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The sparse canopy cover and large contribution of bright background soil, along with the heterogeneous vegetation types in close proximity, are common challenges for mapping dryland vegetation with remote sensing. Consequently, the results of a single classification algorithm or one type of sensor to characterize dryland vegetation typically show low accuracy and lack robustness. In our study, we improved classification accuracy in a semi-arid ecosystem based on the use of vegetation optical (hyperspectral) and structural (lidar) information combined with the environmental characteristics of the landscape. To accomplish this goal, we used both spectral angle mapper (SAM) and multiple endmember spectral mixture analysis (MESMA) for optical vegetation classification. Lidar-derived maximum vegetation height and delineated riparian zones were then used to modify the optical classification. Incorporating the lidar information into the classification scheme increased the overall accuracy from 60% to 89%. Canopy structure can have a strong influence on spectral variability and the lidar provided complementary information for SAM's sensitivity to shape but not magnitude of the spectra. Similar approaches to map large regions of drylands with low uncertainty may be readily implemented with unmixing algorithms applied to upcoming space-based imaging spectroscopy and lidar. This study advances our understanding of the nuances associated with mapping xeric and mesic regions, and highlights the importance of incorporating complementary algorithms and sensors to accurately characterize the heterogeneity of dryland ecosystems.

Background: Favorable collagen fibril density and thickness combined with advances in graft preparation and fixation have significantly increased interest in the quadriceps tendon (QT) autograft for anterior cruciate ligament (ACL) reconstruction. While various suspensory techniques have been described, the biomechanical profile of these constructs is largely undefined., Purpose: To compare the biomechanics of suspensory techniques for soft tissue QT autograft fixation in an in vitro model of ACL reconstruction., Study Design: Controlled laboratory study., Methods: Full-thickness QT grafts were harvested using a 9-mm graft blade. Adjustable-loop devices (ALDs) were secured to the graft (n = 6 per group) with a combination implant containing the ALD and suture tape-reinforced whipstitching (tape-reinforced [TR] group), tethered superficially to the graft with a whipstitch (onlay [OL] group), luggage-tagged through and around the graft (luggage tag [LT] group), or staggered behind superficial suturing (staggered [SG] group). Grafts were tested on an electromechanical testing machine following a validated in vitro reconstruction model of intraoperative workflow and postoperative ACL kinematics, cyclic loading, and load to failure., Results: The TR group had significantly less postcyclic tension loss (mean, 24%) compared with the OL (56%; P = .002), LT (69%; P < .001), and SG (90%; P < .001) constructs. Cyclic elongation was below the 3.0-mm threshold defined as clinical failure for TR (1.6 mm), but not for OL (3.3 mm), LT (7.9 mm), and SG (11.3 mm). All constructs were within native ACL stiffness limits (220 ± 72 N/mm) without significant differences. Ultimate loads significantly exceeded a normal ACL loading limit of 454 N for TR (739 N; P = .023), OL (547 N; P = .020), and LT (769 N; P = .001), but not for SG (346 N; P = .236)., Conclusion: The TR ALD construct demonstrated the most favorable time-zero biomechanical properties of modern soft tissue QT suspensory constructs, with 32% less tension loss and 52% less cyclic elongation versus the closest construct. Failure loading of all constructs was acceptable with respect to the native ACL except for the SG group, which had suboptimal ultimate load., Clinical Relevance: TR ALD implants may protect soft tissue QT autografts before graft-bone healing in ACL reconstruction by minimizing time-zero laxity and fixation failure., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: This work was supported by Arthrex Inc (grant No. AIRR-0246). A.B. has received nonconsulting fees from Arthrex and Synthes GmbH, consulting fees and royalties from Arthrex, and hospitality payments from GE Healthcare. B.L.S. is a paid employee of Arthrex. J.J.M. has received education payments, consulting fees, and nonconsulting fees from Arthrex and hospitality payments from Great Lakes Orthopedics and Smith & Nephew. R.M.F. has received education payments and consulting fees from Arthrex; nonconsulting fees from Arthrex, Bodycad, and Synthes GmbH; and hospitality payments from JRF Ortho and Smith & Nephew. O.L.H. is a paid employee of Arthrex. C.A.W. is a paid employee of Arthrex and has had patents issued (US 10448945 B2,US 11432813 B2, US 11723645 B2, and US 12011156 B2). AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2024.)

Background: Physical activity (PA) is associated with a lower risk of cognitive decline and all-cause dementia in later life. Pathways underpinning this association are unclear but may involve either mediation and/or moderation by cardiorespiratory fitness (CRF)., Methods: Data on PA frequency (exposure) at 42y, non-exercise testing CRF (NETCRF, mediator/moderator) at 45y and overall cognitive function (outcome) at 50y were obtained from 9,385 participants (50.8% female) in the 1958 British birth cohort study. We used a four-way decomposition approach to examine the relative contributions of mediation and moderation by NETCRF on the association between PA frequency at 42y and overall cognitive function at 50y., Results: In males, the estimated overall effect of 42y PA ≥once per week (vs.

Purpose: This study aimed to investigate the association between psychological distress (PD) at age 16 and menstrual symptoms experienced across women's life., Methods: Up to 2584 females from the 1970 British Cohort Study, a study of individuals born within one week in 1970, were included. PD at age 16 was measured with the 12-item General Health Questionnaire. Three categories were derived: low PD (<11), moderate PD (11-15), and severe PD (>15). Five menstrual health symptoms were self-reported at each age (16, 30 and 42 years). Binomial logistic regressions examined associations between PD at age 16 and each individual symptom, adjusted for age of menarche, sleep and appetite problems, physical activity levels and socioeconomic position., Results: The most prevalent symptoms were "pain" (61 %), "painful period" (10 %) and "heavy period" (33 %) at ages 16, 30 and 42, respectively. At age 16, those with severe PD were more likely to experience depression (OR: 2.92; 95% CI: 2.31, 3.70)), irritability (1.67; 1.33, 2.11), menstrual pain (1.34; 1.01, 1.80), and headaches (1.29; 1.02, 1.63). A weak association was found between severe PD at age 16 and pre-menstrual tension at age 30 (1.72; 1.01, 2.83). At age 42, those with severe PD at age 16 were more likely to experience pre-menstrual tension (1.89; 1.46, 2.44), painful periods (1.64; 1.27, 2.11), and heavy periods (1.28; 1.00, 1.62)., Discussion: Menstruating females with higher levels of PD in adolescence have an increased risk of menstrual symptoms across adolescence, early and mid-adulthood. Our findings suggest the need to consider early-life psychological interventions to improve women's menstrual experiences across their reproductive years., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any competing or conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Phenylketonuria (PKU) is a genetically inherited disease caused by a mutation of the gene encoding phenylalanine hydroxylase (PAH) and is the most common inborn error of amino acid metabolism. A deficiency of PAH leads to increased blood and brain levels of phenylalanine (Phe), which may cause permanent neurocognitive symptoms and developmental delays if untreated. Current management strategies for PKU consist of early detection through neonatal screening and implementation of a restrictive diet with minimal amounts of natural protein in combination with Phe-free supplements and low-protein foods to meet nutritional requirements. For milder forms of PKU, oral treatment with synthetic sapropterin (BH4), the cofactor of PAH, may improve metabolic control of Phe and allow for more natural protein to be included in the patient's diet. For more severe forms, daily injections of pegvaliase, a PEGylated variant of phenylalanine ammonia-lyase (PAL), may allow for normalization of blood Phe levels. However, the latter treatment has considerable drawbacks, notably a strong immunogenicity of the exogenous enzyme and the attached polymeric chains. Research for novel therapies of PKU makes use of innovative materials for drug delivery and state-of-the-art protein engineering techniques to develop treatments which are safer, more effective, and potentially permanent., (© 2024 Wiley‐VCH GmbH.)

