Development and validation of search filters to retrieve medication discontinuation articles in Medline and Embase.

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.

The FATIGUE-PRO: a new patient-reported outcome instrument to quantify fatigue in patients affected by systemic lupus erythematosus.

OBJECTIVES: This study aimed to implement a patient-centred and evidence-based approach to develop a novel patient-reported outcome (PRO) instrument to measure fatigue in patients with SLE. METHODS: A three-step mixed methods psychometric (MMP) approach was followed. Steps comprised first draft item generation and review using interview data; evaluation and refinement of second draft items using mixed methods data, including interview and quantitative data from a phase 2 clinical study in SLE analysed using Rasch Measurement Theory (RMT) analysis; and evaluation of the final FATIGUE-PRO items using RMT and complementary Classical Test Theory (CTT) analyses. Guided by MMP criteria, a team of clinicians and outcome-measurement experts assessed evidence to inform instrument development. RESULTS: Step 1 culminated in 55 items (n = 39 patients interviewed). Their refinement in step 2 using mixed methods evidence led to the final FATIGUE-PRO instrument comprising 31 items across three scales of fatigue: physical fatigue (9 items), mental and cognitive fatigue (11 items) and susceptibility to fatigue (11 items). Qualitative (n = 43 patients) and quantitative (n = 106 patients) evidence strongly supported the scales' content comprehensiveness and targeting, item quality and fit, conceptual uniqueness and appropriateness of the response scale. The FATIGUE-PRO further benefited from excellent reliability (RMT: 0.92-0.94 and CTT: 0.95-0.96) and supportive evidence of construct validity from assessments against other PROs. CONCLUSION: The conceptual advances, comprehensive coverage and strong psychometric properties of the FATIGUE-PRO will significantly advance the measurement and management of fatigue in SLE, both in clinical trials and routine practice. TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov), NCT02804763.

Development and validation of search filters to identify articles on deprescribing in Medline and Embase.

BACKGROUND: Deprescribing literature has been increasing rapidly. Our aim was to develop and validate search filters to identify articles on deprescribing in Medline via PubMed and in Embase via Embase.com . METHODS: Articles published from 2011 to 2020 in a core set of eight journals (covering fields of interest for deprescribing, such as geriatrics, pharmacology and primary care) formed a reference set. Each article was screened independently in duplicate and classified as relevant or non-relevant to deprescribing. Relevant terms were identified by term frequency analysis in a 70% subset of the reference set. Selected title and abstract terms, MeSH terms and Emtree terms were combined to develop two highly sensitive filters for Medline via Pubmed and Embase via Embase.com . The filters were validated against the remaining 30% of the reference set. Sensitivity, specificity and precision were calculated with their 95% confidence intervals (95% CI). RESULTS: A total of 23,741 articles were aggregated in the reference set, and 224 were classified as relevant to deprescribing. A total of 34 terms and 4 MeSH terms were identified to develop the Medline search filter. A total of 27 terms and 6 Emtree terms were identified to develop the Embase search filter. The sensitivity was 92% (95% CI: 83-97%) in Medline via Pubmed and 91% (95% CI: 82-96%) in Embase via Embase.com . CONCLUSIONS: These are the first deprescribing search filters that have been developed objectively and validated. These filters can be used in search strategies for future deprescribing reviews. Further prospective studies are needed to assess their effectiveness and efficiency when used in systematic reviews.

Ethical Considerations for the Inclusion of Patient-Reported Outcomes in Clinical Research: The PRO Ethics Guidelines.

Importance: Patient-reported outcomes (PROs) can inform health care decisions, regulatory decisions, and health care policy. They also can be used for audit/benchmarking and monitoring symptoms to provide timely care tailored to individual needs. However, several ethical issues have been raised in relation to PRO use. Objective: To develop international, consensus-based, PRO-specific ethical guidelines for clinical research. Evidence Review: The PRO ethics guidelines were developed following the Enhancing the Quality and Transparency of Health Research (EQUATOR) Network's guideline development framework. This included a systematic review of the ethical implications of PROs in clinical research. The databases MEDLINE (Ovid), Embase, AMED, and CINAHL were searched from inception until March 2020. The keywords patient reported outcome* and ethic* were used to search the databases. Two reviewers independently conducted title and abstract screening before full-text screening to determine eligibility. The review was supplemented by the SPIRIT-PRO Extension recommendations for trial protocol. Subsequently, a 2-round international Delphi process (n = 96 participants; May and August 2021) and a consensus meeting (n = 25 international participants; October 2021) were held. Prior to voting, consensus meeting participants were provided with a summary of the Delphi process results and information on whether the items aligned with existing ethical guidance. Findings: Twenty-three items were considered in the first round of the Delphi process: 6 relevant candidate items from the systematic review and 17 additional items drawn from the SPIRIT-PRO Extension. Ninety-six international participants voted on the relevant importance of each item for inclusion in ethical guidelines and 12 additional items were recommended for inclusion in round 2 of the Delphi (35 items in total). Fourteen items were recommended for inclusion at the consensus meeting (n = 25 participants). The final wording of the PRO ethical guidelines was agreed on by consensus meeting participants with input from 6 additional individuals. Included items focused on PRO-specific ethical issues relating to research rationale, objectives, eligibility requirements, PRO concepts and domains, PRO assessment schedules, sample size, PRO data monitoring, barriers to PRO completion, participant acceptability and burden, administration of PRO questionnaires for participants who are unable to self-report PRO data, input on PRO strategy by patient partners or members of the public, avoiding missing data, and dissemination plans. Conclusions and Relevance: The PRO ethics guidelines provide recommendations for ethical issues that should be addressed in PRO clinical research. Addressing ethical issues of PRO clinical research has the potential to ensure high-quality PRO data while minimizing participant risk, burden, and harm and protecting participant and researcher welfare.

