22r and existing evidence. Interviews were audio and video recorded, transcribed verbatim, coded, and analysed using thematic analysis. Derived themes/codes were compared with SRS-22r contents (domains/items). RESULTS: Eleven participants (mean age 14.9 years [SD = 1.8]; 8 female) were recruited. The mean curve size was 47.5° [SD = 18°] and participants had been managed via different approaches. Four main themes emerged with associated subthemes: 1) Physical effects related to physical symptoms (back hurt, stiffness) and body asymmetry (uneven shoulders), 2) Activity-related effects showed impact on mobility (sitting for long periods), self-care (dressing), and school activities (focus during lessons), 3) Psychological effects revealed emotional (feel worried), mental (sleep quality), and body image effects (hide back from others), 4) Social effects (participation in school and leisure activities), and school, friends and mental health support. A weak association was found between items of the SRS-22r and the identified codes. CONCLUSION: The SRS-22r does not adequately capture important concepts that relate to HRQOL of adolescents with AIS. These findings support revision of the SRS-22r, or the development of a new patient reported outcome measure to evaluate HRQOL of adolescents with AIS.

A Polynesian-specific missense CETP variant alters the lipid profile.

Identifying population-specific genetic variants associated with disease and disease-predisposing traits is important to provide insights into the genetic determinants of health and disease between populations, as well as furthering genomic justice. Various common pan-population polymorphisms at CETP associate with serum lipid profiles and cardiovascular disease. Here, sequencing of CETP identified a missense variant rs1597000001 (p.Pro177Leu) specific to Maori and Pacific people that associates with higher HDL-C and lower LDL-C levels. Each copy of the minor allele associated with higher HDL-C by 0.236 mmol/L and lower LDL-C by 0.133 mmol/L. The rs1597000001 effect on HDL-C is comparable with CETP Mendelian loss-of-function mutations that result in CETP deficiency, consistent with our data, which shows that rs1597000001 lowers CETP activity by 27.9%. This study highlights the potential of population-specific genetic analyses for improving equity in genomics and health outcomes for population groups underrepresented in genomic studies.

Association of rs9939609 in FTO with BMI among Polynesian peoples living in Aotearoa New Zealand and other Pacific nations.

The fat mass and obesity associated (FTO) locus consistently associates with higher body mass index (BMI) across diverse ancestral groups. However, previous small studies of people of Polynesian ancestries have failed to replicate the association. In this study, we used Bayesian meta-analysis to test rs9939609, the most replicated FTO variant, for association with BMI with a large sample (n = 6095) of Aotearoa New Zealanders of Polynesian (Maori and Pacific) ancestry and of Samoan people living in the Independent State of Samoa and in American Samoa. We did not observe statistically significant association within each separate Polynesian subgroup. Bayesian meta-analysis of the Aotearoa New Zealand Polynesian and Samoan samples resulted in a posterior mean effect size estimate of +0.21 kg/m2, with a 95% credible interval [+0.03 kg/m2, +0.39 kg/m2]. While the Bayes Factor (BF) of 0.77 weakly favors the null, the BF = 1.4 Bayesian support interval is [+0.04, +0.20]. These results suggest that rs9939609 in FTO may have a similar effect on mean BMI in people of Polynesian ancestries as previously observed in other ancestral groups.

A stop-gain variant in BTNL9 is associated with atherogenic lipid profiles.

Current understanding of lipid genetics has come mainly from studies in European-ancestry populations; limited effort has focused on Polynesian populations, whose unique population history and high prevalence of dyslipidemia may provide insight into the biological foundations of variation in lipid levels. Here, we performed an association study to fine map a suggestive association on 5q35 with high-density lipoprotein cholesterol (HDL-C) seen in Micronesian and Polynesian populations. Fine-mapping analyses in a cohort of 2,851 Samoan adults highlighted an association between a stop-gain variant (rs200884524; c.652C>T, p.R218∗; posterior probability = 0.9987) in BTNL9 and both lower HDL-C and greater triglycerides (TGs). Meta-analysis across this and several other cohorts of Polynesian ancestry from Samoa, American Samoa, and Aotearoa New Zealand confirmed the presence of this association (ßHDL-C = -1.60 mg/dL, p HDL-C = 7.63 × 10-10; ßTG = 12.00 mg/dL, p TG = 3.82 × 10-7). While this variant appears to be Polynesian specific, there is also evidence of association from other multiancestry analyses in this region. This work provides evidence of a previously unexplored contributor to the genetic architecture of lipid levels and underscores the importance of genetic analyses in understudied populations.