Introduction: Children with chronic conditions have greater health care needs than the general paediatric population but may not receive care that centres their needs and preferences as identified by their families. Clinicians and researchers are interested in developing interventions to improve family-centred care need information about the characteristics of existing interventions, their development and the domains of family-centred care that they address. We conducted a scoping review that aimed to identify and characterize recent family-centred interventions designed to improve experiences with care for children with chronic conditions., Methods: We searched Medline, Embase, PsycInfo and Cochrane databases, and grey literature sources for relevant articles or documents published between 1 January 2019 and 11 August 2020 (databases) or 7-20 October 2020 (grey literature). Primary studies with ≥10 participants, clinical practice guidelines and theoretical articles describing family-centred interventions that aimed to improve experiences with care for children with chronic conditions were eligible. Following citation and full-text screening by two reviewers working independently, we charted data covering study characteristics and interventions from eligible reports and synthesized interventions by domains of family-centred care., Results: Our search identified 2882 citations, from which 63 articles describing 61 unique interventions met the eligibility criteria and were included in this review. The most common study designs were quasiexperimental studies (n = 18), randomized controlled trials (n = 11) and qualitative and mixed-methods studies (n = 9 each). The most frequently addressed domains of family-centred care were communication and information provision (n = 45), family involvement in care (n = 37) and access to care (n = 30)., Conclusion: This review, which identified 61 unique interventions aimed at improving family-centred care for children with chronic conditions across a range of settings, is a concrete resource for researchers, health care providers and administrators interested in improving care for this high-needs population., Patient or Public Contribution: This study was co-developed with three patient partner co-investigators, all of whom are individuals with lived experiences of rare chronic diseases as parents and/or patients and have prior experience in patient engagement in research (I. J., N. P., M. S.). These patient partner co-investigators contributed to this study at all stages, from conceptualization to dissemination., (© 2023 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Background: Generating rigorous evidence to inform care for rare diseases requires reliable, sustainable, and longitudinal measurement of priority outcomes. Having developed a core outcome set for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, we aimed to assess the feasibility of prospective measurement of these core outcomes during routine metabolic clinic visits., Methods: We used existing cohort data abstracted from charts of 124 children diagnosed with MCAD deficiency who participated in a Canadian study which collected data from birth to a maximum of 11 years of age to investigate the frequency of clinic visits and quality of metabolic chart data for selected outcomes. We recorded all opportunities to collect outcomes from the medical chart as a function of visit rate to the metabolic clinic, by treatment centre and by child age. We applied a data quality framework to evaluate data based on completeness, conformance, and plausibility for four core MCAD outcomes: emergency department use, fasting time, metabolic decompensation, and death., Results: The frequency of metabolic clinic visits decreased with increasing age, from a rate of 2.8 visits per child per year (95% confidence interval, 2.3-3.3) among infants 2 to 6 months, to 1.0 visit per child per year (95% confidence interval, 0.9-1.2) among those ≥ 5 years of age. Rates of emergency department visits followed anticipated trends by child age. Supplemental findings suggested that some emergency visits occur outside of the metabolic care treatment centre but are not captured. Recommended fasting times were updated relatively infrequently in patients' metabolic charts. Episodes of metabolic decompensation were identifiable but required an operational definition based on acute manifestations most commonly recorded in the metabolic chart. Deaths occurred rarely in these patients and quality of mortality data was not evaluated., Conclusions: Opportunities to record core outcomes at the metabolic clinic occur at least annually for children with MCAD deficiency. Methods to comprehensively capture emergency care received at outside institutions are needed. To reduce substantial heterogeneous recording of core outcome across treatment centres, improved documentation standards are required for recording of recommended fasting times and a consensus definition for metabolic decompensations needs to be developed and implemented., (© 2024. The Author(s).)

Identifying causal factors to intervene on to delay age-related declines in cognitive function is urgently needed. We examined associations between non-exercise testing cardiorespiratory fitness (NETCRF; estimated using sex, age, body mass index, resting heart rate, and physical activity) at 45 years and cognitive function outcomes (immediate and delayed verbal memory; verbal fluency; visual processing speed) at 50 years in 8130 participants from the 1958 British birth cohort. In unadjusted models, higher NETCRF was associated with better cognitive function across all outcomes. When adjusted for confounding factors, associations disappeared. In this cohort, associations between 45 years NETCRF and 50 years cognitive function likely result from confounding factors., (© 2023 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Melanomas reprogram their metabolism to rapidly adapt to therapy-induced stress conditions, allowing them to persist and ultimately develop resistance. We report that a subpopulation of melanoma cells tolerate MAPK pathway inhibitors (MAPKis) through a concerted metabolic reprogramming mediated by peroxisomes and UDP-glucose ceramide glycosyltransferase (UGCG). Compromising peroxisome biogenesis, by repressing PEX3 expression, potentiated the proapoptotic effects of MAPKis via an induction of ceramides, an effect limited by UGCG-mediated ceramide metabolism. Cotargeting PEX3 and UGCG selectively eliminated a subset of metabolically active, drug-tolerant CD36+ melanoma persister cells, thereby sensitizing melanoma to MAPKis and delaying resistance. Increased levels of peroxisomal genes and UGCG were found in patient-derived MAPKi-relapsed melanomas, and simultaneously inhibiting PEX3 and UGCG restored MAPKi sensitivity in multiple models of therapy resistance. Finally, combination therapy consisting of a newly identified inhibitor of the PEX3-PEX19 interaction, a UGCG inhibitor, and MAPKis demonstrated potent antitumor activity in preclinical melanoma models, thus representing a promising approach for melanoma treatment.

Evidence has linked sporting leisure time physical activity (sporting-LTPA) to healthy cognition throughout adulthood. This may be due to the physiological effects of physical activity (PA), or to other, psychosocial facets of sport. We examined associations between sporting-LTPA and cognition while adjusting for device-measured PA volume devoid of context, both in midlife (N = 4041) participants from the 1970 British Cohort Study and later-life (N = 957) participants from the British Regional Heart Study. Independent of device-measured PA, we identified positive associations between sporting-LTPA and cognition. Sports with team/partner elements were strongly positively associated with cognition, suggesting LTPA context may be critical to this relationship., (© 2023 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Background: Movement behaviours (eg, sedentary behaviour (SB), moderate and vigorous physical activity (MVPA), light intensity physical activity (LIPA) and sleep) are linked to cognition, yet the relative importance of each component is unclear, and not yet explored with compositional methodologies., Objective: To (i) assess the associations of different components of daily movement and participant's overall cognition, memory and executive function, and (ii) understand the relative importance of each individual component for cognition., Methods: The 1970 British Cohort Study (BCS70) is a prospective birth cohort study of UK-born adults. At age 46, participants consented to wear an accelerometer device and complete tests of verbal memory and executive function. Compositional linear regression was used to examine cross-sectional associations between 24-hour movement behaviours and standardised cognition scores. Isotemporal substitution was performed to model the effect of reallocating time between components of daily movement on cognition., Results: The sample comprised 4481 participants (52% female). Time in MVPA relative to SB, LIPA and sleep was positively associated with cognition after adjustments for education and occupational physical activity, but additional adjustment for health status attenuated associations. SB relative to all other movements was robustly positively associated with cognition. Modelling time reallocation between components revealed an increase in cognition centile after MVPA theoretically replaced 9 min of SB (OR=1.31; 95% CI 0.09 to 2.50), 7 min of LIPA (1.27; 0.07 to 2.46) or 7 min of sleep (1.20; 0.01 to 2.39)., Conclusions: Relative to time spent in other behaviours, greater MVPA and SB was associated with higher cognitive scores. Loss of MVPA time, given its smaller relative amount, appears most deleterious. Efforts should be made to preserve MVPA time, or reinforce it in place of other behaviours., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The benefits of moderate to vigorous physical activity(MVPA) in lowering depression risk are well established, but there is mixed evidence on sleep, sedentary behaviour(SB), and light-intensity physical activity(LIPA). These behaviours are often considered in isolation, neglecting their behavioural and biological interdependences. We investigated how time spent in one behaviour relative to others was associated with depression risk., Methods: We included 4738 individuals from the 1970 British Cohort study (age 46 wave). Depression status was ascertained using self-reported doctor visits and prescribed anti-depressant use. MVPA, LIPA, SB and sleep were ascertained using thigh-worn accelerometers worn consecutively for 7 days. Compositional logistic regression was used to examine associations between different compositions of time spent in movement behaviours and depression., Results: More time spent in MVPA, relative to SB, sleep or LIPA, was associated with a lower risk of depression. When modelling reallocation of time (e.g. replacing time in one behaviour with another), replacing sleep, SB or LIPA with MVPA time was strongly associated with lower depression risk. Reallocating time between SB, sleep or LIPA had minimal to no effect., Limitations: Data was cross-sectional, therefore causality cannot be inferred. Accelerometers do not capture SB context (e.g. TV watching, reading) nor separate biological sleep from time spent in bed., Conclusions: Displacing any behaviour with MVPA was associated with a lower risk of depression. This study provides promising support that increasing MVPA, even in small doses, can have a positive impact on prevention, mitigation and treatment of depression., Competing Interests: Conflict of Interest The authors declare that they have no competing interests., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Government enforced restrictions on movement during the COVID-19 pandemic are likely to have had profound impacts on the daily behaviours of many individuals, including physical activity (PA). Given the associations between PA and other health behaviours, changes in PA during the pandemic may have been detrimental for other health behaviours. This study aimed to evaluate whether changes in PA during and after the first national lockdown in the United Kingdom (UK) were associated with concurrent changes in alcohol consumption, sleep, nutrition quality, diet quantity and sedentary time. Data were derived from the UCL COVID-19 Social Study, in which 52,784 adults were followed weekly across 22 weeks of the pandemic from 23rd March to 23rd August 2020. Fixed effects regression models showed that greater PA was positively associated with improved sleep and nutrition quality. However, increases in PA also showed modest associations with increased alcohol consumption and sedentary time. Encouraging people to engage in PA may lead to wider changes in other health behaviours in times of adversity. These associations could be a result of increases in available leisure time for many people during COVID-19 restrictions and are of ongoing importance given the emerging long-term changes to lifestyle and working patterns., (© 2022. The Author(s).)

