Infections diagnosed in children and young people screened for malaria in UK emergency departments: a retrospective multi-centre study.

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.

Urine tenofovir and dried blood spot tenofovir diphosphate concentrations and viraemia in people taking efavirenz and dolutegravir-based antiretroviral therapy.

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.

Diagnostic accuracy of a point-of-care antigen test for SARS-CoV-2 and influenza in a primary care population (RAPTOR-C19).

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.

Evaluation of the diagnostic accuracy of two point-of-care tests for COVID-19 when used in symptomatic patients in community settings in the UK primary care COVID diagnostic accuracy platform trial (RAPTOR-C19).

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.

A Diagnostic Accuracy Study to Evaluate Standard Rapid Diagnostic Test (RDT) Alone to Safely Rule Out Imported Malaria in Children Presenting to UK Emergency Departments.

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 Impact of Point-of-Care Blood C-Reactive Protein Testing on Prescribing Antibiotics in Out-of-Hours Primary Care: A Mixed Methods Evaluation.

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.

The comparative interrupted time series design for assessment of diagnostic impact: methodological considerations and an example using point-of-care C-reactive protein testing.

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.

Rapid community point-of-care testing for COVID-19 (RAPTOR-C19): protocol for a platform diagnostic study.

BACKGROUND: The aim of RApid community Point-of-care Testing fOR COVID-19 (RAPTOR-C19) is to assess the diagnostic accuracy of multiple current and emerging point-of-care tests (POCTs) for active and past SARS-CoV2 infection in the community setting. RAPTOR-C19 will provide the community testbed to the COVID-19 National DiagnOstic Research and Evaluation Platform (CONDOR). METHODS: RAPTOR-C19 incorporates a series of prospective observational parallel diagnostic accuracy studies of SARS-CoV2 POCTs against laboratory and composite reference standards in patients with suspected current or past SARS-CoV2 infection attending community settings. Adults and children with suspected current SARS-CoV2 infection who are having an oropharyngeal/nasopharyngeal (OP/NP) swab for laboratory SARS-CoV2 reverse transcriptase Digital/Real-Time Polymerase Chain Reaction (d/rRT-PCR) as part of clinical care or community-based testing will be invited to participate. Adults (≥ 16 years) with suspected past symptomatic infection will also be recruited. Asymptomatic individuals will not be eligible. At the baseline visit, all participants will be asked to submit samples for at least one candidate point-of-care test (POCT) being evaluated (index test/s) as well as an OP/NP swab for laboratory SARS-CoV2 RT-PCR performed by Public Health England (PHE) (reference standard for current infection). Adults will also be asked for a blood sample for laboratory SARS-CoV-2 antibody testing by PHE (reference standard for past infection), where feasible adults will be invited to attend a second visit at 28 days for repeat antibody testing. Additional study data (e.g. demographics, symptoms, observations, household contacts) will be captured electronically. Sensitivity, specificity, positive, and negative predictive values for each POCT will be calculated with exact 95% confidence intervals when compared to the reference standard. POCTs will also be compared to composite reference standards constructed using paired antibody test results, patient reported outcomes, linked electronic health records for outcomes related to COVID-19 such as hospitalisation or death, and other test results. DISCUSSION: High-performing POCTs for community use could be transformational. Real-time results could lead to personal and public health impacts such as reducing onward household transmission of SARS-CoV2 infection, improving surveillance of health and social care staff, contributing to accurate prevalence estimates, and understanding of SARS-CoV2 transmission dynamics in the population. In contrast, poorly performing POCTs could have negative effects, so it is necessary to undertake community-based diagnostic accuracy evaluations before rolling these out. TRIAL REGISTRATION: ISRCTN, ISRCTN14226970.

Lack of influence of dexmedetomidine on rat glomus cell response to hypoxia, and on mouse acute hypoxic ventilatory response.

