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Objectives: The objective of this research was to generate psychometric evidence supporting the myasthenia gravis (MG) symptoms patient-reported outcome (PRO) scales as a fit-for-purpose measure of severity of core symptoms of MG and provide information allowing their meaningful interpretation using data from a phase 3 study in MG. Methods: Data from the MycarinG study, a phase 3 study of rozanolixizumab in patients with generalized MG who experience moderate to severe symptoms (ClinicalTrials.gov Identifier: NCT03971422) were analyzed with both classical test theory (CTT) and Rasch measurement theory (RMT). Meaningful within-individual change and group-level meaningful change were estimated for three MG Symptoms PRO scales using anchor- and distribution-based methods. Anchor-based methods used patient global impression of severity (PGIS) and change (PGIC) in MG symptoms as anchors. Results: Good measurement properties of the MG Symptoms PRO scales were shown in the sample of 200 participants: good to excellent reliability (test-retest and internal consistency reliability) and validity (associations between items and scores within the MG Symptoms PRO scales and between the MG Symptoms PRO scores and other clinical outcomes-MG ADL, QMG score, MGC score, and MGFA classes-were as expected); and the items showed good coverage of the continuum and fit to the Rasch model. Triangulation of the anchor- and distribution-based method results led to the definition of clinically meaningful within-patient improvement in scores for Muscle Weakness Fatigability (-16.67), Physical Fatigue (-20.00), and Bulbar Muscle Weakness (-20.00), with associated ranges. Benchmarks are also proposed for the interpretation of group-level results. Conclusion: The strong psychometric performance of the MG Symptoms PRO scales and the information generated to guide its interpretation supports its use in clinical trials for demonstrating the clinical benefits of new treatments targeting core symptoms of MG (muscle weakness fatigability, physical fatigue, bulbar muscle weakness, respiratory muscle weakness, and ocular muscle weakness).
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The novel allele HLA-B*44:48:02 differs from HLA-B*44:48:01 by one synonymous nucleotide substitution in exon 3.
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Antígenos HLA-B , Nucleótidos , Humanos , Alelos , Exones/genética , Análisis de Secuencia de ADN , Antígenos HLA-B/genéticaRESUMEN
The novel allele HLA-C*07:02:147 differs from HLA-C*07:02:01:01 by one synonymous nucleotide substitution in exon 2.
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Genes MHC Clase I , Antígenos HLA-C , Humanos , Antígenos HLA-C/genética , Alelos , Exones/genética , NucleótidosRESUMEN
The novel allele HLA-A*36:14 differs from HLA-A*36:01:01:01 by one non-synonymous nucleotide substitution in exon 4.
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Antígenos HLA-A , Nucleótidos , Humanos , Alelos , Exones/genética , Análisis de Secuencia de ADN , Antígenos HLA-A/genéticaRESUMEN
The novel allele HLA-DRB1*03:210 differs from HLA-DRB1*03:01:01:01 by one non-synonymous nucleotide substitution in exon 3.
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Nucleótidos , Humanos , Alelos , Cadenas HLA-DRB1/genética , Exones/genética , Análisis de Secuencia de ADNRESUMEN
The novel allele HLA-DRB1*11:323 differs from HLA-DRB1*11:01:02:01 by one non-synonymous nucleotide substitution in exon 2.
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Nucleótidos , Humanos , Cadenas HLA-DRB1/genética , Alelos , Exones/genética , Análisis de Secuencia de ADNRESUMEN
The novel allele HLA-A*30:01:23 differs from HLA-A*30:01:01:01 by one synonymous nucleotide substitution in exon 2.
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Antígenos HLA-A , Nucleótidos , Humanos , Alelos , Exones/genética , Análisis de Secuencia de ADN , Antígenos HLA-A/genéticaRESUMEN
The novel allele HLA-DPB1*1467:01 differs from HLA-DPB1*09:01:01:01 by one non-synonymous nucleotide substitution in exon 2.