Background: The Morquio A Registry Study (MARS) is an ongoing, multinational, observational study of patients with MPS IVA. Key objectives of MARS are to characterize the heterogeneity and natural history of disease and to evaluate long-term effectiveness and safety of elosulfase alfa enzyme replacement therapy (ERT). Enrollment began in September 2014; data on medical history, clinical outcomes, and safety assessments are collected as part of routine care., Results: As of February 2021, 381 subjects from 17 countries had enrolled in MARS: 58 ERT-naïve subjects and 323 ERT-treated subjects (≥1 infusion), with a mean ERT exposure of 5.5 years (SD 2.8) and median age at first ERT treatment of 9.8 years. ERT-treated subjects were younger at diagnosis (median 3.4 vs 6.5 years) relative to ERT-naïve subjects. Among ERT-treated subjects, urinary keratan sulfate (uKS) levels declined from pre-ERT baseline to last follow-up on treatment (mean % change [95% confidence interval]: -52.5% [-57.5%, -47.4%]; n = 115) and 6-min walk test distance remained stable (mean change: -6.1 [-27.6, 15.5] m; n = 131) over a mean follow-up of 5.5 years. Forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC) increased in subjects who were < 18 years of age at ERT initiation (mean change: +0.3 [0.1, 0.4] L and + 0.4 [0.3, 0.5] L; mean follow-up: ∼6 years; n = 82) and were stable in subjects ≥18 years (mean change: 0.0 [-0.0, 0.1] L and 0.0 [-0.1, 0.1] L; mean follow-up: 4.6 years; n = 38). Overall, 148 (47.1%) ERT-treated subjects experienced ≥1 adverse event (AE) and 110 subjects (35%) reported ≥1 serious AE. Drug-related AEs were reported in 39 (12.4%) subjects; the most common were hypersensitivity (9 subjects [2.9%]), urticaria (8 subjects [2.5%]), and pyrexia (7 subjects [2.2%])., Conclusions: MARS is the longest and largest observational study of MPS IVA patients to date, with a heterogenous population that is representative of the MPS IVA population overall. Data collected over the first 6 years of MARS provide real-world evidence for long-term stabilization of endurance and respiratory function among ERT-treated patients, with no new safety concerns identified., Competing Interests: Declaration of Competing Interest JM reports advisory boards for BioMarin, Genzyme, Takeda, and Ultragenyx, consulting fees from BioMarin, Genzyme, Takeda, and Ultragenyx, contracted research for BioMarin, Genzyme, RegenxBio, and Takeda, honoraria from BioMarin and Genzyme and speaker's bureau for BioMarin. BKB reports consulting fees from Aeglea, BioMarin, Denali, Horizon, JCR Pharma, Moderna, Shire (Takeda), SIO, and Ultragenyx, contracted research for BioMarin, Denali, Homology Medicines, Sangamo, Shire (Takeda), and Ultragenyx, and speaker's bureau for BioMarin, Horizon, and Shire (Takeda). MBB reports advisory boards, consulting fees, and contracted research for BioMarin, and contracted research for RegenxBio. PMC reports consulting fees from BioMarin and Genzyme, and contracted research for BioMarin, Genzyme, and Takeda. CE reports advisory boards for Amicus, BioMarin, Chiesi, and Sanofi Genzyme, consulting fees from BioMarin and Sanofi Genzyme, honoraria from BioMarin, Sanofi Genzyme, and Takeda Shire, speaker's bureau for Amicus, BioMarin, Sanofi Genzyme, and Takeda Shire, and travel expenses from Amicus, BioMarin, Sanofi Genzyme, and Takeda Shire. KB has no conflicts of interest. NG reports advisory boards for BioMarin, Chiesi, Sanofi Genzyme, Takeda Shire HGT, and Ultragenyx, consulting fees from Sanofi Genzyme, and Ultragenyx, contracted research for BioMarin, Chiesi, Sanofi Genzyme, Shire HGT, and Ultragenyx, and travel expenses from Sanofi Genzyme, and Ultragenyx. SL reports advisory boards for BioMarin. MM reports advisory board for BioMarin and speaker's honoraria from BioMarin, Chiesi, and Takeda. JR reports advisory boards for BioMarin, Sanofi, and Takeda. Honoraria from BioMarin, Sanofi, and Takeda, and travel expenses from BioMarin, Sanofi, and Takeda. KMS reports advisory boards for BioMarin, Chiesi, Orchard Therapeutics, Sanofi, and Takeda, and honoraria from BioMarin, Orchard Therapeutics, Sanofi, and Takeda, SC, SD, DH, and AL are employees of BioMarin. LS-S was an employee of BioMarin at the time of submission of the manuscript., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The COVID-19 pandemic has seen repeated government enforced restrictions on movement. This study aimed to evaluate longitudinal trends in physical activity (PA) in a self-selected UK-based sample and identify the key correlates of these trends., Methods: From 23 April 2020 to 30 January 2021, measures of PA engagement were collected in a sample of 1,947 UK-based adults. Generalised estimating equations (GEE) explored trends in PA engagement over time, and how sociodemographic, health and contextual factors impacted participant's attainment of World Health Organization (WHO) recommended levels of PA (constituting muscle strengthening activity (MSA), and moderate or vigorous PA (MVPA))., Results: While one in five achieved the recommended levels of PA in the first UK lockdown in April-June 2020 (19.5%, 95%CI: 17.8-21.3%) and a similar proportion in June-July 2020 (17.7%, 95%CI: 16.1-19.5%), this reduced during the period of eased restrictions in August-September 2020 (15.2%, 95%CI: 13.7-16.9%) and the second UK lockdown in November 2020-January 2021 (14.1%, 95%CI: 12.6-15.9%). Similar trends were observed for MSA and MVPA individually. Better quality of life, higher socioeconomic position and pre-COVID-19 PA levels were associated with meeting the WHO recommended levels of PA, while those living with overweight or obesity, a limiting health condition, or isolating showed the inverse associations. Time-specific associations with MSA or MVPA were observed for gender and age., Conclusion: Reductions in PA levels throughout the first strict lockdown continued without reversal during the ensuing period. The association of negative change with socioeconomic and health-related indices points towards deepening health inequities during the pandemic., Competing Interests: The authors have declared that no competing interests exist.