The protective effect of rs373863828 on type 2 diabetes does not operate through a body composition pathway in adult Samoans.

OBJECTIVE: The aim of this study was to understand whether the paradoxical association of missense variant rs373863828 in CREB3 regulatory factor (CREBRF) with higher BMI but lower odds of diabetes is explained by either metabolically favorable body fat distribution or greater fat-free mass. METHODS: This study explored the association of the minor allele with dual-energy x-ray absorptiometry-derived body composition in n = 421 Samoans and used path analysis to examine the mediating role of fat and fat-free mass on the relationship between rs373863828 and fasting glucose. RESULTS: Among females, the rs373863828 minor A allele was associated with greater BMI. There was no association of genotype with percent body fat, visceral adiposity, or fat distribution in either sex. In both females and males, lean mass was greater with each A allele: 2.16 kg/copy (p = 0.0001) and 1.73 kg/copy (p = 0.02), respectively. Path analysis showed a direct negative effect of rs373863828 genotype on fasting glucose (p = 0.004) consistent with previous findings, but also an indirect positive effect on fasting glucose operating through fat-free mass (p = 0.027). CONCLUSIONS: The protective effect of rs373863828 in CREBRF, common among Pacific Islanders, on type 2 diabetes does not operate through body composition. Rather, the variant's effects on body size/composition and fasting glucose likely operate via different, tissue-specific mechanisms.

Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program.

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.

A machine learning approach to identifying important features for achieving step thresholds in individuals with chronic stroke.

BACKGROUND: While many factors are associated with stepping activity after stroke, there is significant variability across studies. One potential reason to explain this variability is that there are certain characteristics that are necessary to achieve greater stepping activity that differ from others that may need to be targeted to improve stepping activity. OBJECTIVE: Using two step thresholds (2500 steps/day, corresponding to home vs. community ambulation and 5500 steps/day, corresponding to achieving physical activity guidelines through walking), we applied 3 different algorithms to determine which predictors are most important to achieve these thresholds. METHODS: We analyzed data from 268 participants with stroke that included 25 demographic, performance-based and self-report variables. Step 1 of our analysis involved dimensionality reduction using lasso regularization. Step 2 applied drop column feature importance to compute the mean importance of each variable. We then assessed which predictors were important to all 3 mathematically unique algorithms. RESULTS: The number of relevant predictors was reduced from 25 to 7 for home vs. community and from 25 to 16 for aerobic thresholds. Drop column feature importance revealed that 6 Minute Walk Test and speed modulation were the only variables found to be important to all 3 algorithms (primary characteristics) for each respective threshold. Other variables related to readiness to change activity behavior and physical health, among others, were found to be important to one or two algorithms (ancillary characteristics). CONCLUSIONS: Addressing physical capacity is necessary but not sufficient to achieve important step thresholds, as ancillary characteristics, such as readiness to change activity behavior and physical health may also need to be targeted. This delineation may explain heterogeneity across studies examining predictors of stepping activity in stroke.

The missense variant, rs373863828, in CREBRF plays a role in longitudinal changes in body mass index in Samoans.

OBJECTIVE: A missense variant, rs373863828, in CREBRF is associated with obesity in Polynesians. We investigate whether rs373863828 and other factors are associated with body mass index (BMI) rate-of-change between 2010 and 2017-19 in Samoans. METHODS: We used sex-stratified models to test whether BMI rate-of-change was associated with rs373863828, baseline BMI, age, residence, physical activity, and household asset score in a cohort study of 480 Samoan adults measured in both 2010 (mean age 43.8 years) and 2017-19. RESULTS: Mean BMI increased from 32.1 to 33.5 kg/m2 in males (n = 220, p = 1.3 ×10-8) and from 35.9 to 37.8 kg/m2 in females (n = 260, p = 1.2 ×10-13). In females, the A allele was associated with a higher rate-of-change (0.150 kg/m2/year/allele, p = 1.7 ×10-4). Across 10-year age groups, mean BMI rate-of-change was lower in older participants. The BMI rate of change differed by genotype: it was, in females with AA genotype, approximately half that seen in GG and AG participants. In females lower baseline household asset scores were associated with a higher rate-of-change (p = 0.002). CONCLUSIONS: In Samoans, the minor A allele of rs373863828 is associated with an increased rate-of-change in BMI in females. On average, BMI of females with the AA genotype increased 0.30 kg/m2/year more than of those with the GG genotype.