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Secuencia de Bases , Humanos , Alelos , Cadenas beta de HLA-DP/genética , Exones/genética , Análisis de Secuencia de ADNRESUMEN
OBJECTIVES: Overtreatment with glucose-lowering treatment (GLT) is frequent and a source of high morbidity and mortality in older adults with type 2 diabetes mellitus (T2DM). This study aimed to identify and synthesize barriers and enablers for deprescribing GLT in older adults (≥65 years) with T2DM. DESIGN: Systematic review of qualitative and mixed-methods studies. SETTING AND PARTICIPANTS: Older adults with T2DM, any participants [patients, health care providers (HCPs), caregivers], any settings. METHODS: Two researchers (and a referred third researcher at all stages) independently screened original articles reporting qualitative and mixed-methods studies exploring barriers and enablers for deprescribing GLT in older adults published during 2010-2023, identified from MEDLINE, Embase, CINAHL, and gray literature. Quality of the included studies was assessed with the Mixed-Methods Appraisal Tool. Verbatim statements on barriers and enablers were extracted, and determinants of behaviors were identified with the Theoretical Domains Framework (TDF) version 2, and related intervention functions (targets for future interventions) were proposed according to the Behavior Change Wheel (BCW). RESULTS: We identified only 4 studies from 2 countries (United States and the Netherlands), all recently published (2019-2023), that primarily reported barriers to GLT deprescribing from interviews or focus groups of patients or HCPs practicing outpatient medicine. Knowledge, fear, poor communication, inertia, and trust with HCPs were the main determinants of behaviors that influenced deprescribing, and education, training, persuasion and environmental restructuring were the main intervention functions for proposing future interventions. Studies did not cover financial aspects, physician characteristics, or caregiver and family viewpoints. CONCLUSIONS AND IMPLICATIONS: The use of a behavioral theory and a validated implementation framework provided a comprehensive approach to identifying barriers and enablers for deprescribing GLT in older adults (≥65 years) with T2DM. The behavioral determinants identified may be useful in tailoring interventions to improve the implementation of GLT deprescribing in older adults in ambulatory settings.
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Deprescripciones , Diabetes Mellitus Tipo 2 , Medicina , Humanos , Anciano , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Escolaridad , GlucosaRESUMEN
Two deprescribing search filters for MEDLINE and one deprescribing search filter for Embase have been recently developed, including objectively developed search filters. The objective of this case study was to implement these three deprescribing search filters in systematic review (SR) search strategies and to assess their effect on performances. SR that independently developed original search strategies (OSS) were selected. The deprescribing filters were implemented in each OSS, generating two implemented search strategies (ISS1 and ISS2) in MEDLINE and one ISS (ISS3) in Embase. OSS were re-run on the same date as ISS. The performances of ISS and OSS were calculated and compared. Two SR were included (SR1 and SR2). For MEDLINE, SR1 included 12 articles. The sensitivity was 50% for OSS, 58% for ISS1 and 42% for ISS2. SR2 included four articles. The sensitivity of OSS, ISS 1 and 2 was 25%. For Embase, SR1 included 12 articles. The sensitivity was 33% for OSS and 58% for ISS3. SR2 included four articles. None of the four included articles were retrieved with OSS or ISS3. While sensitivity of OSS was moderate, the objectively developed deprescribing filters maintained or slightly improved this sensitivity when implementing.
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Deprescripciones , Bases de Datos Bibliográficas , MEDLINERESUMEN
BACKGROUND: Medication discontinuation studies explore the outcomes of stopping a medication compared to continuing it. Comprehensively identifying medication discontinuation articles in bibliographic databases remains challenging due to variability in terminology. OBJECTIVES: To develop and validate search filters to retrieve medication discontinuation articles in Medline and Embase. METHODS: We identified medication discontinuation articles in a convenience sample of systematic reviews. We used primary articles to create two reference sets for Medline and Embase, respectively. The reference sets were equally divided by randomization in development sets and validation sets. Terms relevant for discontinuation were identified by term frequency analysis in development sets and combined to develop two search filters that maximized relative recalls. The filters were validated against validation sets. Relative recalls were calculated with their 95% confidences intervals (95% CI). RESULTS: We included 316 articles for Medline and 407 articles for Embase, from 15 systematic reviews. The Medline optimized search filter combined 7 terms. The Embase optimized search filter combined 8 terms. The relative recalls were respectively 92% (95% CI: 87-96) and 91% (95% CI: 86-94). CONCLUSIONS: We developed two search filters for retrieving medication discontinuation articles in Medline and Embase. Further research is needed to estimate precision and specificity of the filters.