Purpose: This paper aims to report collective information on safety and efficacy of empagliflozin drug repurposing in individuals with glycogen storage disease type Ib (GSD Ib)., Methods: This is an international retrospective questionnaire study on the safety and efficacy of empagliflozin use for management of neutropenia/neutrophil dysfunction in patients with GSD Ib, conducted among the respective health care providers from 24 countries across the globe., Results: Clinical data from 112 individuals with GSD Ib were evaluated, representing a total of 94 treatment years. The median age at start of empagliflozin treatment was 10.5 years (range = 0-38 years). Empagliflozin showed positive effects on all neutrophil dysfunction-related symptoms, including oral and urogenital mucosal lesions, recurrent infections, skin abscesses, inflammatory bowel disease, and anemia. Before initiating empagliflozin, most patients with GSD Ib were on G-CSF (94/112; 84%). At the time of the survey, 49 of 89 (55%) patients previously treated with G-CSF had completely stopped G-CSF, and another 15 (17%) were able to reduce the dose. The most common adverse event during empagliflozin treatment was hypoglycemia, occurring in 18% of individuals., Conclusion: Empagliflozin has a favorable effect on neutropenia/neutrophil dysfunction-related symptoms and safety profile in individuals with GSD Ib., Competing Interests: Conflict of Interest All authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

BACKGROUND: Mucopolysaccharidosis type VI (MPS VI) is an inherited multisystem lysosomal disorder due to arylsulfatase B (ARSB) deficiency that leads to widespread accumulation of glycosaminoglycans (GAG), which are excreted in increased amounts in urine. MPS VI is characterized by progressive dysostosis multiplex, connective tissue and cardiac involvement, and hepatosplenomegaly. Enzyme replacement therapy (ERT) is available but requires life-long and costly intravenous infusions; moreover, it has limited efficacy on diseased skeleton and cardiac valves, compromised pulmonary function, and corneal opacities. METHODS: We enrolled nine patients with MPS VI 4 years of age or older in a phase 1/2 open-label gene therapy study. After ERT was interrupted, patients each received a single intravenous infusion of an adeno-associated viral vector serotype 8 expressing ARSB. Participants were sequentially enrolled in one of three dose cohorts: low (three patients), intermediate (two patients), or high (four patients). The primary outcome was safety; biochemical and clinical end points were secondary outcomes. RESULTS: The infusions occurred without severe adverse events attributable to the vector, meeting the prespecified end point. Participants in the low and intermediate dose cohorts displayed stable serum ARSB of approximately 20% of the mean healthy value but returned to ERT by 14 months after gene therapy because of increased urinary GAG. Participants in the high-dose cohort had sustained serum ARSB of 30% to 100% of the mean healthy value and a modest urinary GAG increase that did not reach a concentration at which ERT reintroduction was needed. In the high-dose group, there was no clinical deterioration for up to 2 years after gene therapy. CONCLUSIONS: Liver-directed gene therapy for participants with MPS VI did not have a dose-limiting side-effect and adverse event profile; high-dose treatment resulted in ARSB expression over at least 24 months with preliminary evidence of disease stabilization. (Funded by the Telethon Foundation ETS, the European Commission Seventh Framework Programme, and the Isaac Foundation; ClinicalTrials.gov number, NCT03173521; EudraCT number, 2016-002328-10.)

Background and Objective: Children with inherited metabolic diseases often require complex and highly specialized care. Patient and family-centered care can improve health outcomes that are important to families. This study aimed to examine experiences of family caregivers (parents/guardians) of children diagnosed with inherited metabolic diseases with healthcare to inform strategies to improve those experiences., Methods: A cross-sectional mailed survey was conducted of family caregivers recruited from an ongoing cohort study. Participants rated their healthcare experiences during their child's visits to five types of healthcare settings common for inherited metabolic diseases: the metabolic clinic, the emergency department, hospital inpatient units, the blood laboratory, and the pharmacy. Participants provided narrative descriptions of any memorable negative or positive experiences., Results: There were 248 respondents (response rate 49%). Caregivers were generally very or somewhat satisfied with the care provided at each care setting. Appropriate treatment, provider knowledge, provider communication, and care coordination were deemed essential aspects of satisfaction with care by the majority of participants across many settings. Memorable negative experiences were reported by 8-22% of participants, varying by setting. Among participants who reported memorable negative experiences, contributing factors included providers' demeanor, lack of communication, lack of involvement of the family, and disregard of an emergency protocol letter provided by the family., Conclusions: While caregivers' satisfaction with care for children with inherited metabolic diseases was high, we identified gaps in family-centered care and factors contributing to negative experiences that are important to consider in the future development of strategies to improve pediatric care for inherited metabolic diseases., (© 2021. The Author(s).)

Introduction: Children with inherited metabolic diseases (IMDs) often have complex and intensive healthcare needs and their families face challenges in receiving high-quality, family centred health services. Improvement in care requires complex interventions involving multiple components and stakeholders, customised to specific care contexts. This study aims to comprehensively understand the healthcare experiences of children with IMDs and their families across Canada., Methods and Analysis: A two-stage explanatory sequential mixed methods design will be used. Stage 1: quantitative data on healthcare networks and encounter experiences will be collected from 100 parent/guardians through a care map, 2 baseline questionnaires and 17 weekly diaries over 5-7 months. Care networks will be analysed using social network analysis. Relationships between demographic or clinical variables and ratings of healthcare experiences across a range of family centred care dimensions will be analysed using generalised linear regression. Other quantitative data related to family experiences and healthcare experiences will be summarised descriptively. Ongoing analysis of quantitative data and purposive, maximum variation sampling will inform sample selection for stage 2: a subset of stage 1 participants will participate in one-on-one videoconference interviews to elaborate on the quantitative data regarding care networks and healthcare experiences. Interview data will be analysed thematically. Qualitative and quantitative data will be merged during analysis to arrive at an enhanced understanding of care experiences. Quantitative and qualitative data will be combined and presented narratively using a weaving approach (jointly on a theme-by-theme basis) and visually in a side-by-side joint display., Ethics and Dissemination: The study protocol and procedures were approved by the Children's Hospital of Eastern Ontario's Research Ethics Board, the University of Ottawa Research Ethics Board and the research ethics boards of each participating study centre. Findings will be published in peer-reviewed journals and presented at scientific conferences., Competing Interests: Competing interests: SD has been or is a member of advisory boards for, received indirect educational grants from, and/or received indirect speakers’ fees from Sanofi-Genzyme, Takeda, and Horizon Therapeutics. IDG is a recipient of a CIHR Foundation Grant (FDN# 143237). MP has been an advisory board member with honoraria from Ultragenyx (Mar/Apr 2021) and Horizon Therapeutics (Oct 2020), and received a speakers’ honorarium (Sep 2020) and small investigator grant ($6,000, 2019) from Horizon Therapeutics. SS received educational grants from Biomarin, Shire, Recordati and serves/served as PI in clinical trials and postmarketing registries sponsored by Actelion, Biomarin, Shire, Ultragenyx. KW is the CEO of CANImmunize Inc., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

COVID-19 pandemic restrictions impacted dietary habits during the initial months of the pandemic, but long-term effects are unclear. In this longitudinal study, self-selected UK adults ( n = 1,733, 71.1% female, 95.7% white ethnicity) completed three online surveys (May-June, August-September, and November-December 2020, with a retrospective pre-pandemic component in the baseline survey), self-reporting sociodemographics, lifestyle, and behaviours, including high fat, salt, and sugar (HFSS) snacks, HFSS meals, and fruit and vegetable (FV) intake. Data were analysed using generalised estimating equations. Monthly HFSS snacks portion intake increased from pre-pandemic levels (48.3) in May-June (57.6, p < 0.001), decreased in August-September (43.7, p < 0.001), before increasing back to pre-pandemic levels in November-December (49.2, p < 0.001). A total of 48.5% self-reported increased [25.9 (95% confidence interval: 24.1, 27.8)] and 47.7% self-reported decreased [24.1 (22.4, 26.0)] monthly HFSS snacks portion intakes in November-December compared with pre-pandemic levels. Monthly HFSS meals portion intake decreased from pre-pandemic levels (7.1) in May-June (5.9, p < 0.001), was maintained in August-September (5.9, p = 0.897), and then increased again in November-December (6.6, p < 0.001) to intakes that remained lower than pre-pandemic levels ( p = 0.007). A total of 35.2% self-reported increased [4.8 (4.3, 5.3)] and 44.5% self-reported decreased [5.1 (4.6, 5.6)] monthly HFSS meals portion intakes in November-December compared with pre-pandemic levels. The proportion meeting FV intake recommendations was stable from pre-pandemic through to August-September (70%), but decreased in November-December 2020 (67%, p = 0.034). Increased monthly HFSS snacks intake was associated with female gender, lower quality of life, and - in a time - varying manner - older age and higher HFSS meals intake. Increased monthly HFSS meals intake was associated with female gender, living with adults only, and higher HFSS snacks intake. Reduced FV intake was associated with higher body mass index (BMI) and lower physical activity. These results suggest large interindividual variability in dietary change during the first year of the pandemic, with important public health implications in individuals experiencing persistent increases in unhealthy diet choices, associated with BMI, gender, quality of life, living conditions, physical activity, and other dietary behaviours., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer LS declared a shared affiliation with the authors to the handling Editor at time of review., (Copyright © 2022 Dicken, Mitchell, Newberry Le Vay, Beard, Kale, Herbec and Shahab.)

