Systematic Review and Metaanalysis of Pharmacological Interventions in Adult-Onset Still Disease and the Role of Biologic Disease-Modifying Antirheumatic Drugs.

OBJECTIVE: To conduct a systematic review of the effectiveness and safety of pharmacological treatments for adult-onset Still disease (AOSD). METHODS: Six databases, 2 trial registries, and conference abstracts were searched from January 2012 to February 2023 for studies of pharmacological interventions in people with AOSD. Outcomes were rates of remission and response, discontinuation of concurrent treatments, complications of AOSD, and treatment-related adverse events. Risk of bias was assessed with the Cochrane risk of bias tool and the Joanna Briggs Institute tool for case series. RESULTS: Forty-four studies evaluated treatments, including nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids (CS), conventional synthetic disease-modifying antirheumatic drugs (DMARDs), and biologic DMARDs (bDMARDs). For bDMARDs, tocilizumab (TCZ), anakinra (ANK), and canakinumab (CNK) had the most available data. Although 3 randomized controlled trials did not show statistically significant benefits of bDMARDs, metaanalyses showed high rates of complete remission and CS discontinuation. Complete remission was 80% (95% CI 59-92%, I 2 36%), 73% (95% CI 58-84%, I 2 66%), and 77% (95% CI 29-97%, I 2 82%) and CS discontinuation was 57% (95% CI 29-81%, I 2 66%), 47% (95% CI 18-78%, I 2 79%), and 34% (95% CI 6-81%, I 2 59%), respectively, for TCZ, ANK, and CNK. Studies with a higher proportion of patients previously treated with bDMARDs showed a trend toward lower rates of CS discontinuation (P = 0.05). The analyses had high clinical heterogeneity, largely because treatments were prescribed as different lines of therapy. CONCLUSION: Evidence supports TCZ, ANK, and CNK therapy for AOSD. However, the magnitude of effect and comparative effectiveness of treatments is uncertain.

Is the Comparator in Your Diagnostic Cost-Effectiveness Model "Standard of Care"? Recommendations from Literature Reviews and Expert Interviews on How to Identify and Operationalize It.

OBJECTIVES: This research aimed to develop best-practice recommendations for identifying the "standard of care" (SoC) and integrate it when it is the comparator in diagnostic economic models (SoC comparator). METHODS: A multi-methods approach comprising 2 pragmatic literature reviews and 9 expert interviews was used. Experts rated their agreement with draft recommendations based on the authors' analysis of the reviews. These were refined iteratively to produce final recommendations. RESULTS: Fourteen best-practice recommendations are provided. Care pathway mapping (using quantitative, qualitative, or mixed-methods approaches) should be used for identifying the SoC comparator. Guidelines analysis can be integrated with expert opinion to identify pathway variability and discrepancies from clinical practice. For integrating the SoC comparator into the model, recommendations around structure, input sourcing, data aggregation and reporting, input uncertainty, and model variability are presented. For example, modelers should consider that the reference standard is not synonymous with the SoC, and the SoC may not be the only comparator. The comparator limitations should be discussed with clinical experts, but elicitation of its diagnostic accuracy is not recommended. Probabilistic sensitivity analysis is recommended when evaluating the overall input uncertainty, and deterministic sensitivity analysis is useful when there is high model uncertainty or SoC variability. Consensus could not be reached for some topics (eg, the role of real-world data, model averaging, and alternative model structures), but the reported discussions provide points for consideration. CONCLUSIONS: To our knowledge, this is the first guidance to support modelers when identifying and operationalizing the SoC comparator in diagnostic cost-effectiveness models.

Functional and structural brain network correlates of visual hallucinations in Lewy body dementia.