Hormographiella aspergillata: an emerging basidiomycete in the clinical setting? A case report and literature review.

BACKGROUND: Filamentous basidiomycetes are mainly considered to be respiratory tract colonizers but the clinical significance of their isolation in a specimen is debatable. Hormographiella aspergillata was first reported as a human pathogen in 1971. We discuss the role of this mold as a pathogen or colonizer and give an update on diagnostic tools and in vitro antifungal susceptibility. CASE PRESENTATION: We identified three cases of H. aspergillata with respiratory symptoms in a short period of time. One invasive infection and two colonizations were diagnosed. Culture supernatants showed that H. aspergillata can produce galactomannan and ß-D-glucan but not glucuronoxylomannan. For the first time, isavuconazole susceptibility was determined and high minimum inhibitory concentrations (MICs) were found. Liposomal amphotericin B and voriconazole have the lowest MICs. CONCLUSION: To date, 22 invasive infections involving H. aspergillata have been reported. On isolation of H. aspergillata, its pathogenic potential in clinical settings can be tricky. Molecular identification and antifungal susceptibility testing are essential considering high resistance against several antifungal therapies.

Challenges in Research and Health Technology Assessment of Rare Disease Technologies: Report of the ISPOR Rare Disease Special Interest Group.

BACKGROUND: Successful development of new treatments for rare diseases (RDs) and their sustainable patient access require overcoming a series of challenges related to research and health technology assessment (HTA). These impediments, which may be unique to RDs or also apply to common diseases but are particularly pertinent in RDs, are diverse and interrelated. OBJECTIVE: To develop for the first time a catalog of primary impediments to RD research and HTA, and to describe the cause and effect of individual challenges. METHODS: Challenges were identified by an international 22-person expert working group and qualitative outreach to colleagues with relevant expertise. A broad range of stakeholder perspectives is represented. Draft results were presented at annual European and North American International Society for Pharmacoeconomics and Outcomes Research (ISPOR) congresses, and written comments were received by the 385-strong ISPOR Rare Disease Review Group from two rounds of review. Findings were refined and confirmed via targeted literature search. RESULTS: Research-related challenges linked to the low prevalence of RDs were categorized into those pertaining to disease recognition and diagnosis, evaluation of treatment effect, and patient recruitment for clinical research. HTA-related challenges were classified into issues relating to the lack of a tailored HTA method for RD treatments and uncertainty for HTA agencies and health care payers. CONCLUSIONS: Identifying and highlighting diverse, but interrelated, key challenges in RD research and HTA is an essential first step toward developing implementable and sustainable solutions. A collaborative multistakeholder effort is required to enable faster and less costly development of safe, efficacious, and appropriate new RD therapies that offer value for money.

Clinical meaningfulness and psychometric robustness of the MG Symptoms PRO scales in clinical trials in adults with myasthenia gravis.

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).

The novel HLA-DRB1*11:323 allele characterized by two different sequencing-based typing techniques.

The novel allele HLA-DRB1*11:323 differs from HLA-DRB1*11:01:02:01 by one non-synonymous nucleotide substitution in exon 2.

The novel HLA-A*30:01:23 allele characterised by two different sequencing-based typing techniques.

The novel allele HLA-A*30:01:23 differs from HLA-A*30:01:01:01 by one synonymous nucleotide substitution in exon 2.

The novel HLA-DPB1*1467:01 allele characterised by two different sequencing-based typing techniques.

The novel allele HLA-DPB1*1467:01 differs from HLA-DPB1*09:01:01:01 by one non-synonymous nucleotide substitution in exon 2.

The novel HLA-B*44:48:02 allele characterised by two different sequencing-based typing techniques.

The novel allele HLA-B*44:48:02 differs from HLA-B*44:48:01 by one synonymous nucleotide substitution in exon 3.

The novel HLA-C*07:02:147 allele characterised by two different sequencing-based typing techniques.

The novel allele HLA-C*07:02:147 differs from HLA-C*07:02:01:01 by one synonymous nucleotide substitution in exon 2.

The novel HLA-A*36:14 allele characterised by two different sequencing-based typing techniques.

The novel allele HLA-A*36:14 differs from HLA-A*36:01:01:01 by one non-synonymous nucleotide substitution in exon 4.

The novel HLA-DRB1*03:210 allele characterised by two different sequencing-based typing techniques.

The novel allele HLA-DRB1*03:210 differs from HLA-DRB1*03:01:01:01 by one non-synonymous nucleotide substitution in exon 3.

Use of deprescribing search filters in systematic review search strategies: A case study.

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.

Barriers and Enablers for Deprescribing Glucose-Lowering Treatment in Older Adults: A Systematic Review.

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.

The novel HLA-B*44:369 allele characterised by two different sequencing-based typing techniques.

The novel allele HLA-B*44:369 differs from HLA-B*44:02:01:01 by one non-synonymous nucleotide substitution in exon 3.

The novel HLA-B*53:01:30 allele characterised by two different sequencing-based typing techniques.

The novel allele HLA-B*53:01:30 differs from HLA-B*53:01:01:01 by one synonymous nucleotide substitution in exon 3.

The novel HLA-DRB1*16:71 allele characterised by two different sequencing-based typing techniques.

The novel allele HLA-DRB1*16:71 differs from HLA-DRB1*16:01:01:01 by one non-synonymous nucleotide substitution in exon 2.

The novel HLA-B*56:91 allele characterised by three different sequencing-based typing techniques.

The novel allele HLA-B*56:91 differs from HLA-B*56:33 by one non-synonymous nucleotide substitution in exon 2.