Utilising primary care electronic health records to deliver the ALABAMA randomised controlled trial of penicillin allergy assessment.

BACKGROUND: Use of electronic health records (EHR) to provide real-world data for research is established, but using EHR to deliver randomised controlled trials (RCTs) more efficiently is less developed. The Allergy AntiBiotics And Microbial resistAnce (ALABAMA) RCT evaluated a penicillin allergy assessment pathway versus usual clinical care in a UK primary care setting. The aim of this paper is to describe how EHRs were used to facilitate efficient delivery of a large-scale randomised trial of a complex intervention embracing efficient participant identification, supporting minimising GP workload, providing accurate post-intervention EHR updates of allergy status, and facilitating participant follow up and outcome data collection. The generalisability of the EHR approach and health economic implications of EHR in clinical trials will be reported in the main ALABAMA trial cost-effectiveness analysis. METHODS: A descriptive account of the adaptation of functionality within SystmOne used to deliver/facilitate multiple trial processes from participant identification to outcome data collection. RESULTS: An ALABAMA organisation group within SystmOne was established which allowed sharing of trial functions/materials developed centrally by the research team. The 'ALABAMA unit' within SystmOne was also created and provided a secure efficient environment to access participants' EHR data. Processes of referring consented participants, allocating them to a trial arm, and assigning specific functions to the intervention arm were developed by adapting tools such as templates, reports, and protocols which were already available in SystmOne as well as pathways to facilitate allergy de-labelling processes and data retrieval for trial outcome analysis. CONCLUSIONS: ALABAMA is one of the first RCTs to utilise SystmOne EHR functionality and data across the RCT delivery, demonstrating feasibility and applicability to other primary care RCTs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04108637, registered 05/03/2019. ISRCTN: ISRCTN20579216.

New Therapeutic Strategies for the Inflammatory Rheumatoid Arthritis Disease: Emphasizing Mesenchymal Stem Cells and Associated exo-miRNA or exo-lncRNA.

The most prevalent inflammatory arthritis and a leading contributor to disability is rheumatoid arthritis (RA). Although it may not have arrived in Europe until the 17th century, it was present in early Native American communities several thousand years ago. Exosomes released by mesenchymal stem cells (MSCs) are highly immunomodulatory due to the origin of the cell. As a cell-free therapy, MSCs-exosomes are less toxic and elicit a weakened immune response than cell-based therapies. Exosomal noncoding RNAs (ncRNAs) are closely associated with a number of biological and functional facets of human health, especially microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). Various exo-miRNAs and lncRNAs such as HAND2-AS1, miR-150-5p, miRNA-124a, and miR-320a lodged with MSC could be appropriate therapeutic ways for RA treatment. These MSC-derived exosomes affect RA disorders via different molecular pathways such as NFK-ß, MAPK, and Wnt. The purpose of this review is to review the research that has been conducted since 2020 so far in the field of RA disease treatment with MSC-loaded exo-miRNAs and exo-lncRNAs.

Penicillin allergy status and its effect on antibiotic prescribing, patient outcomes and antimicrobial resistance (ALABAMA): protocol for a multicentre, parallel-arm, open-label, randomised pragmatic trial.

INTRODUCTION: Incorrect penicillin allergy records are recognised as an important barrier to the safe treatment of infection and affect an estimated 2.7 million people in England. Penicillin allergy records are associated with worse health outcome and antimicrobial resistance. The ALlergy AntiBiotics And Microbial resistAnce (ALABAMA) trial aims to determine if an intervention package, centred around a penicillin allergy assessment pathway (PAAP) initiated in primary care, is safe and effective in improving patient health outcomes and antibiotic prescribing. METHODS AND ANALYSIS: The ALABAMA trial is a multicentre, parallel-arm, open-label, randomised pragmatic trial with a nested pilot study. Adults (≥18 years) with a penicillin allergy record and who have received antibiotics in the previous 24 months will be eligible for participation. Between 1592 and 2090 participants will be recruited from participating National Health Service general practices in England. Participants will be randomised to either usual care or intervention to undergo a pre-emptive PAAP using a 1:1 allocation ratio. The primary outcome measure is the percentage of treatment response failures within 28 days of an index prescription. 2090 and 1592 participants are estimated to provide 90% and 80% power, respectively, to detect a clinically important absolute difference of 7.9% in primary outcome at 1 year between groups. The trial includes a mixed-methods process evaluation and cost-effectiveness evaluation. ETHICS AND DISSEMINATION: This trial has been approved by London Bridge Research Ethics Committee (ref: 19/LO/0176). It will be conducted in compliance with Good Clinical Practice guidelines according to the Declaration of Helsinki. Informed consent will be obtained from all subjects involved in the study. The primary trial results will be submitted for publication to an international, peer-reviewed journal. TRIAL REGISTRATION: ISRCTN20579216.