Visual hallucinations are a common feature of Lewy body dementia. Previous studies have shown that visual hallucinations are highly specific in differentiating Lewy body dementia from Alzheimer's disease dementia and Alzheimer-Lewy body mixed pathology cases. Computational models propose that impairment of visual and attentional networks is aetiologically key to the manifestation of visual hallucinations symptomatology. However, there is still a lack of experimental evidence on functional and structural brain network abnormalities associated with visual hallucinations in Lewy body dementia. We used EEG source localization and network based statistics to assess differential topographical patterns in Lewy body dementia between 25 participants with visual hallucinations and 17 participants without hallucinations. Diffusion tensor imaging was used to assess structural connectivity between thalamus, basal forebrain and cortical regions belonging to the functionally affected network component in the hallucinating group, as assessed with network based statistics. The number of white matter streamlines within the cortex and between subcortical and cortical regions was compared between hallucinating and not hallucinating groups and correlated with average EEG source connectivity of the affected subnetwork. Moreover, modular organization of the EEG source network was obtained, compared between groups and tested for correlation with structural connectivity. Network analysis showed that compared to non-hallucinating patients, those with hallucinations feature consistent weakened connectivity within the visual ventral network, and between this network and default mode and ventral attentional networks, but not between or within attentional networks. The occipital lobe was the most functionally disconnected region. Structural analysis yielded significantly affected white matter streamlines connecting the cortical regions to the nucleus basalis of Meynert and the thalamus in hallucinating compared to not hallucinating patients. The number of streamlines in the tract between the basal forebrain and the cortex correlated with cortical functional connectivity in non-hallucinating patients, while a correlation emerged for the white matter streamlines connecting the functionally affected cortical regions in the hallucinating group. This study proposes, for the first time, differential functional networks between hallucinating and not hallucinating Lewy body dementia patients, and provides empirical evidence for existing models of visual hallucinations. Specifically, the outcome of the present study shows that the hallucinating condition is associated with functional network segregation in Lewy body dementia and supports the involvement of the cholinergic system as proposed in the current literature.

Systematic review of studies investigating ventilator associated pneumonia diagnostics in intensive care.

BACKGROUND: Ventilator-associated pneumonia (VAP) is an important diagnosis in critical care. VAP research is complicated by the lack of agreed diagnostic criteria and reference standard test criteria. Our aim was to review which reference standard tests are used to evaluate novel index tests for suspected VAP. METHODS: We conducted a comprehensive search using electronic databases and hand reference checks. The Cochrane Library, MEDLINE, CINHAL, EMBASE, and web of science were searched from 2008 until November 2018. All terms related to VAP diagnostics in the intensive treatment unit were used to conduct the search. We adopted a checklist from the critical appraisal skills programme checklist for diagnostic studies to assess the quality of the included studies. RESULTS: We identified 2441 records, of which 178 were selected for full-text review. Following methodological examination and quality assessment, 44 studies were included in narrative data synthesis. Thirty-two (72.7%) studies utilised a sole microbiological reference standard; the remaining 12 studies utilised a composite reference standard, nine of which included a mandatory microbiological criterion. Histopathological criteria were optional in four studies but mandatory in none. CONCLUSIONS: Nearly all reference standards for VAP used in diagnostic test research required some microbiological confirmation of infection, with BAL culture being the most common reference standard used.

Care pathway and prioritization of rapid testing for COVID-19 in UK hospitals: a qualitative evaluation.

OBJECTIVES: The second wave of the coronavirus pandemic is now established, occurring at a time of winter pressure on acute care in the NHS. This is likely to be more challenging then the first wave for the diagnosis of COVID-19 because of the similar symptomology with other respiratory conditions highly prevalent in winter. This study sought to understand the care pathways in place in UK NHS hospitals during the first wave (March-July 2020) for identification of patients with COVID-19 and to learn lessons to inform optimal testing strategies within the COVID-19 National Diagnostic Research and Evaluation Platform (CONDOR). DESIGN, SETTING & PARTICIPANTS: Sixteen hospital-based clinicians from 12 UK NHS Trusts covering 10 different specialties were interviewed following a semi-structured topic guide. Data were coded soon after the interviews and analysed thematically. RESULTS: We developed a diagrammatic, high-level visualisation of the care pathway describing the main clinical decisions associated with the diagnosis and management of patients with suspected COVID-19. COVID-19 testing influenced infection control considerations more so than treatment decisions. Two main features of service provision influenced the patient management significantly: access to rapid laboratory testing and the number of single occupancy rooms. If time to return of result was greater than 24 h, patients with a presumptive diagnosis would often be cohorted based on clinical suspicion alone. Undetected COVID-19 during this time could therefore lead to an increased risk of viral transmission. CONCLUSIONS: During the winter months, priority for provision of rapid testing at admission should be given to hospitals with limited access to laboratory services and single room availability. Access to rapid testing is essential for urgent decisions related to emergency surgery, maternity services and organ transplant. The pathway and prioritization of need will inform the economic modelling, clinical evaluations, and implementation of new clinical tests in UK.