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BACKGROUND: In support of UCB pharmaceutical research programs, the aim of this research was to implement a novel process for patient involvement in a multidisciplinary research group to co-create a clinical outcome assessment strategy to accurately reflect the experience of people living with early-stage Parkinson's. Patient experts were an integral part of the decision-making process for patient-reported outcome (PRO) research and instrument development. METHODS: In partnership with two patient organizations (Parkinson's UK and the Parkinson's Foundation), 6 patient experts were recruited into a multidisciplinary research group alongside clinical, patient engagement and involvement, regulatory science, and outcome measurement experts. The group was involved across two phases of research; the first phase identified what symptoms are cardinal to the experience of living with early-stage Parkinson's and the second phase involved the development of PRO instruments to better assess the symptoms that are important to people living with early-stage Parkinson's. Patient experts were important in performing a variety of roles, in particular, qualitative study protocol design, conceptual model development, and subsequent co-creation of two PRO instruments. RESULTS: Involving people with Parkinson's in PRO research ensured that the expertise of these representatives from the Parkinson's community shaped and drove the research; as such, PRO instruments were being developed with the patient at the forefront. Working with patient experts required considerable resource and time allocation for planning, communication, document development, and organizing meetings; however, their input enriched the development of PRO instruments and was vital in developing PRO instruments that are more meaningful for people with Parkinson's and clinicians. CONCLUSIONS: Conducting PRO research, in the context of clinical development involving pharmaceutical companies, requires balancing regulatory and scientific rigor with tight time constraints. Incorporating a multi-stakeholder perspective, which included patient experts as joint investigators, had a strong positive impact on our research, despite the logistical complexities of their involvement. Due to the input of patient experts, the innovative clinical outcome assessment strategy and the co-created novel PRO instruments were more relevant and holistic to the patient experience of early-stage Parkinson's.
Patient-reported outcome (PRO) instruments allow people living with a disease and participating in a clinical study to describe the symptoms and experiences that they consider meaningful. PRO instruments use tools such as questionnaires and scales to capture patient perspectives on a treatment that might not be captured by a clinical measurement. It is recommended that the patient community and patient experts are included in the development of PRO instruments to accurately capture information that is important to them. Building on the experience of a recent PRO research project in support of UCB pharmaceutical programs, this article provides recommendations on how pharmaceutical companies can partner with patient organizations and involve patient experts as joint investigators in the co creation of PRO instruments. Despite the additional resource and time required, involving patient experts and patient organizations into the research collaboration had a strong positive impact and ensured that the PROs were meaningful to patients (in this instance, people living with early-stage Parkinson's). Patient organizations facilitated patient engagement and recruitment in research activities, maintained communication with the pharmaceutical company's research team, and built trust between collaborators by implementing patient engagement tools and best practices. Patient experts contributed to several parts of the PRO instrument development process: study design, identifying key symptoms and experiences, and developing individual PRO questions. Co-creation between the pharmaceutical company, patient experts, and patient organizations resulted in considerable improvements to typical PRO instrument development for use in clinical trials and is thus recommended.
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The novel allele HLA-C*07:1058 differs from HLA-C*07:02:01:01 by one non-synonymous nucleotide substitution in exon 4.
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Genes MHC Clase I , Antígenos HLA-C , Humanos , Antígenos HLA-C/genética , Alelos , Prueba de Histocompatibilidad , Exones/genética , Análisis de Secuencia de ADNRESUMEN
The novel allele HLA-B*44:369 differs from HLA-B*44:02:01:01 by one non-synonymous nucleotide substitution in exon 3.
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Antígenos HLA-B , Humanos , Alelos , Exones/genética , Análisis de Secuencia de ADN , Antígenos HLA-B/genéticaRESUMEN
The novel allele HLA-B*53:01:30 differs from HLA-B*53:01:01:01 by one synonymous nucleotide substitution in exon 3.
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Genes MHC Clase I , Antígenos HLA-B , Humanos , Alelos , Antígenos HLA-B/genética , Exones/genética , Análisis de Secuencia de ADNRESUMEN
INTRODUCTION: Accurate measurement of myasthenia gravis (MG) severity is required for appropriate clinical monitoring of patients with MG and assessment of the benefit of new treatments in clinical trials. Our objective was to explore how MG severity can be measured and to determine how the newly developed MG Symptoms Patient-Reported Outcome (PRO) instrument complements the available measures of MG severity. METHODS: The conceptual coverage of the Quantitative MG (QMG), MG Composite (MGC), MG-Activities of Daily Living (MG-ADL), and MG Symptoms PRO was scrutinized against core symptoms of MG: muscle weakness in three muscle groups (ocular, bulbar, and respiratory), muscle weakness fatigability, and physical fatigue. Post hoc analyses of the MG0002 study, a Phase 2a clinical trial of rozanolixizumab in adults with moderate to severe generalized MG, included correlation and Rasch model analyses. RESULTS: The qualitative appraisal highlighted that only the MG Symptoms PRO captured physical fatigue. Data from 541 assessments (43 unique patients) were used for the analyses. Correlations ranged between 0.56 and 0.74 for the MG-ADL, QMG, MGC, and MG Symptoms PRO Muscle Weakness Fatigability score, and between 0.20 and 0.71 for the MG Symptoms PRO scores focusing on independent muscle groups. Analyses with the Rasch model estimated a meaningful continuum of severity of MG, including all items, except ocular muscles, from the four instruments. The QMG and MG Symptoms PRO had the broadest coverage of the MG severity continuum. Muscle fatigability and physical fatigue were more characteristic of low severity while bulbar weakness indicated more severe MG. CONCLUSION: The severity of MG can be reflected in a meaningful continuum underpinned by the MG-specific outcome measures. Only ocular muscle manifestations were shown to reflect a possibly different facet of MG severity. With its modular nature and comprehensive content, the MG Symptoms PRO provides complementary information to the outcome measures widely used in MG. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03052751.
