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Introduction: Acute uncomplicated urinary tract infection (UTI) is a common condition with potentially serious sequelae that is mostly diagnosed and managed in primary care settings. Around half of all women have a UTI in their lifetime, and a quarter experience an infection caused by organisms resistant to more than one antibiotic. Reducing inappropriate prescribing of antibiotics is a core tenet of antimicrobial stewardship. However, current diagnostics for UTI are unfit for purpose in acute (highest prescribing) settings, being too slow to inform the required immediate decision-making and often confounded by sample contamination.Rapid point-of-care diagnostic tests (POCTs) that facilitate timely decision-making are potential solutions to this problem. Several such tests have reached advanced stages of technology readiness, but their diagnostic performance has not been evaluated in primary care with clinical users. To progress novel tests towards implementation, a diagnostic field study is required, to allow for parallel and sequential evaluation of multiple tests in a primary care population., Methods and Analysis: We will recruit participants assigned female at birth from primary care clinics in England who contact their clinic with symptoms of acute uncomplicated UTI. Eligible participants will complete a short questionnaire to capture symptoms and symptom severity and will provide a urine sample. Samples will be split and initially tested using novel index tests (POCTs) and conventional urinalysis 'dipstick' at the primary care clinic. The second part of the sample will be processed at a National Health Service-based reference laboratory using a modified reference standard including microscopy, microbiological culture, pathogen speciation and antimicrobial susceptibility testing. The UTI reference standard culture, although based on the national methods, is modified to provide accurate bacterial counts, better to define a microbiological diagnosis of UTI. Susceptibility testing will be performed using 'gold-standard' methods, not usually performed in diagnostic laboratories. The primary outcome will be the diagnostic performance (sensitivity, specificity, positive and negative predictive values) of POCTs for detection of UTI and antimicrobial susceptibility for POCTs that include antimicrobial susceptibility testing. Secondary outcomes will include the symptom profile of patients presenting with uncomplicated UTI, a theoretical determination of how use of POCT results might change prescribing, an understanding of POCT failure rate and qualitative capture of the experiences of those using the POCT to deliver the study in primary care clinics., Ethics and Dissemination: Ethical approval was received from the London Central Research Ethics Committee (23/LO/0371) and the UK Health Research Authority. We will publish the findings of The plaTform fOr Urinary tract infection diagnostiC evAluatioN evaluations in peer-reviewed medical journals and more broadly following a dissemination plan formulated by a communications specialist in consultation with patients and the public., Trial Registration Number: ISRCTN80937472., Competing Interests: Competing interests: It is the intention that technology (POCT), associated consumables and training will be provided free of charge to the study under contractual arrangements that preserve the team’s unrestricted rights to publish results. CCB is a member of the Editorial Advisory Board of BMJ Open., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY. Published by BMJ Group.)

Introduction: To perform a systematic review of the diagnostic accuracy of point-of-care lung ultrasound, compared to chest radiography, in children and young people (0-21 years) who present to ambulatory settings with suspected community-acquired pneumonia., Methods: Registration: Prospero June 2021 CRD42021260552. Electronic searching performed on Medline, Embase, CINAHL and Science Citation Index from inception to 20 June 2023. Two researchers independently screened titles, abstracts, and full texts for study selection. Risk of bias was assessed using the Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS-2) tool. Meta-analysis of included studies., Results: The six studies included in this systematic review described point-of-care lung ultrasound performed primarily by paediatric emergency medicine clinicians on a total of 1099 paediatric patients, with a reference standard of chest radiography or chest radiography with clinical findings. The majority of included studies lacked clarity on training for the index test with potential bias around flow and timing of testing. Meta-analysis of the combined results of the included six studies calculated a pooled sensitivity of 90.9% (95% CI [85.5%, 94.4%]) and pooled specificity of 80.7% (95% CI [63.6%, 91.0%])., Conclusions: Point-of-care lung ultrasound has high sensitivity but lower specificity to diagnose acute pneumonia in children. Further research is needed which overcomes issues around training in point-of-care lung ultrasound, study design and reliability of the reference test (chest radiography) to better evidence the role of point-of-care lung ultrasound in diagnosing pneumonia in children in ambulatory and resource-limited settings., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s) 2024.)