The effectiveness of interventions that support penicillin allergy assessment and delabeling of adult and pediatric patients by nonallergy specialists: a systematic review and meta-analysis.

OBJECTIVES: Penicillin allergy records are often incorrect and may result in harm. We aimed to systematically review the effectiveness and safety of nonallergist health care worker delivery of penicillin allergy delabeling. METHODS: We searched EMBASE/MEDLINE/CINAHL (Ovid), PsycInfo, Web of Science, and Cochrane CENTRAL from inception to January 21, 2022 and unpublished studies and gray literature. The proportion of patients allergic to penicillin delabeled and harmed was calculated using random-effects models. RESULTS: Overall, 5019 patients were delabeled. Using allergy history alone, 14% (95% confidence interval [CI], 9-21%) of 4350 assessed patients were delabeled without reported harm. Direct drug provocation testing resulted in delabeling in 27% (95% CI, 18-37%) of 4207 assessed patients. Of the 1373 patients tested, 98% were delabeled (95% CI, 97-99%), and nonserious harm was reported in 1% (95% CI, 0-2%). Using skin testing, followed by drug provocation testing, 41% (95% CI, 24-59%) of 2890 assessed patients were delabeled. Of the 1294 tested patients, 95.0% (95% CI, 90-99%) were delabeled, and the reported harm was low (0%; (95% CI 0-1%). CONCLUSION: Penicillin allergy delabeling by nonallergists is efficacious and safe. The proportion of assessed patients who can be delabeled increases with the complexity of testing method, but substantial numbers can be delabeled without skin testing.

Effectiveness of interventions that support penicillin allergy assessment and de-labeling of patients by non-allergy specialists: a systematic review protocol.

OBJECTIVE: This review will systematically examine and synthesize the evidence evaluating the effectiveness and safety of interventions that enable non-allergy specialist health care workers to assess allergy risk in patients with reported penicillin allergies and subsequently remove erroneous allergy records. INTRODUCTION: The potential benefits of removing erroneous penicillin allergy labels (de-labeling) are wide-ranging. Penicillin allergy assessment and de-labeling is an antibiotic stewardship priority. Delivery of such assessment and de-labeling by non-allergy specialists has been reported in several studies, but the effectiveness and safety have not been formally synthesized. This is a necessary step in the upscaling of penicillin allergy assessment services. INCLUSION CRITERIA: This review will consider quantitative studies using appropriate designs. The studies will include adults and pediatric patients who have undergone penicillin allergy assessment and de-labeling by non-allergy specialists in any health care setting. METHODS: A range of databases will be searched to identify studies published in English, with no date limit applied. Unpublished studies and gray literature will also be searched. Title and abstract screening, and assessment of selected full texts against the inclusion criteria will be conducted by at least two independent reviewers. Identified studies will be assessed for methodological quality using standardized critical appraisal instruments. Data will be extracted and categorized using the EPOC taxonomy, and the effectiveness and safety of the intervention will be determined. Where possible, data will be pooled to facilitate meta-analysis. Data from heterogeneous studies will be reported narratively. The GRADE approach for grading the certainty of evidence will be followed. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42020219044.