Myasthenia gravis (MG) is a chronic disease affecting the communication between nerves and muscles. People with MG experience muscle weakness that worsens after activity and improves after rest. MG can affect different groups of body muscles (e.g., around the eyes, in the limbs, and face or throat).We show that the various symptoms of MG can be used to summarize the overall severity of the disease: people with mild and moderate MG often report only the fast onset of weakness in their limb muscles and mild physical fatigue, while those with more severe MG report more severe fatigue and also difficulties associated with weakness in facial and throat muscles (leading to difficulty with swallowing or speaking) and in respiratory muscles (making breathing difficult). This ordering of MG manifestations will help create more accurate methods to assess the severity of MG that can be used to evaluate new treatments or to monitor patients in the clinic.We also suggest that weakness of muscles around the eyes (leading to eyelid drooping or double vision) may represent a unique aspect of MG, and may not provide as much information to summarize the severity of MG as other symptoms. However, this needs further investigation as our study did not include participants who had weakness in eye muscles as their only symptom.We also document the ability of the MG Symptoms Patient-Reported Outcome questionnaire, a new questionnaire completed by patients, to provide useful information for measuring the severity of MG.
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The novel allele HLA-A*11:443 differs from HLA-A*11:01:01:01 by one non-synonymous nucleotide substitution in exon 2.
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Antígenos HLA-A , Humanos , Alelos , Prueba de Histocompatibilidad , Exones/genética , Análisis de Secuencia de ADN , Antígenos HLA-A/genéticaRESUMEN
BACKGROUND: Previous research on concepts that are important to people living with early-stage Parkinson's indicated that 'functional' slowness, fine motor skills, and subtle gait abnormalities are cardinal concepts that are not comprehensively captured by existing patient-reported outcome (PRO) instruments that are used in clinical practice and research to assess symptoms and daily functioning within this patient population. We sought to develop novel PRO instruments to address this unmet need. METHODS: PRO instrument development was led by a multidisciplinary research group, including people living with Parkinson's (termed 'patient experts'), as well as patient engagement and involvement, regulatory science, clinical, and outcome measurement experts. A first set of PRO instruments, termed Early Parkinson's Function Slowness (42 items) and Early Parkinson's Mobility (26 items), were drafted to capture 'functional' slowness, fine motor skills, and subtle gait abnormalities. These PRO instruments were used in cognitive debriefing interviews with people living with early-stage Parkinson's (who were not involved with the multidisciplinary research group) to identify issues with relevance, clarity, ease of completion, conceptual overlap, or missing concepts. RESULTS: Sixty people living with early-stage Parkinson's were interviewed, which led to refining the items to 45 for the Early Parkinson's Functional Slowness and 23 for the Early Parkinson's Mobility PRO instruments. Refinement included rewording items to address clarity issues, merging or splitting items to address overlap issues, and adding new items to address missing concepts. The Early Parkinson's Function Slowness PRO instrument resulted in a multidimensional instrument covering upper limb, complex/whole body, general activity, and cognitive functional slowness. The Early Parkinson's Mobility PRO instrument resulted in comprehensive coverage of everyday mobility tasks, with a focus on gait concepts, plus complex/whole body, balance, and lower limb mobility. CONCLUSIONS: The Early Parkinson's Function Slowness and Early Parkinson's Mobility PRO instruments aim to address gaps in existing PRO instruments to measure meaningful symptoms and daily functioning in people living with early-stage Parkinson's. Utilizing a meticulous study design led by a multidisciplinary research group that included patient experts helped to ensure that the PRO instruments were patient-centric, content valid, and meaningful from a clinical and measurement perspective.