Background: Mucopolysaccharidoses (MPS) are a group of inherited metabolic diseases characterized by chronic, progressive multi-system manifestations with varying degrees of severity. Disease-modifying therapies exist to treat some types of MPS; however, they are not curative, underscoring the need to identify and evaluate co-interventions that optimize functioning, participation in preferred activities, and quality of life. A Canadian pediatric MPS registry is under development and may serve as a platform to launch randomized controlled trials to evaluate such interventions. To promote the standardized collection of patient/family-reported and clinical outcomes considered important to patients/families, health care providers (HCPs), and policymakers, the choice of outcomes to include in the registry will be informed by a core outcome set (COS). We aim to establish a patient-oriented COS for pediatric MPS using a multi-stakeholder approach., Methods: In step 1 of the six-step process to develop the COS, we will identify relevant outcomes through a rapid literature review and candidate outcomes survey. A two-phase screening approach will be implemented to identify eligible publications, followed by extraction of outcomes and other pre-specified data elements. Simultaneously, we will conduct a candidate outcomes survey with children with MPS and their families to identify outcomes most important to them. In step 2, HCPs experienced in treating patients with MPS will be invited to review the list of outcomes generated in step 1 and identify additional clinically relevant outcomes. We will then ask patients/families, HCPs, and policymakers to rate the outcomes in a set of Delphi Surveys (step 3), and to participate in a subsequent consensus meeting to finalize the COS (step 4). Step 5 involves establishing a set of outcome measurement instruments for the COS. Finally, we will disseminate the COS to knowledge users (step 6)., Discussion: The proposed COS will inform the choice of outcomes to include in the MPS registry and, more broadly, promote the standardized collection of patient-oriented outcomes for pediatric MPS research. By involving patients/families from the earliest stage of the research, we will ensure that the COS will be relevant to those who will ultimately benefit from the research., Trial Registration: PROSPERO CRD42021267531 , COMET., (© 2021. The Author(s).)

Articular cartilage injuries of the knee are being observed with increasing frequency in athletes and have proven to be difficult to treat given the limited regenerative ability of cartilage and the potential for progressive joint degeneration. A wide range of surgical treatments such as microfracture, autologous chondrocyte implantation, and osteochondral autograft and allograft have demonstrated promising results in these high-demand individuals. These procedures permit healing of cartilage defects while decreasing pain and restoring function with patient-reported outcomes demonstrating significant improvement at short-, mid-, and long-term follow-up. Most athletes are able to return to play after cartilage restoration of the knee, regardless of the surgical technique used. Although there is a large degree of heterogeneity across the literature and no consensus as to the optimal technique, osteochondral autograft transfer seems to offer the highest rate of return to sport and return to play at preinjury level. However, autologous chondrocyte implantation and osteochondral allograft transplantation are often used for larger defects or salvage after previous procedures, so results may be confounded. In addition, a multitude of factors including patient history, characteristics of the chondral lesion, and postoperative management may affect functional outcomes in athletes., (Copyright © 2021 by the American Academy of Orthopaedic Surgeons.)

Recent studies have shown reduced physical activity at early stages of the COVID-19 pandemic. However, there is a lack of investigation on longitudinal changes in physical activity beyond lockdowns and stay-at-home orders. Moreover, it is unclear if there is heterogeneity in physical activity growth trajectories. This study aimed to explore longitudinal patterns of physical activity and factors associated with them. Data were from the UCL COVID-19 Social Study. The analytical sample consisted of 35,915 adults in England who were followed up for 22 weeks from 24th March to 23rd August 2020. Data were analysed using growth mixture models. Our analyses identified six classes of growth trajectories, including three stable classes showing little change over time (62.4% in total), two classes showing decreasing physical activity (28.6%), and one class showing increasing physical activity over time (9%). A range of factors were found to be associated the class membership of physical activity trajectories, such as age, gender, education, income, employment status, and health. There is substantial heterogeneity in longitudinal changes in physical activity during the COVID-19 pandemic. However, a substantial proportion of our sample showed persistent physical inactivity or decreasing physical activity. Given the well-established link between physical activity and health, persistent or increased physical inactivity is likely to have both immediate and long-term implications for people's physical and mental health, as well as general wellbeing. More efforts are needed to promote physical activity during the pandemic and beyond., (© 2021. The Author(s).)

COVID-19-related restrictions impacted weight and weight-related factors during the initial months of the pandemic. However, longitudinal analyses are scarce. An online, longitudinal study was conducted among self-selected UK adults (n = 1818), involving three surveys (May-June, August-September, November-December 2020), covering anthropometric, sociodemographic, COVID-19-related and behavioural measures. Data were analysed using generalised estimating equations. Self-reported average weight/body mass index (BMI) significantly increased between the May-June period and the August-September period (74.95 to 75.33 kg/26.22 kg/m 2 to 26.36kg/m 2 , p < 0.001, respectively), and then significantly decreased to November-December (to 75.06 kg/26.27 kg/m 2 , p < 0.01), comparable to May-June levels ( p = 0.274/0.204). However, there was great interindividual variation, 37.0%/26.7% increased (average 3.64 kg (95% confidence interval: 3.32, 3.97)/1.64 kg/m 2 (1.49, 1.79)), and 34.5%/26.3% decreased (average 3.59 kg (3.34, 3.85)/1.53 kg/m 2 (1.42, 1.63)) weight/BMI between May-June and November-December. Weight/BMI increase was significantly negatively associated with initial BMI, and positively associated with monthly high fat, salt and sugar (HFSS) snacks intake and alcohol consumption, and for BMI only, older age. Associations were time-varying; lower initial BMI, higher HFSS snacks intake and high-risk alcohol consumption were associated with maintaining weight/BMI increases between August-September and November-December. The average weight/BMI of UK adults fluctuated between May-June and November-December 2020. However, the substantial interindividual variation in weight/BMI trajectories indicates long-term health impacts from the pandemic, associated with food and alcohol consumption.

Graphene-based point-of-care (PoC) and chemical sensors can be fabricated using photolithographic processes at wafer-scale. However, these approaches are known to leave polymer residues on the graphene surface, which are difficult to remove completely. In addition, graphene growth and transfer processes can introduce defects into the graphene layer. Both defects and resist contamination can affect the homogeneity of graphene-based PoC sensors, leading to inconsistent device performance and unreliable sensing. Sensor reliability is also affected by the harsh chemical environments used for chemical functionalisation of graphene PoC sensors, which can degrade parts of the sensor device. Therefore, a reliable, wafer-scale method of passivation, which isolates the graphene from the rest of the device, protecting the less robust device features from any aggressive chemicals, must be devised. This work covers the application of molecular vapour deposition technology to create a dielectric passivation film that protects graphene-based biosensing devices from harsh chemicals. We utilise a previously reported "healing effect" of Al 2 O 3 on graphene to reduce photoresist residue from the graphene surface and reduce the prevalence of graphene defects to improve graphene device homogeneity. The improvement in device consistency allows for more reliable, homogeneous graphene devices, that can be fabricated at wafer-scale for sensing and biosensing applications.