Background and Aims: There is a lack of basic science data on the effect of dexmedetomidine on the hypoxic chemosensory reflex with both depression and stimulation suggested. The primary aim of this study was to assess if dexmedetomidine inhibited the cellular response to hypoxia in rat carotid body glomus cells, the cells of the organs mediating acute hypoxic ventilatory response (AHVR). Additionally, we used a small sample of mice to assess if there was any large influence of subsedative doses of dexmedetomidine on AHVR. Material and Methods: In the primary study, glomus cells isolated from neonatal rats were used to study the effect of 0.1 nM (n = 9) and 1 nM (n = 13) dexmedetomidine on hypoxia-elicited intracellular calcium [Ca2%]i influx using ratiometric fluorimetry. Secondarily, whole animal unrestrained plethysmography was used to study AHVR in a total of 8 age-matched C57BL6 mice, divided on successive days into two groups of four mice randomly assigned to receive sub-sedative doses of 5, 50, or 500 µg.kg-1 dexmedetomidine versus control in a crossover study design (total n = 12 exposures to drug with n = 12 controls). Results: There was no effect of dexmedetomidine on the hypoxia-elicited increase in [Ca2%]i in glomus cells (a mean ± SEM increase of 95 ± 32 nM from baseline with control hypoxia, 124 ± 41 nM with 0.1 nM dexmedetomidine; P = 0.514). In intact mice, dexmedetomidine had no effect on baseline ventilation during air-breathing (4.01 ± 0.3 ml.g-1.min-1 in control and 2.99 ± 0.5 ml.g-1.min-1 with 500 µg.kg-1 dexmedetomidine, the highest dose; P = 0.081) or on AHVR (136 ± 19% increase from baseline in control, 152 ± 46% with 500 µg.kg-1 dexmedetomidine, the highest dose; P = 0.536). Conclusion: Dexmedetomidine had no effect on the cellular responses to hypoxia. We conclude that it unlikely acts via inhibition of oxygen sensing at the glomus cell. The respiratory chemoreflex effects of this drug remain an open question. In our small sample of intact mice, hypoxic chemoreflex responses and basal breathing were preserved.

At what times during infection is SARS-CoV-2 detectable and no longer detectable using RT-PCR-based tests? A systematic review of individual participant data.

BACKGROUND: Tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral ribonucleic acid (RNA) using reverse transcription polymerase chain reaction (RT-PCR) are pivotal to detecting current coronavirus disease (COVID-19) and duration of detectable virus indicating potential for infectivity. METHODS: We conducted an individual participant data (IPD) systematic review of longitudinal studies of RT-PCR test results in symptomatic SARS-CoV-2. We searched PubMed, LitCOVID, medRxiv, and COVID-19 Living Evidence databases. We assessed risk of bias using a QUADAS-2 adaptation. Outcomes were the percentage of positive test results by time and the duration of detectable virus, by anatomical sampling sites. RESULTS: Of 5078 studies screened, we included 32 studies with 1023 SARS-CoV-2 infected participants and 1619 test results, from - 6 to 66 days post-symptom onset and hospitalisation. The highest percentage virus detection was from nasopharyngeal sampling between 0 and 4 days post-symptom onset at 89% (95% confidence interval (CI) 83 to 93) dropping to 54% (95% CI 47 to 61) after 10 to 14 days. On average, duration of detectable virus was longer with lower respiratory tract (LRT) sampling than upper respiratory tract (URT). Duration of faecal and respiratory tract virus detection varied greatly within individual participants. In some participants, virus was still detectable at 46 days post-symptom onset. CONCLUSIONS: RT-PCR misses detection of people with SARS-CoV-2 infection; early sampling minimises false negative diagnoses. Beyond 10 days post-symptom onset, lower RT or faecal testing may be preferred sampling sites. The included studies are open to substantial risk of bias, so the positivity rates are probably overestimated.

Competitive Interactions between Halothane and Isoflurane at the Carotid Body and TASK Channels.