Identifying mental health needs of children and youth with skin disease: A systematic review of screening and assessment tools.

BACKGROUND AND OBJECTIVES: (1) To identify patient reported outcome measures (PROMs) which have been used to screen and assess mental health symptoms in studies of youth with skin disease. (2) To critically appraise their evidence base in this population. METHODS: A systematic literature search was conducted within PubMed and PsycINFO combining search terms for pediatric populations, dermatology, screening and assessment tools, and psychological and psychiatric conditions, to identify PROMs which screened or assessed for mental health symptoms in youth with skin disease. PROMs which had undergone validation within this population were assessed for quality and evidence base using the COSMIN risk of bias tool. RESULTS: One hundred eleven PROMs which assess mental health symptoms in studies of youth with skin disease were identified. These included generic mental health scales which are extensively validated in different populations. Only one PROM, the "Skin Picking Scale-Revised" has undergone specific validation in youth with skin disease. This showed poor quality of evidence for content validity and therefore cannot be recommended. CONCLUSION: There is an urgent need to identify mental health problems early and treat proactively to improve outcomes in youth with skin disease. This review highlights the current lack of consensus around the best way to assess our patients. It is likely that existing generic mental health methods and PROMS will be appropriate for our needs. More work is required to examine the utility, feasibility, and acceptability of existing generic, validated mental health screening tools in youth with skin disease.

CREBRF missense variant rs373863828 has both direct and indirect effects on type 2 diabetes and fasting glucose in Polynesian peoples living in Samoa and Aotearoa New Zealand.

INTRODUCTION: The minor allele of a missense variant, rs373863828, in CREBRF is associated with higher body mass index (BMI), lower fasting glucose, and lower odds of type 2 diabetes. rs373863828 is common in Pacific Island populations (minor allele frequency (MAF) 0.096-0.259) but rare in non-Pacific Island populations (MAF <0.001). We examined the cross-sectional associations between BMI and rs373863828 in type 2 diabetes and fasting glucose with a large sample of adults of Polynesian ancestries from Samoa, American Samoa, and Aotearoa New Zealand, and estimated the direct and indirect (via BMI) effects of rs373863828 on type 2 diabetes and fasting glucose. RESEARCH DESIGN AND METHODS: We regressed type 2 diabetes and fasting glucose on BMI and rs373863828 stratified by obesity, regressed type 2 diabetes and fasting glucose on BMI stratified by rs373863828 genotype, and assessed the effects of rs373863828 on type 2 diabetes and fasting glucose with path analysis. The regression analyses were completed separately in four samples that were recruited during different time periods between 1990 and 2010 and then the results were meta-analyzed. All samples were pooled for the path analysis. RESULTS: Association of BMI with type 2 diabetes and fasting glucose may be greater in those without obesity (OR=7.77, p=0.015 and ß=0.213, p=9.53×10-5, respectively) than in those with obesity (OR=5.01, p=1.12×10-9 and ß=0.162, p=5.63×10-6, respectively). We did not observe evidence of differences in the association of BMI with type 2 diabetes or fasting glucose by genotype. In the path analysis, the minor allele has direct negative (lower odds of type 2 diabetes and fasting glucose) and indirect positive (higher odds of type 2 diabetes and fasting glucose) effects on type 2 diabetes risk and fasting glucose, with the indirect effects mediated through a direct positive effect of rs373863828 on BMI. CONCLUSIONS: There may be a stronger effect of BMI on fasting glucose in Polynesian individuals without obesity than in those with obesity. Carrying the rs373863828 minor allele does not decouple higher BMI from higher odds of type 2 diabetes.