Background: Evidence to guide treatment of pediatric medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency and phenylketonuria (PKU) is fragmented because of large variability in outcome selection and measurement. Our goal was to develop core outcome sets (COSs) for these diseases to facilitate meaningful future evidence generation and enhance the capacity to compare and synthesize findings across studies., Methods: Parents and/or caregivers, health professionals, and health policy advisors completed a Delphi survey and participated in a consensus workshop to select core outcomes from candidate lists of outcomes for MCAD deficiency and PKU. Delphi participants rated the importance of outcomes on a nine-point scale (1-3: not important, 4-6: important but not critical, 7-9: critical). Candidate outcomes were progressively narrowed down over 3 survey rounds. At the workshop, participants evaluated the remaining candidate outcomes using an adapted nominal technique, open discussion, and voting. After the workshop, we finalized the COSs and recommended measurement instruments for each outcome., Results: There were 85, 61, and 53 participants across 3 Delphi rounds, respectively. The candidate core outcome lists were narrowed down to 20 outcomes per disease to be discussed at the consensus workshop. Voting by 18 workshop participants led to COSs composed of 8 and 9 outcomes for MCAD deficiency and PKU, respectively, with measurement recommendations., Conclusions: These are the first known pediatric COSs for MCAD deficiency and PKU. Adoption in future studies will help to ensure best use of limited research resources to ultimately improve care for children with these rare diseases., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Dyack has been on expert panels and committees funded by Genzyme and Horizon Therapeutics and contributed to a survey for MD Analytics. Dr Mitchell has received funding from Biomarin for clinical support, speaker fees, and conference support; the other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Biodiversity is a complex, yet essential, concept for undergraduate students in ecology and other natural sciences to grasp. As beginner scientists, students must learn to recognize, describe, and interpret patterns of biodiversity across various spatial scales and understand their relationships with ecological processes and human influences. It is also increasingly important for undergraduate programs in ecology and related disciplines to provide students with experiences working with large ecological datasets to develop students' data science skills and their ability to consider how ecological processes that operate at broader spatial scales (macroscale) affect local ecosystems. To support the goals of improving student understanding of macroscale ecology and biodiversity at multiple spatial scales, we formed an interdisciplinary team that included grant personnel, scientists, and faculty from ecology and spatial sciences to design a flexible learning activity to teach macroscale biodiversity concepts using large datasets from the National Ecological Observatory Network (NEON). We piloted this learning activity in six courses enrolling a total of 109 students, ranging from midlevel ecology and GIS/remote sensing courses, to upper-level conservation biology. Using our classroom experiences and a pre/postassessment framework, we evaluated whether our learning activity resulted in increased student understanding of macroscale ecology and biodiversity concepts and increased familiarity with analysis techniques, software programs, and large spatio-ecological datasets. Overall, results suggest that our learning activity improved student understanding of biological diversity, biodiversity metrics, and patterns of biodiversity across several spatial scales. Participating faculty reflected on what went well and what would benefit from changes, and we offer suggestions for implementation of the learning activity based on this feedback. This learning activity introduced students to macroscale ecology and built student skills in working with big data (i.e., large datasets) and performing basic quantitative analyses, skills that are essential for the next generation of ecologists., Competing Interests: The authors declare no conflicts of interest., (© 2021 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Background: Morquio A syndrome is a rare, autosomal recessive, progressively debilitating disorder, with multi-system impairments and high medical burden. Quebec, Canada has a large Morquio A population, which is considered unique due to the presence of founder pathogenic variants. The objectives of this study were to document the genetic and clinical heterogeneity of patients with Morquio A in Quebec, to better characterize the phenotype of those with the French Canadian founder pathogenic variant (NM&#95;000512.5: c.1171A>G, p.Met391Val), and to describe the natural history of the patients treated with elosulfase alfa enzyme replacement therapy. Patients with Morquio A were genotyped for pathogenic variants in the lysosomal enzyme N-acetylgalactosamine-6-sulfatase. Clinical data were retrospectively collected from medical charts of patients and included medical history, height, physical examination, respiratory function tests, electrocardiogram, echocardiogram, endurance in the 6-min walk test (6MWT), and activities of daily living (ADL) as assessed by the Mucopolysaccharidosis Health Assessment Questionnaire (MPS-HAQ). Longitudinal data were collected retrospectively and prospectively for patients treated with elosulfase alfa., Results: A total of 33 patients, aged 5-63 years, were included in the analysis. Patients with the founder pathogenic variant (n = 17) generally exhibited a non-classical form of Morquio A. As compared with patients with a non-founder pathogenic variant (n = 16), these patients were generally taller, had greater endurance and were better able to perform ADL. However, they still had significant musculoskeletal disease. Most of the 26 patients treated with elosulfase alfa, regardless of pathogenic variant, showed improvements in endurance and ADL. After 5 to 12 months of treatment, the mean improvement from baseline in the 6MWT was 23% and 10 of 14 patients improved in at least one MPS-HAQ domain. Endurance and ADL generally continued to improve or maintained stable in the long term (up to 7 years). Four out of 19 treated patients with echocardiogram data at follow-up showed progression of cardiac disease., Conclusions: In Quebec, Canada, Morquio A frequently manifests as a non-classical form of the syndrome due to a founder effect. Patients treated with elosulfase alfa generally show long-term improvement or stability in endurance and function, regardless of pathogenic variant.

Affinity biosensors based on graphene field-effect transistor (GFET) or resistor designs require the utilization of graphene's exceptional electrical properties. Therefore, it is critical when designing these sensors, that the electrical properties of graphene are maintained throughout the functionalization process. To that end, non-covalent functionalization may be preferred over covalent modification. Drop-cast 1,5-diaminonaphthalene (DAN) was investigated as a quick and simple method for the non-covalent amine functionalization of carbon-based surfaces such as graphene, for use in biosensor development. In this work, multiple graphene surfaces were functionalized with DAN via a drop-cast method, leading to amine moieties, available for subsequent attachment to receptor molecules. Successful modification of graphene with DAN via a drop-cast method was confirmed using X-ray photoelectron spectroscopy (XPS), Raman spectroscopy and real-time resistance measurements. Successful attachment of receptor molecules also confirmed using the aforementioned techniques. Furthermore, an investigation into the effect of sequential wash steps which are required in biosensor manufacture, on the presence of the DAN layer, confirmed that the functional layer was not removed, even after multiple solvent exposures. Drop-cast DAN is thus, a viable fast and robust method for the amine functionalization of graphene surfaces for use in biosensor development.

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

Background: Inherited metabolic diseases (IMDs) are a group of individually rare single-gene diseases. For many IMDs, there is a paucity of high-quality evidence that evaluates the effectiveness of clinical interventions. Clinical effectiveness trials of IMD interventions could be supported through the development of core outcome sets (COSs), a recommended minimum set of standardized, high-quality outcomes and associated outcome measurement instruments to be incorporated by all trials in an area of study. We began the process of establishing pediatric COSs for two IMDs, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency and phenylketonuria (PKU), by reviewing published literature to describe outcomes reported by authors, identify heterogeneity in outcomes across studies, and assemble a candidate list of outcomes., Methods: We used a comprehensive search strategy to identify primary studies and guidelines relevant to children with MCAD deficiency and PKU, extracting study characteristics and outcome information from eligible studies including outcome measurement instruments for select outcomes. Informed by an established framework and a previously published pediatric COS, outcomes were grouped into five, mutually-exclusive, a priori core areas: growth and development, life impact, pathophysiological manifestations, resource use, and death., Results: For MCAD deficiency, we identified 83 outcomes from 52 articles. The most frequently represented core area was pathophysiological manifestations, with 33 outcomes reported in 29/52 articles (56%). Death was the most frequently reported outcome. One-third of outcomes were reported by a single study. The most diversely measured outcome was cognition and intelligence/IQ for which eight unique measurement instruments were reported among 14 articles. For PKU, we identified 97 outcomes from 343 articles. The most frequently represented core area was pathophysiological manifestations with 31 outcomes reported in 281/343 articles (82%). Phenylalanine concentration was the most frequently reported outcome. Sixteen percent of outcomes were reported by a single study. Similar to MCAD deficiency, the most diversely measured PKU outcome was cognition and intelligence/IQ with 39 different instruments reported among 82 articles., Conclusions: Heterogeneity of reported outcomes and outcome measurement instruments across published studies for both MCAD deficiency and PKU highlights the need for COSs for these diseases, to promote the use of meaningful outcomes and facilitate comparisons across studies.