BACKGROUND: The degree to which different volatile anesthetics depress carotid body hypoxic response relates to their ability to activate TASK potassium channels. Most commonly, volatile anesthetic pairs act additively at their molecular targets. We examined whether this applied to carotid body TASK channels. METHODS: We studied halothane and isoflurane effects on hypoxia-evoked rise in intracellular calcium (Ca2+i, using the indicator Indo-1) in isolated neonatal rat glomus cells, and TASK single-channel activity (patch clamping) in native glomus cells and HEK293 cell line cells transiently expressing TASK-1. RESULTS: Halothane (5%) depressed glomus cell Ca2+i hypoxic response (mean ± SD, 94 ± 4% depression; P < 0.001 vs. control). Isoflurane (5%) had a less pronounced effect (53 ± 10% depression; P < 0.001 vs. halothane). A mix of 3% isoflurane/1.5% halothane depressed cell Ca2+i response (51 ± 17% depression) to a lesser degree than 1.5% halothane alone (79 ± 15%; P = 0.001), but similar to 3% isoflurane alone (44 ± 22%; P = 0.224), indicating subadditivity. Halothane and isoflurane increased glomus cell TASK-1/TASK-3 activity, but mixes had a lesser effect than that seen with halothane alone: 4% halothane/4% isoflurane yielded channel open probabilities 127 ± 55% above control, versus 226 ± 12% for 4% halothane alone (P = 0.009). Finally, in HEK293 cell line cells, progressively adding isoflurane (1.5 to 5%) to halothane (2.5%) reduced TASK-1 channel activity from 120 ± 38% above control, to 88 ± 48% (P = 0.034). CONCLUSIONS: In all three experimental models, the effects of isoflurane and halothane combinations were quantitatively consistent with the modeling of weak and strong agonists competing at a common receptor on the TASK channel.

Impact of point-of-care panel tests in ambulatory care: a systematic review and meta-analysis.

OBJECTIVES: This article summarises all the available evidence on the impact of introducing blood-based point-of-care panel testing (POCT) in ambulatory care on patient outcomes and healthcare processes. DESIGN: Systematic review and meta-analysis of randomised-controlled trials and before-after studies. DATA SOURCES: Ovid Medline, Embase, Cochrane Database of Systematic Reviews, Cochrane CENTRAL, Database of Abstracts of Reviews and Effects, Science Citation Index from inception to 22 October 2019. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Included studies were based in ambulatory care and compared POCT with laboratory testing. The primary outcome was the time to decision regarding disposition that is, admission/referral termed disposition decision (DD) time. Secondary outcomes included length of stay (LOS) at the ambulatory care unit/practice and mortality. RESULTS: 19 562 patients from nine studies were included in the review, eight of these were randomised-controlled trials, and one was a before-after study. All the studies were based in either emergency departments or the ambulance service; no studies were from primary care settings. General panel tests performed at the POCT resulted in DDs being made 40 min faster (95% CI -42.2 to -36.6, I2=0%) compared with the group receiving usual care, including central laboratory testing. This in turn resulted in a reduction in LOS for patients who were subsequently discharged by 34 min (95% CI -63.7 to -5.16). No significant difference in mortality was reported. DISCUSSION: Although statistical and clinical heterogeneity is evident and only a small number of studies were included in the meta-analysis, our results suggest that POCTs might lead to faster discharge decisions. Future research should be performed in primary care and identify how POCTs can contribute meaningful changes to patient care rather than focusing on healthcare processes. PROSPERO REGISTRATION NUMBER: CRD42016035426.

Pre-analytical error for three point of care venous blood testing platforms in acute ambulatory settings: A mixed methods service evaluation.

