150 research outputs found
LongâTerm Outcomes Following Achievement of Clinically Inactive Disease in Juvenile Idiopathic Arthritis
OBJECTIVE: Potential targets for treatâtoâtarget strategies in juvenile idiopathic arthritis are minimal disease activity (MDA) and clinically inactive disease (CID). We undertook this study to compare shortâ and longâterm outcomes following achievement of MDA and CID on the 10âjoint clinical Juvenile Arthritis Disease Activity Score (cJADAS10) and following achievement of CID on Wallace et al's preliminary criteria. METHODS: Children recruited to the Childhood Arthritis Prospective Study, a UK multicenter inception cohort, were selected if they were recruited prior to January 2011 and diagnosed as having oligoarthritis or rheumatoid factorânegative or âpositive polyarthritis. One year following diagnosis, children were assessed for MDA on the cJADAS10 and for CID on both Wallace et al's preliminary criteria and the cJADAS10. Associations were tested between those disease states and functional ability, absence of joints with limited range of motion, psychosocial health, and pain at 1 year and annually to 5 years. RESULTS: Of 832 children, 70% were female and the majority had oligoarthritis (68%). At 1 year, 21% had achieved CID according to both definitions, 7% according to Wallace et al's preliminary criteria alone, and 16% according to the cJADAS10 alone; 56% had not achieved CID. Only 10% of children in the entire cohort achieved MDA without also achieving CID. Achieving either early CID state was associated with a greater absence of joints with limited range of motion. However, only CID according to the cJADAS10 was associated with improved functional ability and psychosocial health. Achieving CID was superior to achieving MDA in terms of shortâ and longâterm pain and the absence of joints with limited range of motion
Common Functional Ability Score for Young People With Juvenile Idiopathic Arthritis
From Wiley via Jisc Publications RouterHistory: received 2019-12-13, accepted 2020-03-31, pub-electronic 2021-06-04Article version: VoRPublication status: PublishedFunder: Medical Research Council; Id: http://dx.doi.org/10.13039/501100000265; Grant(s): UK Grant number: MR/K501311/1Funder: Versus Arthritis; Id: http://dx.doi.org/10.13039/501100012041; Grant(s): 20380, 20542Funder: NIHR Manchester Biomedical Research Centre; Id: http://dx.doi.org/10.13039/100014653Objective: As young people enter adulthood, the interchangeable use of child and adult outcome measures may inaccurately capture changes over time. This study aimed to use item response theory (IRT) to model a continuous score for functional ability that can be used no matter which questionnaire is completed. Methods: Adolescents (ages 11â17 years) in the UK Childhood Arthritis Prospective Study (CAPS) selfâcompleted an adolescent Childhood Health Assessment Questionnaire (CHAQ) and a Health Assessment Questionnaire (HAQ). Their parents answered the proxyâcompleted CHAQ. Those children with at least 2 simultaneously completed questionnaires at initial presentation or 1 year were included. Psychometric properties of item responses within each questionnaire were tested using Mokken analyses to assess the applicability of IRT modeling. A previously developed IRT model from the PharmachildâNL registry from The Netherlands was validated in CAPS participants. Agreement and correlations between IRTâscaled functional ability scores were tested using intraclass correlations and Wilcoxonâs signed rank tests. Results: In 303 adolescents, the median age at diagnosis was 13 years, and 61% were female. CHAQ scores consistently exceeded HAQ scores. Mokken analyses demonstrated high scalability, monotonicity, and the fact that each questionnaire yielded reliable scores. There was little difference in item response characteristics between adolescents enrolled in CAPS and PharmachildâNL (maximum item residual 0.08). Significant differences were no longer evident between IRTâscaled HAQ and CHAQ scores. Conclusion: IRT modeling allows the direct comparison of function scores regardless of different questionnaires being completed by different people over time. IRT modeling facilitates the ongoing assessment of function as adolescents transfer from pediatric clinics to adult services
Patient-reported wellbeing and clinical disease measures over time captured by multivariate trajectories of disease activity in individuals with juvenile idiopathic arthritis in the UK: a multicentre prospective longitudinal study
Background: Juvenile idiopathic arthritis (JIA) is a heterogeneous disease, the signs and symptoms of which can be
summarised with use of composite disease activity measures, including the clinical Juvenile Arthritis Disease Activity
Score (cJADAS). However, clusters of children and young people might experience different global patterns in their
signs and symptoms of disease, which might run in parallel or diverge over time. We aimed to identify such clusters in
the 3 years after a diagnosis of JIA. The identification of these clusters would allow for a greater understanding of
disease progression in JIA, including how physician-reported and patient-reported outcomes relate to each other over
the JIA disease course. /
Methods: In this multicentre prospective longitudinal study, we included children and young people recruited before
Jan 1, 2015, to the Childhood Arthritis Prospective Study (CAPS), a UK multicentre inception cohort. Participants
without a cJADAS score were excluded. To assess groups of children and young people with similar disease patterns in
active joint count, physicianâs global assessment, and patient or parental global evaluation, we used latent profile analysis
at initial presentation to paediatric rheumatology and multivariate group-based trajectory models for the following
3 years. Optimal models were selected on the basis of a combination of model fit, clinical plausibility, and model parsimony. /
Finding: Between Jan 1, 2001, and Dec 31, 2014, 1423 children and young people with JIA were recruited to CAPS,
239 of whom were excluded, resulting in a final study population of 1184 children and young people. We identified
five clusters at baseline and six trajectory groups using longitudinal follow-up data. Disease course was not well
predicted from clusters at baseline; however, in both cross-sectional and longitudinal analyses, substantial proportions
of children and young people had high patient or parent global scores despite low or improving joint counts and
physician global scores. Participants in these groups were older, and a higher proportion of them had enthesitisrelated JIA and lower socioeconomic status, compared with those in other groups. /
Interpretation: Almost one in four children and young people with JIA in our study reported persistent, high patient
or parent global scores despite having low or improving active joint counts and physicianâs global scores. Distinct
patient subgroups defined by disease manifestation or trajectories of progression could help to better personalise
health-care services and treatment plans for individuals with JIA. /
Funding: Medical Research Council, Versus Arthritis, Great Ormond Street Hospital Childrenâs Charity, Oliviaâs Vision,
and National Institute for Health Researc
Genetic Selection of Low Fertile Onchocerca volvulus by Ivermectin Treatment
Onchocerca volvulus is the causative agent of onchocerciasis, or
âriver blindnessâ. Ivermectin has been used for mass
treatment of onchocerciasis for up to 18 years, and recently there have been
reports of poor parasitological responses to the drug and evidence of drug
resistance. Drug resistance has a genetic basis. In this study, genetic changes
in β-tubulin, a gene associated with ivermectin
resistance in nematodes, were seen in parasites obtained from the patients
exposed to repeated ivermectin treatment compared with parasites obtained from
the same patients before any exposure to ivermectin. Furthermore, the extent of
the genetic changes was dependent on the level of ivermectin treatment exposure.