Background: Data on imported infections in children and young people (CYP) are sparse., Aims: To describe imported infections in CYP arriving from malaria-endemic areas and presenting to UK emergency departments (ED) who were screened for malaria., Methods: This is a retrospective, multi-centre, observational study nested in a diagnostic accuracy study for malaria rapid diagnostic tests. Any CYP < 16 years presenting to a participating ED with a history of fever and travel to a malaria-endemic area between 1 January 2016 and 31 December 2017 and who had a malaria screen as a part of standard care were included. Geographical risk was calculated for the most common tropical infections., Results: Of the 1414 CYP screened for malaria, 44.0% ( n  = 622) arrived from South Asia and 33.3% ( n  = 471) from sub-Saharan Africa. Half (50.0%) had infections common in both tropical and non-tropical settings such as viral upper respiratory tract infection (URTI); 21.0% of infections were coded as tropical if gastro-enteritis is included, with a total of 4.2% (60) cases of malaria. CYP diagnosed with malaria were 7.44 times more likely to have arrived from sub-Saharan Africa than from South Asia (OR 7.44, 3.78-16.41)., Conclusion: A fifth of CYP presenting to participating UK EDs with fever and a history of travel to a malaria-endemic area and who were screened for malaria had a tropical infection if diarrhoea is included. A third of CYP had no diagnosis. CYP arriving from sub-Saharan Africa had the greatest risk of malaria. Abbreviations: CYP: children and young people; ED: emergency department; PERUKI: Paediatric Emergency Research in the UK and Ireland; RDT: rapid diagnostic test; VFR: visiting friends and relatives.

Objective: We aimed to determine whether urine tenofovir (TFV) and dried blood spot (DBS) tenofovir diphosphate (TFV-DP) concentrations are associated with concurrent HIV viraemia., Design: Cross-sectional study among people with HIV (PWH) receiving tenofovir disoproxil fumarate (TDF)-based antiretroviral therapy (ART)., Methods: We used dual tandem liquid chromatography and mass spectrometry to measure urine TFV and DBS TFV-DP concentrations, and evaluated their associations with concurrent viraemia at least 1000 copies/ml using logistic regression models. In exploratory analyses, we used receiver operating curves (ROCs) to estimate optimal urine TFV and DBS TFV-DP thresholds to predict concurrent viraemia., Results: Among 124 participants, 68 (54.8%) were women, median age was 39 years [interquartile range (IQR) 34-45] and 74 (59.7%) were receiving efavirenz versus 50 (40.3%) receiving dolutegravir. Higher concentrations of urine TFV [1000 ng/ml increase, odds ratio (OR) 0.97 95% CI 0.94-0.99, P  = 0.005] and DBS TFV-DP (100 fmol/punch increase, OR 0.76, 95% CI 0.67-0.86, P  < 0.001) were associated with lower odds of viraemia. There was evidence that these associations were stronger among people receiving dolutegravir than among people receiving efavirenz (urine TFV, P  = 0.072; DBS TFV-DP, P  = 0.003). Nagelkerke pseudo- R2 for the DBS TFV-DP models was higher for the urine TFV models, demonstrating a stronger relationship between DBS TFV-DP and viraemia. Among people receiving dolutegravir, a DBS TFV-DP concentration of 483 fmol/punch had 88% sensitivity and 85% specificity to predict concurrent viraemia ≥1000 copies/ml., Conclusion: Among PWH receiving TDF-based ART, urine TFV concentrations, and in particular DBS TFV-DP concentrations, were strongly associated with concurrent viraemia, especially among people receiving dolutegravir., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Limited evidence exists for the diagnostic performance of point-of-care tests for SARS-CoV-2 and influenza in community healthcare. We carried out a prospective diagnostic accuracy study of the LumiraDx™ SARS-CoV-2 and influenza A or B assay in primary care., Methods: Total of 913 adults and children with symptoms of current SARS-CoV-2 infection were recruited from 18 UK primary care practices during a period when Omicron was the predominant COVID variant of concern (June 2022 to December 2022). Trained health care staff performed the index test, with diagnostic accuracy parameters estimated for SARS-CoV-2 and influenza against real-time reverse-transcription PCR (rtRT-PCR)., Results: 151/887 participants were SARS-CoV-2 rtRT-PCR positive, 109 positive for Influenza A, 6 for Influenza B. Index test sensitivity for SARS-CoV-2 was 80.8% (122 of the 151, 95% CI, 73.6-86.7%) and specificity 98.9% (728 of the 736, 95% CI, 97.9-99.5%). For influenza A, sensitivity was 61.5% (67 of the 109, 95% CI, 51.7-70.6%) and specificity 99.4% (771 of the 776, 95% CI, 98.5-99.8%). Sensitivity to detect SARS-CoV-2 and influenza dropped sharply at rtRT-PCR cycle thresholds (Ct) > 30., Discussions: The LumiraDx™ SARS-CoV-2 and influenza A/B assay had moderate sensitivity for SARS-CoV-2 in symptomatic patients in primary care, with lower performance with high rtRT-PCR Ct. Negative results in this patient group cannot definitively rule out SARS-CoV-2 or influenza., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Cellulitis