INTRODUCTION: Point of care blood testing to aid diagnosis is becoming increasingly common in acute ambulatory settings and enables timely investigation of a range of diagnostic markers. However, this testing allows scope for errors in the pre-analytical phase, which depends on the operator handling and transferring specimens correctly. The extent and nature of these pre-analytical errors in clinical settings has not been widely reported. METHODS: We carried out a convergent parallel mixed-methods service evaluation to investigate pre-analytical errors leading to a machine error reports in a large acute hospital trust in the UK. The quantitative component comprised a retrospective analysis of all recorded error codes from Abbott Point of Care i-STAT 1, i-STAT Alinity and Abbott Rapid Diagnostics Afinion devices to summarise the error frequencies and reasons for error, focusing on those attributable to the operator. The qualitative component included a prospective ethnographic study and a secondary analysis of an existing ethnographic dataset, based in hospital-based ambulatory care and community ambulatory care respectively. RESULTS: The i-STAT had the highest usage (113,266 tests, January 2016-December 2018). As a percentage of all tests attempted, its device-recorded overall error rate was 6.8% (95% confidence interval 6.6% to 6.9%), and in the period when reliable data could be obtained, the operator-attributable error rate was 2.3% (2.2% to 2.4%). Staff identified that the most difficult step was the filling of cartridges, but that this could be improved through practice, with a perception that cartridge wastage through errors was rare. CONCLUSIONS: In the observed settings, the rate of errors attributable to operators of the primary point of care device was less than 1 in 40. In some cases, errors may lead to a small increase in resource use or time required so adequate staff training is necessary to prevent adverse impact on patient care.

Validity and Reliability of Firefighting Simulation Test Performance.

OBJECTIVE: To assess the validity and reliability of a firefighting simulation test (FFST). METHODS: Sixty-nine operational firefighters completed a best-effort FFST on one occasion and 22 participants completed a further FFST. All participants completed a maximal treadmill test to determine cardiorespiratory fitness (VO2max). RESULTS: Time to complete the FFST demonstrated a strong inverse relationship with VO2max (r = -0.73), although the prediction error was high. Reliability of the FFST was high (r = 0.84, P = 0.01), demonstrating a coefficient of variation of 4.5%. CONCLUSIONS: The FFST demonstrated reasonable validity as a surrogate assessment of cardiorespiratory fitness for firefighting. The FFST also demonstrated good reliability. Given the apparent magnitude of the prediction error, the FFST would be best used as a training tool, rather than as a primary means of assessing cardiorespiratory fitness for firefighting.

Is stratification testing for treatment of chronic obstructive pulmonary disease exacerbations cost-effective in primary care? an early cost-utility analysis.

OBJECTIVES: Patients with chronic obstructive pulmonary disease (COPD) who experience acute exacerbations usually require treatment with oral steroids or antibiotics, depending on the etiology of the exacerbation. Current management is based on clinician's assessment and judgement, which lacks diagnostic accuracy and results in overtreatment. A test to guide these decisions in primary care is in development. We developed an early decision model to evaluate the cost-effectiveness of this treatment stratification test in the primary care setting in the United Kingdom. METHODS: A combined decision tree and Markov model was developed of COPD progression and the exacerbation care pathway. Sensitivity analysis was carried out to guide technology development and inform evidence generation requirements. RESULTS: The base case test strategy cost GBP 423 (USD 542) less and resulted in a health gain of 0.15 quality-adjusted life-years per patient compared with not testing. Testing reduced antibiotic prescriptions by 30 percent, potentially lowering the risk of antimicrobial resistance developing. In sensitivity analysis, the result depended on the clinical effects of treating patients according to the test result, as opposed to treating according to clinical judgement alone, for which there is limited evidence. The results were less sensitive to the accuracy of the test. CONCLUSIONS: Testing may be cost-saving in primary care, but this requires robust evidence on whether test-guided treatment is effective. High quality evidence on the clinical utility of testing is required for early modeling of diagnostic tests generally.

Impact of point-of-care C reactive protein in ambulatory care: a systematic review and meta-analysis.