The CABI Trial: an Unblinded Parallel Group Randomised Controlled Feasibility Trial of Long-Course Antibiotic Therapy (28 Days) Compared with Short Course (≤ 10 Days) in the Prevention of Relapse in Adults Treated for Complicated Intra-Abdominal Infection.

PURPOSE: Relapse after complicated intra-abdominal infection (cIAI) remains common after treatment. The optimal antibiotic treatment duration for cIAIs is uncertain, especially in cases where source control is not achieved. We hypothesised that in patients with cIAIs, regardless of source control intervention, there would be a lower relapse rate with long-course antibiotics (28 days) compared with short course (≤ 10 days). We piloted a trial comparing ≤ 10-day with 28-day antibiotic treatment for cIAI. METHODS: A randomised controlled unblinded feasibility trial was conducted. Eligible participants were adult patients with a cIAI that were diagnosed ≤ 6 days prior to screening. Randomisation was to long-course (28 days) or short-course (≤10 days) antibiotic therapy. Choice of antibiotics was determined by the clinical team. Participants were followed up for 90 days. Primary outcomes were willingness of participants to be randomised and feasibility of trial procedures. RESULTS: In total, 172 patients were screened, 84/172 (48.8%) were eligible, and 31/84 (36.9%) were randomised. Patients were assigned to either the short-course arm (18/31, 58.0%) or the long-course arm (13/31, 41.9%). One patient in the short-course arm withdrew after randomisation. In the short-course arm, 4/17 (23.5%) were treated for a cIAI relapse vs 0/13 (0.0%) relapses in the long-course arm. Protocol violations included deviations from protocol-assigned antibiotic duration and interruptions to antibiotic therapy. CONCLUSIONS: This feasibility study identified opportunities to increase recruitment in a full trial. This study demonstrates completion of a randomised controlled trial to further evaluate if the optimum antibiotic duration for cIAIs is feasible. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03265834.

Measuring outcomes in complicated intra-abdominal infections.

PURPOSE OF REVIEW: Complicated intra-abdominal infections (cIAIs) are associated with significant morbidity and mortality. Clinical trials should help guide and improve the management of cIAIs. However, inappropriate selection or measurement of outcomes in cIAIs clinical trials can lead to misleading results on the effectiveness of interventions. This review aims to describe how outcomes are reported in randomized controlled trials evaluating antibiotic treatment for cIAIs and discuss how outcome reporting may be improved. RECENT FINDINGS: Commonly used primary outcomes are treatment success or failure, and these outcomes are endorsed by regulatory bodies. However, a consensus objective definition of either is not available and current measures are prone to bias. Variation exists in timing of outcome evaluation and analysis populations, which can lead to further bias. Use of core outcome sets can help standardize outcome reporting. SUMMARY: Inconsistency in outcome selection and reporting can lead to misleading results and impedes meta-analysis of data. Further progress, engaging clinical trialists, regulatory authorities, clinicians and patients is required to achieve consensus on which outcomes should be reported and how and when to measure them.

Molecular versus culture-based testing for gastrointestinal infection.

PURPOSE OF REVIEW: Molecular-based diagnostic methods for the detection of gastrointestinal pathogens are becoming increasingly commonplace in microbiology laboratories. This review aims to summarize recent developments in this field and discuss the clinical application and limitations of implementing these techniques. RECENT FINDINGS: Recent evaluations of multiplex PCR assays show increased sensitivity whenever compared with standard microbiological culture-based methods. In addition to shorter turnaround times, assays can detect an increased repertoire of pathogens from a single specimen and provide useful information for infection prevention and control practices. There are many limitations, however, associated with their use, including clinical interpretation of results and lack of concordance between different test panels. Newer technologies, such as metagenomic analysis, can provide comprehensive information useful to both patient management and public health surveillance. SUMMARY: Molecular techniques are capable of replacing culture in the diagnosis of gastrointestinal infections. Whether all positive results, however, represent true infection is still debateable, as is the clinical significance of identifying more than one pathogen. As it currently stands, microbiological culture remains vital for public health surveillance, monitoring antibiotic resistance and managing outbreaks.