Background: Anterior tibial spine fractures (ATSF) in the skeletally immature parallel anterior cruciate ligament (ACL) tears in adult patients, yet these injuries are generally regarded as mutually exclusive. Biomechanical analysis suggests that intrinsic ACL damage occurs during ATSF, and long-term clinical studies demonstrate residual anteroposterior knee laxity following ATSF. We aim to describe prevalence, demographics, and characteristics of pediatric patients who sustained ATSF with concomitant ACL injury., Methods: We included 129 patients with ATSF over a 16-year period. Age, sex, injury mechanism, ATSF type, magnetic resonance imaging (MRI) evaluation, treatment modality, ACL injury, and concomitant meniscal/chondral injuries were analyzed. Concurrent ACL injury was confirmed either from MRI or intraoperatively., Results: Nineteen percent (n=25) of ATSF patients had concomitant ACL injury, with ACL injury significantly more likely in type II or type III ATSF compared with type I ATSF (P=0.03). Patients with combined ATSF/ACL injury were significantly older (P=0.02) and more likely to be male (P=0.01). Mechanism of ATSF injury was not associated with ACL injury (P=0.83). Preoperative MRI had low sensitivity (0.09) for recognizing ACL injury at the time of ATSF relative to intraoperative assessment. Half of ATSF/ACL-injured patients had additional meniscal or chondral injury, with meniscal repair or debridement required in 37.5% of the type II ATSF/ACL injury., Conclusions: There are demographic characteristics, such as age (older) and sex (male), associated with a higher risk of concomitant ACL injury at the time of ATSF. Type II and type III ATSF patterns had a higher prevalence of ACL injury. MRI failed to correctly identify ACL injury at the time of ATSF. Concomitant ACL injury at the time of ATSF is highly prevalent in the skeletally immature, occurring in 19.4% of patients with ATSF., Level of Evidence: Level IV-case series.

Introduction: Mucopolysaccharidosis (MPS) IVA or Morquio A syndrome is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the N-acetylgalactosamine-6-sulfatase (GALNS) enzyme, which impairs lysosomal degradation of keratan sulphate and chondroitin-6-sulphate. The multiple clinical manifestations of MPS IVA present numerous challenges for management and necessitate the need for individualised treatment. Although treatment guidelines are available, the methodology used to develop this guidance has come under increased scrutiny. This programme was conducted to provide evidence-based, expert-agreed recommendations to optimise management of MPS IVA., Methods: Twenty six international healthcare professionals across multiple disciplines, with expertise in managing MPS IVA, and three patient advocates formed the Steering Committee (SC) and contributed to the development of this guidance. Representatives from six Patient Advocacy Groups (PAGs) were interviewed to gain insights on patient perspectives. A modified-Delphi methodology was used to demonstrate consensus among a wider group of healthcare professionals with experience managing patients with MPS IVA and the manuscript was evaluated against the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument by three independent reviewers., Results: A total of 87 guidance statements were developed covering five domains: (1) general management principles; (2) recommended routine monitoring and assessments; (3) disease-modifying interventions (enzyme replacement therapy [ERT] and haematopoietic stem cell transplantation [HSCT]); (4) interventions to support respiratory and sleep disorders; (5) anaesthetics and surgical interventions (including spinal, limb, ophthalmic, cardio-thoracic and ear-nose-throat [ENT] surgeries). Consensus was reached on all statements after two rounds of voting. The overall guideline AGREE II assessment score obtained for the development of the guidance was 5.3/7 (where 1 represents the lowest quality and 7 represents the highest quality of guidance)., Conclusion: This manuscript provides evidence- and consensus-based recommendations for the management of patients with MPS IVA and is for use by healthcare professionals that manage the holistic care of patients with the intention to improve clinical- and patient-reported outcomes and enhance patient quality of life. It is recognised that the guidance provided represents a point in time and further research is required to address current knowledge and evidence gaps.

Introduction: Mucopolysaccharidosis (MPS) VI or Maroteaux-Lamy syndrome (253200) is an autosomal recessive lysosomal storage disorder caused by deficiency in N-acetylgalactosamine-4-sulfatase (arylsulfatase B). The heterogeneity and progressive nature of MPS VI necessitates a multidisciplinary team approach and there is a need for robust guidance to achieve optimal management. This programme was convened to develop evidence-based, expert-agreed recommendations for the general principles of management, routine monitoring requirements and the use of medical and surgical interventions in patients with MPS VI., Methods: 26 international healthcare professionals from various disciplines, all with expertise in managing MPS VI, and three patient advocates formed the Steering Committee group (SC) and contributed to the development of this guidance. Members from six Patient Advocacy Groups (PAGs) acted as advisors and attended interviews to ensure representation of the patient perspective. A modified-Delphi methodology was used to demonstrate consensus among a wider group of healthcare professionals with expertise and experience managing patients with MPS VI and the manuscript has been evaluated against the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument by three independent reviewers., Results: A total of 93 guidance statements were developed covering five domains: (1) general management principles; (2) recommended routine monitoring and assessments; (3) enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT); (4) interventions to support respiratory and sleep disorders; (5) anaesthetics and surgical interventions. Consensus was reached on all statements after two rounds of voting. The greatest challenges faced by patients as relayed by consultation with PAGs were deficits in endurance, dexterity, hearing, vision and respiratory function. The overall guideline AGREE II assessment score obtained for the development of the guidance was 5.3/7 (where 1 represents the lowest quality and 7 represents the highest quality of guidance)., Conclusion: This manuscript provides evidence- and consensus-based recommendations for the management of patients with MPS VI and is for use by healthcare professionals that manage the holistic care of patients with the intention to improve clinical- and patient-reported outcomes and enhance patient quality of life. It is recognised that the guidance provided represents a point in time and further research is required to address current knowledge and evidence gaps.

Background: Loss of meniscal tissue in the pediatric population can have long-term consequences on joint health, highlighting the importance of meniscal preservation in this group., Purpose: To systematically review reported knee outcome measures and complication rates after repair of meniscal tears in children and adolescents., Study Design: Systematic review; Level of evidence, 4., Methods: A review of the literature regarding the existing evidence for pediatric meniscal tear outcomes was performed through use of the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, PubMed (1980-present), and MEDLINE (1980-present). Included were articles in English that reported the outcomes of meniscal tears in the pediatric population (<18 years old) with a follow-up of more than 12 months. Clinical outcome scores were reviewed., Results: A total of 1003 total studies were initially retrieved, with 8 meeting the inclusion criteria. The review included 287 patients (165 male, 122 female), mean age 15.1 years (range, 4-18 years), with 301 meniscal tears (reported: 134 medial, 127 lateral, and 32 both medial and lateral, 8 location unspecified). Concomitant anterior cruciate ligament reconstruction was performed in 52% (158/301) of meniscal repairs. The average reported postoperative Lysholm scores ranged from 85.4 to 96.3, and the average reported postoperative Tegner activity scores ranged from 6.2 to 8., Conclusion: Arthroscopic repair of a meniscal tear in the pediatric and adolescent population is an effective treatment option that has a low failure rate, enhances postoperative clinical outcomes, and preserves meniscal tissues., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: J.J.M. has received educational support from Arthrex, DJO, and Smith & Nephew and hospitality payments from Great Lakes Orthopedics. A.R.V. has received educational support from DJO, Smith & Nephew, and Supreme Orthopedic Systems; grant support from DJO; and hospitality payments from RTI Surgical. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Background: We describe early health services utilization for children diagnosed with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency through newborn screening in Ontario, Canada, relative to a screen negative comparison cohort., Methods: Eligible children were identified via newborn screening between April 1, 2006 and March 31, 2010. Age-stratified rates of physician encounters, emergency department (ED) visits and inpatient hospitalizations to March 31, 2012 were compared using incidence rate ratios (IRR) and incidence rate differences (IRD). We used negative binomial regression to adjust IRRs for sex, gestational age, birth weight, socioeconomic status and rural/urban residence., Results: Throughout the first few years of life, children with MCAD deficiency (n = 40) experienced statistically significantly higher rates of physician encounters, ED visits, and hospital stays compared with the screen negative cohort. The highest rates of ED visits and hospitalizations in the MCAD deficiency cohort occurred from 6 months to 2 years of age (ED use: 2.1-2.5 visits per child per year; hospitalization: 0.5-0.6 visits per child per year), after which rates gradually declined., Conclusions: This study confirms that young children with MCAD deficiency use health services more frequently than the general population throughout the first few years of life. Rates of service use in this population gradually diminish after 24 months of age.