OBJECTIVE: The aim of this review was to collate all available evidence on the impact of point-of-care C reactive protein (CRP) testing on patient-relevant outcomes in children and adults in ambulatory care. DESIGN: This was a systematic review to identify controlled studies assessing the impact of point-of-care CRP in patients presenting to ambulatory care services. Ovid Medline, Embase, Cochrane Database of Systematic Reviews, Cochrane CENTRAL, DARE, Science Citation Index were searched from inception to March 2017. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Controlled studies assessing the impact of point-of-care CRP in patients presenting to ambulatory care services, measuring a change in clinical care, including but not limited to antibiotic prescribing rate, reconsultation, clinical recovery, patient satisfaction, referral and additional tests. No language restrictions were applied. DATA EXTRACTION: Data were extracted on setting, date of study, a description of the intervention and control group, patient characteristics and results. Methodological quality of selected studies and assessment of potential bias was assessed independently by two authors using the Cochrane Risk of Bias tool. RESULTS: 11 randomised controlled trials and 8 non-randomised controlled studies met the inclusion criteria, reporting on 16 064 patients. All included studies had a high risk of performance and selection bias. Compared with usual care, point-of-care CRP reduces immediate antibiotic prescribing (pooled risk ratio 0.81; 95% CI 0.71 to 0.92), however, at considerable heterogeneity (I2=72%). This effect increased when guidance on antibiotic prescribing relative to the CRP level was provided (risk ratios of 0.68; 95% CI 0.63 to 0.74 in adults and 0.56; 95% CI 0.33 to 0.95 in children). We found no significant effect of point-of-care CRP testing on patient satisfaction, clinical recovery, reconsultation, further testing and hospital admission. CONCLUSIONS: Performing a point-of-care CRP test in ambulatory care accompanied by clinical guidance on interpretation reduces the immediate antibiotic prescribing in both adults and children. As yet, available evidence does not suggest an effect on other patient outcomes or healthcare processes. PROSPERO REGISTRATION NUMBER: CRD42016035426; Results.

Influence of propofol on isolated neonatal rat carotid body glomus cell response to hypoxia and hypercapnia.

In humans the intravenous anaesthetic propofol depresses ventilatory responses to hypoxia and CO2. Animal studies suggest that this may in part be due to inhibition of synaptic transmission between chemoreceptor glomus cells of the carotid body and the afferent carotid sinus nerve. It is however unknown if propofol can also act directly on the glomus cell. Here we report that propofol can indeed inhibit intracellular Ca2+ responses to hypoxia and hypercapnia in isolated rat glomus cells. Neither this propofol effect, nor the glomus cell response to hypoxia in the absence of propofol, were influenced by GABA receptor activation (using GABA, muscimol and baclofen) or inhibition (using bicuculline and 5-aminovaleric acid). Suggesting that these effects of propofol are not mediated through GABA receptors. Propofol inhibited calcium responses to nicotine in glomus cells but the nicotinic antagonists vecuronium and methyllycaconitine did not inhibit calcium responses to hypoxia. TASK channel activity was not altered by propofol. The glomus cell Ca2+ response to depolarisation with 30 mM K+ was however modestly inhibited by propofol. In summary we conclude that propofol does have a direct effect upon hypoxia signalling in isolated type-1 cells and that this may be partially due to its ability to inhibit voltage gated Ca2+v channels. We also note that propofol has the capacity to supress glomus cell excitation via nicotinic receptors and may therefore also interfere with paracrine/autocrine cholinergic signalling in the intact organ. The effects of propofol on chemoreceptor function are however clearly complex and require further investigation.

A1899, PK-THPP, ML365, and Doxapram inhibit endogenous TASK channels and excite calcium signaling in carotid body type-1 cells.