Weighted network measures reveal differences between dementia types: An EEG study.

The diagnosis of dementia with Lewy bodies (DLB) versus Alzheimer's disease (AD) can be difficult especially early in the disease process. However, one inexpensive and non-invasive biomarker which could help is electroencephalography (EEG). Previous studies have shown that the brain network architecture assessed by EEG is altered in AD patients compared with age-matched healthy control people (HC). However, similar studies in Lewy body diseases, that is, DLB and Parkinson's disease dementia (PDD) are still lacking. In this work, we (a) compared brain network connectivity patterns across conditions, AD, DLB and PDD, in order to infer EEG network biomarkers that differentiate between these conditions, and (b) tested whether opting for weighted matrices led to more reliable results by better preserving the topology of the network. Our results indicate that dementia groups present with reduced connectivity in the EEG α band, whereas DLB shows weaker posterior-anterior patterns within the ß-band and greater network segregation within the θ-band compared with AD. Weighted network measures were more consistent across global thresholding levels, and the network properties reflected reduction in connectivity strength in the dementia groups. In conclusion, ß- and θ-band network measures may be suitable as biomarkers for discriminating DLB from AD, whereas the α-band network is similarly affected in DLB and PDD compared with HC. These variations may reflect the impairment of attentional networks in Parkinsonian diseases such as DLB and PDD.

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.

Assessment of the comparative agreement between chest radiographs and CT scans in intensive care units.

PURPOSE: Chest radiographs in critically ill patients can be difficult to interpret due to technical and clinical factors. We sought to determine the agreement of chest radiographs and CT scans, and the inter-observer variation of chest radiograph interpretation, in intensive care units (ICUs). METHODS: Chest radiographs and corresponding thoracic computerised tomography (CT) scans (as reference standard) were collected from 45 ICU patients. All radiographs were analysed by 20 doctors (radiology consultants, radiology trainees, ICU consultants, ICU trainees) from 4 different centres, blinded to CT results. Specificity/sensitivity were determined for pleural effusion, lobar collapse and consolidation/atelectasis. Separately, Fleiss' kappa for multiple raters was used to determine inter-observer variation for chest radiographs. RESULTS: The median sensitivity and specificity of chest radiographs for detecting abnormalities seen on CTs scans were 43.2% and 85.9% respectively. Diagnostic sensitivity for pleural effusion was significantly higher among radiology consultants but no specialty/experience distinctions were observed for specificity. Median inter-observer kappa coefficient among assessors was 0.295 ("fair"). CONCLUSIONS: Chest radiographs commonly miss important radiological features in critically ill patients. Inter-observer agreement in chest radiograph interpretation is only "fair". Consultant radiologists are least likely to miss thoracic radiological abnormalities. The consequences of misdiagnosis by chest radiographs remain to be determined.

The burden of mitochondrial disease with associated seizures: systematic literature reviews of health-related quality of life, utilities, costs and healthcare resource use data.

BACKGROUND: Mitochondrial disease is a degenerative, progressive, heterogeneous group of genetic disorders affecting children and adults. Mitochondrial disease is associated with morbidity and mortality, with predominantly neurological and neuromuscular symptoms including dystonia, weakness, encephalopathy, developmental delay and seizures. Seizures are one of the most common and severe manifestations of mitochondrial disease. These seizures are typically refractory to common anti-seizure therapies. There are no approved disease-modifying treatments for mitochondrial disease. Our objective was to conduct two systematic literature reviews to identify health-related quality of life (HRQoL), utilities, costs and healthcare resource use data in mitochondrial disease with associated seizures. METHODS: A range of databases and information sources were searched up to July 2022 to identify eligible studies. Search strategies included a range of variant terms for mitochondrial disease and HRQoL, utilities, cost and healthcare resource use outcomes. Two reviewers independently assessed articles against the eligibility criteria; studies were extracted by one reviewer and checked by a second. Risk of bias was assessed for studies reporting HRQoL data. Results were narratively assessed. RESULTS: Seven studies were eligible for the HRQoL and utilities review. The studies used different tools to report data, and despite the variability in methods, HRQoL scores across the studies showed moderate/severe disease in patients with mitochondrial disease with associated seizures. Parents of patients with mitochondrial disease with associated seizures were characterised by high total parenting stress. No studies reported utilities data. Two case reports and one retrospective review of medical records of children who died in hospital were eligible for the costs and resource use review. These provided limited information on the duration of hospital stay, in an intensive care unit (ICU), on mechanical ventilation. No studies reported costs data. CONCLUSION: These reviews highlight the limited HRQoL, utilities, costs and resource use data and the variability of instruments used in mitochondrial disease with associated seizures. However, the data available indicate that mitochondrial disease with associated seizures affects patients' and caregivers' HRQoL alike. No robust conclusion can be drawn on the impact of mitochondrial disease with associated seizures on hospital or ICU length of stay. Trial registration PROSPERO: CRD42022345005.