Farber disease (FD) is an inherited autosomal recessive disorder of lipid metabolism. The hallmark of the disease is systemic accumulation of ceramide due to lysosomal acid ceramidase deficiency. The involvement of the central nervous system is critical in this disorder leading to rapid deterioration and death within a few years after birth. Efforts to treat patients by hematopoietic stem cell transplant (HSCT) have resulted in favorable results in the absence of neurological manifestations. We report the outcomes of HSCT in two patients with FD who received early HSCT and had neurological deterioration posttransplant. We also present a new understanding of the limitations of HSCT in FD management based on our observations of the clinical course of the two patients after therapy., Competing Interests: There are no conflicts of interest to declare.

Background: Historically, bicycle accidents were described as the most common mechanism for pediatric anterior tibial spine fractures (ATSFs). There is a paucity of current literature examining the demographic factors associated with these injuries. The purpose of this cohort study was to characterize the epidemiology of ATSFs presenting to a single tertiary referral pediatric hospital., Methods: A consecutive cohort of 122 pediatric patients with ATSFs between 1996 and 2014 were reviewed. Radiographic variables, classification of fractures (Meyers and McKeever type), age, sex, height, weight, body mass index, and mechanism of injury were retrieved. Categories of mechanism of injury included organized sports (football, soccer, basketball, lacrosse, wrestling, and gymnastics), bicycling, outdoor sports (skiing, skateboarding, and sledding), fall, motor vehicle collision/pedestrian versus motor vehicle, and trampoline., Results: Organized sports-related injuries represented the most common cause of ATSFs (36%). Other common mechanisms of injury included bicycle accidents (25%), outdoor sports (18%), and falls (11%). There was a higher proportion of males (69%) compared with females (31%). Males (mean age, 11.6 y) were significantly older than females (mean age, 9.8 y) (P=0.004). Younger patients (aged 11.5 y and below) were more likely to have displaced fractures (type III), whereas type I and type II were more common in patients above 11.5 years (P=0.02). Patients with fracture type I were significantly taller than patients with fracture type III. No other variables were found to differ significantly according to fracture severity, including sex, weight, and body mass index., Conclusions: To our knowledge, our study represents both the largest (n=122) and most up-to-date epidemiological ATSF study in pediatric patients. A higher rate of ATSF occurs due to organized sports rather than bicycling or motor vehicle collision. This 18-year data collection represents a change in the paradigm, and is likely multifactorial, including increased participation in youth sports and early sport specialization., Level of Evidence: Level IV-retrospective, cohort study.

Background: Imaging of the femoral trochlea has been inherently difficult because of its convex anatomy., Purpose/hypothesis: The purpose of this study was to compare the diagnostic utility of a standard axial magnetic resonance imaging (MRI) sequence with an axial-oblique MRI sequence of the knee for the detection of trochlear articular cartilage lesions on a high-field 3-T MRI scanner. We hypothesized that axial-oblique MRI scans of the knee obtained along the true axis of the trochlea would significantly improve the detection of high-grade cartilage lesions., Study Design: Cohort study (diagnosis); Level of evidence, 2., Methods: Patients who underwent MRI and subsequent surgery for any indication were prospectively enrolled into this study between June 2014 and February 2015. The articular cartilage of the trochlea was evaluated independently by 3 raters on axial and axial-oblique MRI and compared with arthroscopic findings (gold standard). The interrater and intrarater reliability of mild (International Cartilage Repair Society [ICRS] grades 1 or 2) and severe (ICRS grades 3 or 4) lesions on MRI were assessed as well as the sensitivity, specificity, positive predictive value, and negative predictive value., Results: A total of 99 knees in 96 patients were included in the study. Interrater and intrarater agreement for the identification of severe lesions were moderate to good on the proximal trochlea and fair to moderate on the distal trochlea. No significant differences in sensitivity were found between axial and axial-oblique scans for any grade of lesion (55% vs 51%, respectively; P = .700) or for severe lesions (61% vs 52%, respectively; P = .289). Similarly, specificity for detecting severe lesions was not significantly different between axial and axial-oblique scans (95% vs 87%, respectively; P = .219). Last, no significant differences in sensitivity or specificity were found between MRI sequences when separately evaluating proximal and distal trochlear lesions (all P > .05)., Conclusion: The axial-oblique sequence was unable to improve the sensitivity of MRI in detecting articular cartilage lesions on the trochlea. Both conventional axial and axial-oblique sequences, reviewed independently of the complete MRI series, had low sensitivity in detecting trochlear articular cartilage lesions. For this reason, clinicians should utilize all MRI planes to evaluate the articular cartilage of the trochlea. Future studies should focus on improving MRI techniques for detecting and characterizing cartilage lesions of the trochlea., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: R.F.L. is a consultant for and receives royalties from Arthrex, Ossur, and Smith & Nephew. J.J.M. and A.G.G. have received research and educational funding from Arthrex, Smith & Nephew, and DJO. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Hypothesis: We aimed to determine patient-reported outcomes in patients undergoing open subpectoral biceps tenodesis with a dual-fixation construct who had no postoperative range-of-motion or weight-bearing restrictions. Our hypothesis was that patients without postoperative restrictions would have low failure rates with improved patient-reported outcomes. We further hypothesized that this technique would allow an earlier return to activity and similar functional outcomes when compared with those reported in the literature., Methods: In this institutional review board-approved retrospective outcome study, we evaluated 105 patients who underwent primary open subpectoral biceps tenodesis with a bicortical suture button and interference screw construct without postoperative restrictions. The primary outcome measure was failure of the biceps tenodesis. Postoperative outcome scores included the Short Form 12 (SF-12) Physical Component Score; SF-12 Mental Component Score; American Shoulder and Elbow Surgeons total score and subscales; and Disabilities of the Arm, Shoulder and Hand score., Results: A total of 98 patients (85%) were available for final follow-up at an average of 3.5 years. There were 2 failures (2.2%), at 5 weeks and 9 weeks postoperatively. Four patients underwent additional surgery unrelated to the previous tenodesis procedure. Final outcome scores indicated high levels of function, including the SF-12 Physical Component Score (mean, 51.5; SD, 7.8), SF-12 Mental Component Score (mean, 54.7; SD, 6.7), American Shoulder and Elbow Surgeons total score (mean, 89.4; SD, 14.2), and Disabilities of the Arm, Shoulder and Hand score (mean, 11.3; SD, 13.4)., Conclusion: Open subpectoral biceps tenodesis using a dual-fixation construct with no postoperative motion restrictions resulted in excellent outcomes with a low incidence of failure., (Copyright © 2018. Published by Elsevier Inc.)

Introduction: Hepatic glycogen storage diseases (GSDs) are a group of inherited disorders of carbohydrate metabolism for which dietary management is the cornerstone. Safety and acute complications associated with dietary management have been poorly documented. We hypothesized that safety issues and complications associated with dietary management are prevalent amongst patients with these ultra-rare disorders., Methods: A questionnaire was developed consisting of 40 questions and was distributed via eight GSD patient organizations from multiple countries. Respondents were (caregivers of) patients with self-reported hepatic GSD., Results: 249 GSD patients from 26 countries responded with a median age of 14.8 years (range: 0.5-66.1). Although management was considered safe by 71% of patients, 51% reported at least one acute complication associated with dietary management, with a total number of 425 reported complications. Most frequently reported causes were: not waking up by an alarm clock (n = 70), forgetting a meal (n = 57) and infections (n = 43). Most frequently reported complications were: hypoglycemia (n = 112), hospital admissions (n = 79) and drowsiness (n = 74). Most complications occurred before the age of 12 years (82%; 637/774 total number of reported events) and during night time (63%; 340/536). Only 61% (152/249) of the GSD patients reported using a written emergency protocol., Conclusions: Safety issues and complications associated with dietary management are prevalently reported by (caregivers of) 249 GSD patients. A discrepancy has been observed between the patient's perspective on safety of dietary management and occurrence of complications as a result of dietary management., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)