is often treated with antibiotics for longer than recommended by guidelines. Prolonged therapy may reduce recurrence in certain patients, but it is not known which patients are at greatest risk. Our objective was to develop and temporally validate a risk prediction score to identify patients attending hospital with cellulitis at highest risk of recurrence., Methods: We included UK adult patients with cellulitis attending hospital in an electronic health records (EHR) study to identify demographic, comorbid, physiological, and laboratory factors predicting recurrence (before death) within 90 days, using multivariable logistic regression with backwards elimination in complete cases. A points-based risk score integerised model coefficients for selected predictors. Performance was assessed using the C-index in development and temporal validation samples., Results: The final model included 4938 patients treated for median 8 days (IQR 6-11); 8.8% (n = 436) experienced hospitalisation-associated recurrence. A risk score using eight variables (age, heart rate, urea, platelets, albumin, previous cellulitis, venous insufficiency, and liver disease) ranged from 0-15, with C-index = 0.65 (95%CI: 0.63-0.68). Categorising as low (score 0-1), medium (2-5) and high (6-15) risk, recurrence increased fourfold; 3.2% (95%CI: 2.3-4.4%), 9.7% (8.7-10.8%), and 16.6% (13.3-20.4%). Performance was maintained in the validation sample (C-index = 0.63 (95%CI: 0.58-0.67)). Among patients at high risk, four distinct clinical phenotypes were identified using hierarchical clustering 1) young, acutely unwell with liver disease; 2) comorbid with previous cellulitis and venous insufficiency; 3) chronic renal disease with severe renal impairment; and 4) acute severe illness, with substantial inflammatory responses., Conclusions: Risk of cellulitis recurrence varies markedly according to individual patient factors captured in the Baseline Recurrence Risk in Cellulitis (BRRISC) score. Further work is needed to optimise the score, considering baseline and treatment response variables not captured in EHR data, and establish the utility of risk-based approaches to guide optimal antibiotic duration., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Objectives: Given the lack of accurate rapid diagnostics for urinary tract infection (UTI) in women, many countries have developed guidelines aiming to support appropriate antibiotic prescribing, but some guidelines have not been validated. We performed a diagnostic accuracy validation study of two guidelines: Public Health England (GW-1263) and Scottish Intercollegiate Guidelines Network (SIGN160)., Methods: We used data from women with symptoms suggestive of uncomplicated UTI from a randomized controlled trial comparing urine collection devices. Symptom information was recorded via baseline questionnaire and primary care assessment. Women provided urine samples for dipstick testing and culture. We calculated the number within each risk category of diagnostic flowcharts who had positive/mixed growth/no significant growth urine culture. Results were presented as positive/negative predictive values, with 95% CIs., Results: Of women aged under 65 years, 311/509 (61.1%, 95% CI 56.7%-65.3%) classified to the highest risk category (recommended to consider immediate antibiotic prescribing) and 80/199 (40.2%, 95% CI 33.4%-47.4%) classified to the lowest risk category (recommended to reassure that UTI is less likely) by the GW-1263 guideline (n = 810) had positive culture. For the SIGN160 guideline (n = 814), the proportion with positive culture ranged from 60/82 (73.2%, 95% CI 62.1%-82.1%) in those for whom immediate treatment was indicated to 33/76 (43.4%, 95% CI 32.3%-55.3%) in those recommended a self-care/waiting strategy., Conclusions: Clinicians should be aware of the potential for diagnostic error when using diagnostic guidelines for managing uncomplicated UTI and making antimicrobial prescribing decisions. Infection cannot be excluded on the basis of symptoms and dipstick testing alone., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background and Objective: Point-of-care lateral flow device antigen testing has been used extensively to identify individuals with active SARS-CoV-2 infection in the community. This study aimed to evaluate the diagnostic accuracy of two point-of-care tests (POCTs) for SARS-CoV-2 in routine community care., Methods: Adults and children with symptoms consistent with suspected current COVID-19 infection were prospectively recruited from 19 UK general practices and two COVID-19 testing centres between October 2020 and October 2021. Participants were tested by trained healthcare workers using at least one of two index POCTs (Roche-branded SD Biosensor Standard™ Q SARS-CoV-2 Rapid Antigen Test and/or BD Veritor™ System for Rapid Detection of SARS-CoV-2). The reference standard was laboratory triplex reverse transcription quantitative PCR (RT-PCR) using a combined nasal/oropharyngeal swab. Diagnostic accuracy parameters were estimated, with 95% confidence intervals (CIs), overall, in relation to RT-PCR cycle threshold and in pre-specified