This genetic selection was associated with a lower reproductive rate in the
female parasites. The data indicates that this genetic selection is for a
population of O. volvulus that is more tolerant to ivermectin.
This selection could have implications for the development of ivermectin
resistance in O. volvulus and for the ongoing onchocerciasis
control programmes. Monitoring for the possible development and spread of
ivermectin resistance, as part of the control programmes, should be implemented
so that any foci of resistant parasites can be treated by alternative control
measures
The successes and challenges of harmonising juvenile idiopathic arthritis (JIA) datasets to create a large-scale JIA data resource
Background
CLUSTER is a UK consortium focussed on precision medicine research in JIA/JIA-Uveitis. As part of this programme, a large-scale JIA data resource was created by harmonizing and pooling existing real-world studies. Here we present challenges and progress towards creation of this unique large JIA dataset.
Methods
Four real-world studies contributed data; two clinical datasets of JIA patients starting first-line methotrexate (MTX) or tumour necrosis factor inhibitors (TNFi) were created. Variables were selected based on a previously developed core dataset, and encrypted NHS numbers were used to identify children contributing similar data across multiple studies.
Results
Of 7013 records (from 5435 individuals), 2882 (1304 individuals) represented the same child across studies. The final datasets contain 2899 (MTX) and 2401 (TNFi) unique patients; 1018 are in both datasets. Missingness ranged from 10 to 60% and was not improved through harmonisation.
Conclusions
Combining data across studies has achieved dataset sizes rarely seen in JIA, invaluable to progressing research. Losing variable specificity and missingness, and their impact on future analyses requires further consideration
Engineered Single-Domain Antibodies with High Protease Resistance and Thermal Stability
The extreme pH and protease-rich environment of the upper gastrointestinal tract is a major obstacle facing orally-administered protein therapeutics, including antibodies. Through protein engineering, several Clostridium difficile toxin A-specific heavy chain antibody variable domains (VHHs) were expressed with an additional disulfide bond by introducing Ala/Gly54Cys and Ile78Cys mutations. Mutant antibodies were compared to their wild-type counterparts with respect to expression yield, non-aggregation status, affinity for toxin A, circular dichroism (CD) structural signatures, thermal stability, protease resistance, and toxin A-neutralizing capacity. The mutant VHHs were found to be well expressed, although with lower yields compared to wild-type counterparts, were non-aggregating monomers, retained low nM affinity for toxin A, albeit the majority showed somewhat reduced affinity compared to wild-type counterparts, and were capable of in vitro toxin A neutralization in cell-based assays. Far-UV and near-UV CD spectroscopy consistently showed shifts in peak intensity and selective peak minima for wild-type and mutant VHH pairs; however, the overall CD profile remained very similar. A significant increase in the thermal unfolding midpoint temperature was observed for all mutants at both neutral and acidic pH. Digestion of the VHHs with the major gastrointestinal proteases, at biologically relevant concentrations, revealed a significant increase in pepsin resistance for all mutants and an increase in chymotrypsin resistance for the majority of mutants. Mutant VHH trypsin resistance was similar to that of wild-type VHHs, although the trypsin resistance of one VHH mutant was significantly reduced. Therefore, the introduction of a second disulfide bond in the hydrophobic core not only increases VHH thermal stability at neutral pH, as previously shown, but also represents a generic strategy to increase VHH stability at low pH and impart protease resistance, with only minor perturbations in target binding affinities. These are all desirable characteristics for the design of protein-based oral therapeutics
Fungal Origins of the Bicyclo[2.2.2]diazaoctane Ring System of Prenylated Indole Alkaloids
Over eight different families of natural products, consisting of nearly seventy secondary metabolites, which contain the bicyclo[2.2.2]diazaoctane ring system, have been isolated from various Aspergillus, Penicillium, and Malbranchea species. Since 1968, these secondary metabolites have been the focus of numerous biogenetic, synthetic, taxonomic, and biological studies, and, as such, have made a lasting impact across multiple scientific disciplines. This review covers the isolation, biosynthesis, and biological activity of these unique secondary metabolites containing the bridging bicyclo[2.2.2]diazaoctane ring system. Furthermore, the diverse fungal origin of these natural products is closely examined and, in many cases, updated to reflect the currently accepted fungal taxonomy
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