Care pathway analysis and evidence gaps in adult-onset Still's disease: interviews with experts from the UK, France, Italy, and Germany.

Introduction: Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease of unknown etiology. Published AOSD data are limited, and clinical guidelines were lacking until recently. Managing AOSD remains largely empirical with uncertainties and high variability about the optimal care pathway. Therefore, we used a qualitative approach to collect clinical judgments from the UK, Italy, France and Germany to inform the development of an agreed care pathway. Our work aimed to decrease the uncertainty associated with clinical practice, inform future research in AOSD, and help identify standardized definitions and outcomes in this population. Methods: Semi-structured interviews and thematic analysis were conducted. Eleven clinicians were interviewed between May and July 2022: four were based in Italy, three in the UK, two in France, and two in Germany. Results: In this work, we identified the structure of the typical care pathway for AOSD patients, which can be used to inform future economic models in AOSD. The general structure of the pathway was similar across countries. Non-steroidal anti-inflammatory drugs are prescribed during the diagnostic workup while an additive approach is commonly used in confirmed cases: corticosteroids, conventional synthetic disease-modifying antirheumatic drugs, then biologic disease-modifying antirheumatic drugs (bDMARDs) (dose increased before switching). For severe presentations, more aggressive approaches with higher doses and early use of bDMARDs are used. The main elements of variation among countries and clinicians were the criteria used for diagnosis; order of bDMARDs and preferential treatments for articular and systemic patients; and tests for patient monitoring. There is also a lack of standardized outcome measures making comparisons and evidence synthesis challenging. Conclusion: We identified important evidence gaps for clinical practice, e.g., reliable tests or scores predictive of disease progression and treatment outcome, and recommendations for research, e.g., reporting of compliance rates and use of the Yamaguchi criteria for clinical study inclusion. Consensus is needed around the use of the Systemic score in clinical practice and the clinical utility of this score. A standardized definition of remission is also required in AOSD, and further research should look to identify and validate the specific laboratory markers to be considered when assessing remission.

Comparative Efficacy and Safety of Tirbanibulin for Actinic Keratosis of the Face and Scalp in Europe: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

Actinic keratosis (AK) is a chronic skin condition that may progress to cutaneous squamous cell carcinoma. We conducted a systematic review of efficacy and safety for key treatments for AK of the face and scalp, including the novel 5-day tirbanibulin 1% ointment. MEDLINE, PubMed, Embase, Cochrane Library, clinical trial registries and regulatory body websites were searched. The review included 46 studies, of which 35 studies included interventions commonly used in Europe and were sufficiently homogenous to inform a Bayesian network meta-analysis of complete clearance against topical placebo or vehicle. The network meta-analysis revealed the following odds ratios and 95% credible intervals: cryosurgery 13.4 (6.2-30.3); diclofenac 3% 2.9 (1.9-4.3); fluorouracil 0.5% + salicylic acid 7.6 (4.6-13.5); fluorouracil 4% 30.3 (9.1-144.7); fluorouracil 5% 35.0 (10.2-164.4); imiquimod 3.75% 8.5 (3.5-22.4); imiquimod 5% 17.9 (9.1-36.6); ingenol mebutate 0.015% 12.5 (8.1-19.9); photodynamic therapy with aminolevulinic acid 24.1 (10.9-52.8); photodynamic therapy with methyl aminolevulinate 11.7 (6.0-21.9); tirbanibulin 1% 11.1 (6.2-20.9). Four sensitivity analyses, from studies assessing efficacy after one treatment cycle only, for ≤25 cm2 treatment area, after 8 weeks post-treatment, and with single placebo/vehicle node confirmed the findings from the base case. Safety outcomes were assessed qualitatively. These results suggest that tirbanibulin 1% offers a novel treatment for AK, with a single short treatment period, favourable safety profile and efficacy, in line with existing topical treatments available in Europe.