subgroups., Results: Of 663 participants included in the primary analysis, 39.2% (260/663, 95% CI 35.5% to 43.0%) had a positive RT-PCR result. The SD Biosensor POCT had sensitivity 84.0% (178/212, 78.3% to 88.6%) and specificity 98.5% (328/333, 96.5% to 99.5%), and the BD Veritor POCT had sensitivity 76.5% (127/166, 69.3% to 82.7%) and specificity 98.8% (249/252, 96.6% to 99.8%) compared with RT-PCR. Sensitivity of both devices dropped substantially at cycle thresholds ≥30 and in participants more than 7 days after onset of symptoms., Conclusions: Both POCTs assessed exceed the Medicines and Healthcare products Regulatory Agency target product profile's minimum acceptable specificity of 95%. Confidence intervals for both tests include the minimum acceptable sensitivity of 80%. In symptomatic patients, negative results on these two POCTs do not preclude the possibility of infection. Tests should not be expected to reliably detect disease more than a week after symptom onset, when viral load may be reduced., Registration: ISRCTN142269., Competing Interests: We have read the journal’s policy and the authors of this manuscript have the following competing interests: The authorship declares funding support for this study from the University of Oxford Medical Sciences Division Benefactors Urgent COVID-19 Fund, the National Institute for Health and Care (NIHR) School of Primary Care Research, and Urgent Public Health funding for the CONDOR Platform from the NIHR and Asthma+Lung UK. The RAPTOR-C19 study team received analysers and assays free of charge from Becton Dickinson for evaluation in this study. GNH declares funding from the National Institute for Health and Care Research (NIHR) paid to the University of Oxford. KD declares grant funding from Alere Inc and Cepheid Inc paid to her institution for unrelated research. TRF declares NIHR support from the NIHR Community Healthcare MIC for diagnostic evaluation research. AJW declares grant funding received by the University of Oxford through a Wellcome Trust Enriching Engagement grant which has supported unrelated patient participation work carried out by the Royal College of General Practitioners Research Surveillance Centre (based at the University of Oxford) for surveillance work. GE declares funding support from the NIHR Community Healthcare MIC recieved by the University of Oxford. AM declares the support of a Wellcome Trust Doctoral Research Fellowship and an NIHR In-practice Fellowship unrelated to this research. PJT declares support from the NIHR Community Healthcare MIC for diagnostic evaluation research. PJT has provided expert support to the Longitude Prize AMR competition administration which is unrelated to this project and for which the University of Oxford received an honorarium. RB declares grant funding for this project from the NIHR and Asthma+Lung UK, with additional funding from the Department of Health and Social Care paid to his host institution. RB declares grants from Siemens Healthineers, Abbott Point-of-Care and Ancon, all paid to his institution for unrelated research. He declares consulting fees received by his institution from Roche, Siemens, Aptamer Group, LumiraDx, Beckman Coulter and Radiometer, with personal fees received from Psyros Diagnostics. RB has received support for attending meetings / travel from Roche and EMCREG International. RB has participated on data safety monitoring boards or advisory boards for the unrelated FORCE Trial, REWIRE Trial, TARGET-CTA, and Magnetocardiography study (MAGNETIC - sponsored by Creavo). RB is the Deputy National Specialty Lead for Trauma & Emergency Care, National Institute for Health and Care Research Clinical Research Network. RB declares receipt of donated reagents for research not detailed in this paper from Roche, LumiraDx, BD, iXensor, Abbott Point-of-Care, Randox, Avacta, Menarini, loan of analysers from Randox and Menarini, and assays run free of charge for research purposes by Chronomics, My110, and Ancon. JJL declares funding from an NIHR Doctoral Research Fellowship which is unrelated to this research. LM declares support from the NIHR Community Healthcare MIC and other NIHR grants to the University of Oxford in support of this work. EL declares unrelated project funding received by the UKHSA Vaccine Evaluation Unit for contract research from GSK, Pfizer and Sanofi. MZ declares her unpaid activities as the Chair of the charitable organisation ISIRV and her membership of the UK SAGE, NERVTAG and JCVI groups. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Nicholson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Microscopy is the gold standard for malaria diagnosis but is dependent on trained personnel. Rapid diagnostic tests (RDTs) form the mainstay of diagnosis in endemic areas without access to high-quality microscopy. We aimed to evaluate whether RDT alone could rule out imported malaria in children presenting to UK emergency departments (EDs)., Methods: UK-based, multi-center, retrospective, diagnostic accuracy study. Included: any child <16 years presenting to ED with history of fever and travel to a malaria-endemic country, between 01/01/2016 and 31/12/2017. Diagnosis: microscopy for malarial parasites (clinical reference standard) and RDT (index test). UK Health Research Authority approval: 20/HRA/1341., Results: There were 47 cases of malaria out of 1,414 eligible cases (prevalence 3.3%) in a cohort of children whose median age was 4 years (IQR 2-9), of whom 43% were female. Cases of Plasmodium falciparum totaled 36 (77%, prevalence 2.5%). The sensitivity of RDT alone to detect malaria infection due to any Plasmodium species was 93.6% (95% CI 82.5-98.7%), specificity 99.4% (95% CI 98.9-99.7%), positive predictive value 84.6% (95% CI 71.9-93.1%) and negative predictive value 99.8% (95% CI 99.4-100.0%). Sensitivity of RDT to detect P. falciparum infection was 100% (90.3-100%), specificity 98.8% (98.1-99.3%), positive predictive value 69.2% (54.9-81.2%, n = 46/52) and negative predictive value 100% (99.7-100%, n = 1,362/1,362)., Conclusions: RDTs were 100% sensitive in detecting P. falciparum malaria. However, lower sensitivity for other malaria species and the rise of pfhrp2 and pfhrp3 (pfhrp2/3) gene deletions in the P. falciparum parasite mandate the continued use of microscopy for diagnosing malaria., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society.)

Improving prescribing antibiotics appropriately for respiratory infections in primary care is an antimicrobial stewardship priority. There is limited evidence to support interventions to reduce prescribing antibiotics in out-of-hours (OOH) primary care. Herein, we report a service innovation where point-of-care C-Reactive Protein (CRP) machines were introduced to three out-of-hours primary care clinical bases in England from August 2018-December 2019, which were compared with four control bases that did not have point-of-care CRP testing. We undertook a mixed-method evaluation, including a comparative interrupted time series analysis to compare monthly antibiotic prescription rates between bases with CRP machines and those without, an analysis of the number of and reasons for the tests performed, and qualitative interviews with clinicians. Antibiotic prescription rates declined during follow-up, but with no clear difference between the two groups of out-of-hours practices. A single base contributed 217 of the 248 CRP tests performed. Clinicians reported that the tests supported decision making and communication about not prescribing antibiotics, where having 'objective' numbers were helpful in navigating non-prescribing decisions and highlighted the challenges of training a fluctuant staff group and practical concerns about using the CRP machine. Service improvements to reduce prescribing antibiotics in out-of-hours primary care need to be developed with an understanding of the needs and context of this service.

Background: In diagnostic evaluation, it is necessary to assess the clinical impact of a new diagnostic as well as its diagnostic accuracy. The comparative interrupted time series design has been proposed as a quasi-experimental approach to evaluating interventions. We show how it can be used in the design of a study to evaluate a point-of-care diagnostic test for C-reactive protein in out-of-hours primary care services, to guide antibiotic prescribing among patients presenting with possible respiratory tract infection. This study consisted of a retrospective phase that used routinely collected monthly antibiotic prescribing data from different study sites, and a prospective phase in which antibiotic prescribing rates were monitored after the C-reactive protein diagnostic was introduced at some of the sites., Methods: Of 8 study sites, 3 were assigned to receive the diagnostic and 5 were assigned as controls. We obtained retrospective monthly time series of respiratory tract targeted antibiotic prescriptions at each site. Separate ARIMA models at each site were used these to forecast monthly prescription counts that would be expected in the prospective phase, using simulation to obtain a set of 1-year predictions alongside their standard errors. We show how these forecasts can be combined to test for a change in prescription rates after introduction of the diagnostic and estimate power to detect this change., Results: Fitted time series models at each site were stationary and showed second-order annual seasonality, with a clear December peak in prescriptions, although the timing and extent of the peak varied between sites and between years. Mean one-year predictions of antibiotic prescribing rates based on the retrospective time series analysis differed between sites assigned to receive the diagnostic and those assigned to control. Adjusting for the trend in the retrospective time series at each site removed these differences., Conclusions: Quasi-experimental designs such as comparative interrupted time series can be used in diagnostic evaluation to estimate effect sizes before conducting a full randomised controlled trial or if a randomised trial is infeasible. In multi-site studies, existing retrospective data should be used to adjust for underlying differences between sites to make outcome data from different sites comparable, when possible., (© 2022. The Author(s).)