Sensing of hypoxia and acidosis in arterial chemoreceptors is thought to be mediated through the inhibition of TASK and possibly other (e.g., BKCa ) potassium channels which leads to membrane depolarization, voltage-gated Ca-entry, and neurosecretion. Here, we investigate the effects of pharmacological inhibitors on TASK channel activity and [Ca2+ ]i -signaling in isolated neonatal rat type-1 cells. PK-THPP inhibited TASK channel activity in cell attached patches by up to 90% (at 400 nmol/L). A1899 inhibited TASK channel activity by 35% at 400 nmol/L. PK-THPP, A1899 and Ml 365 all evoked a rapid increase in type-1 cell [Ca2+ ]i . These [Ca2+ ]i responses were abolished in Ca2+ -free solution and greatly attenuated by Ni2+ (2 mM) suggesting that depolarization and voltage-gated Ca2+ -entry mediated the rise in [Ca2+ ]i. Doxapram (50 µmol/L), a respiratory stimulant, also inhibited type-1 cell TASK channel activity and increased [Ca2+ ]i. . We also tested the effects of combined inhibition of BKCa and TASK channels. TEA (5 mmol/L) slightly increased [Ca2+ ]i in the presence of PK-THPP and A1899. Paxilline (300 nM) and iberiotoxin (50 nmol/L) also slightly increased [Ca2+ ]i in the presence of A1899 but not in the presence of PK-THPP. In general [Ca2+ ]i responses to TASK inhibitors, alone or in combination with BKCa inhibitors, were smaller than the [Ca2+ ]i responses evoked by hypoxia. These data confirm that TASK channel inhibition is capable of evoking membrane depolarization and robust voltage-gated Ca2+ -entry but suggest that this, even with concomitant inhibition of BKCa channels, may be insufficient to account fully for the [Ca2+ ]i -response to hypoxia.

Frequencies and patterns of laboratory test requests from general practice: a service evaluation to inform point-of-care testing.

AIMS: The demand for test requests from general practice to laboratory services remains high. Tests performed at the point of care could reduce turnaround time and speed up clinical decision making. Replicating laboratory testing in the community would require panels of tests to be performed simultaneously, which is now approaching technological feasibility. We assessed frequencies and combinations of test requests from community settings to inform the potential future development of multiplex point-of-care panels. METHODS: We assessed all laboratory test requests made from general practice in Oxfordshire, UK, from January 2014 to March 2017. We summarised test request frequency overall and in combination, using heatmaps and hierarchical cluster analysis. Results are also presented by age/sex subgroups. We further assessed patterns of tests requested within 7 and 14 days after an initial test request. RESULTS: 11 763 473 test requests were made for 413 073 individuals (28% age >65). Of more than 500 test types, 62 were requested at least 5000 times, most commonly renal function tests (approximately 296 000/year), full blood count (278 000/year) and liver function tests (237 000/year). Cluster analysis additionally identified a clear grouping of tests commonly used to investigate anaemia. Follow-up test frequency was much lower than the frequency of multiple tests ordered at initial presentation. CONCLUSIONS: The current high volume of single and combination test requests highlights an opportunity for reliable multiplex point-of-care panels to cover a core set of frequently requested tests. The impact on test use of introducing such panels to general practice requires additional research.

Physical and Physiological Performance Determinants of a Firefighting Simulation Test.

OBJECTIVE: To examine determinants of firefighting simulation test performance. METHODS: Sixty-eight (63 male; 5 female) firefighters completed a firefighting simulation (eg, equipment carry, casualty evacuation) previously validated to test occupational fitness among UK firefighters. Multiple linear regression methods were used to determine physiological and physical attributes that best predicted completion time. RESULTS: Mean (±SD) time taken to complete the simulation was 610 (±79) seconds. The prediction model combining absolute cardiorespiratory capacity (L min) and fat mass explained the greatest variance in performance and elicited the least random error (R = 0.765, R = 0.585, standard error of the estimate [SEE]: ±52 seconds). Higher fitness and lower fat mass were associated with faster performance. CONCLUSIONS: Firefighter simulation test performance is associated with absolute cardiorespiratory fitness and fat mass. Fitter and leaner individuals perform the task more quickly. Work-based interventions should enhance these attributes to promote safe and effective operational performance.