Developmental tuning and decay in senescence of oscillations linking the corticospinal system.

There is increasing evidence of the importance of synchronous activity within the corticospinal system for motor control. We compared oscillatory activity in the primary sensorimotor cortex [EEG of sensorimotor cortex (SMC-EEG)] and a motor neuronal pool [surface electromyogram of opponens pollicis (OP-EMG)], and their coherence in children (4-12 years of age), young adults (20-35 years of age), and elderly adults (>55 years of age). The ratio between lower (2-13 Hz) and higher (14-32 Hz) frequencies in both SMC-EEG and OP-EMG decreased with age, correlating inversely with motor performance. There was evidence for larger, more distributed cortical networks in the children and elderly compared with young adults. Corticomuscular coherence (CMC) was present in all age groups and shifted between frontal and parietal cortical areas. In children, CMC was smaller and less stationary in amplitude and frequency than in adults. Young adults had single peaks of CMC clustered near the modal frequency (23 Hz); multiple peaks with a broad spread of frequencies occurred in children and the elderly; the further the frequency of the maximum peak CMC was from 23 Hz, the poorer the performance. CMC amplitude was inversely related to performance in young adults but was not modulated in relation to performance in children and the elderly. We propose that progressive fine-tuning of the frequency coding and stabilization of the dynamic properties within and between corticospinal networks occurs during adolescence, refining the capacity for efficient dynamic communication in adulthood. In old age, blurring of the tuning between networks and breakdown in their integration occurs and is likely to contribute to a decrement in motor control.

Developmental plasticity connects visual cortex to motoneurons after stroke.

We report motor cortical function in the left occipital cortex of a subject who suffered a left middle cerebral artery stroke early in development. Transcranial magnetic stimulation of the left occipital cortex evoked contraction of right hand muscles. Electroencephalogram recorded over the left occipital cortex showed: 1) coherence with electromyogram from a right hand muscle; 2) a typical sensorimotor Mu rhythm at rest that was suppressed during contraction of right hand muscles. This is the first evidence that cortical plasticity extends beyond reshaping of primary sensory cortical fields to respecification of the cortical origin of subcortically projecting pathways.

Purines for Rapid Identification of Stroke Mimics (PRISM): study protocol for a diagnostic accuracy study.

BACKGROUND: Rapid treatment of stroke improves outcomes, but accurate early recognition can be challenging. Between 20 and 40% of patients suspected to have stroke by ambulance and emergency department staff later receive a non-stroke 'mimic' diagnosis after stroke specialist investigation. This early diagnostic uncertainty results in displacement of mimic patients from more appropriate services, inappropriate demands on stroke specialist resources and delayed access to specialist therapies for stroke patients. Blood purine concentrations rise rapidly during hypoxic tissue injury, which is a key mechanism of damage during acute stroke but is not typical in mimic conditions. A portable point of care fingerprick test has been developed to measure blood purine concentration which could be used to triage patients experiencing suspected stroke symptoms into those likely to have a non-stroke mimic condition and those likely to have true stroke. This study is evaluating test performance for identification of stroke mimic conditions. METHODS: Design: prospective observational cohort study Setting: regional UK ambulance and acute stroke services Participants: a convenience series of two populations will be tested: adults with a label of suspected stroke assigned (and tested) by attending ambulance personnel and adults with a label of suspected stroke assigned at hospital (who have not been tested by ambulance staff). INDEX TEST: SMARTChip Purine assay Reference standard tests: expert clinician opinion informed by brain imaging and/or other investigations will assign the following diagnoses which constitute the suspected stroke population: ischaemic stroke, haemorrhagic stroke, TIA and stroke mimic conditions. SAMPLE SIZE: ambulance population (powered for mimic sensitivity) 935 participants; hospital population (powered for mimic specificity) 377 participants. ANALYSES: area under the receiver operating curve (ROC) and optimal sensitivity, specificity, and negative and positive predictive values for identification of mimic conditions. Optimal threshold for the ambulance population will maximise sensitivity, minimum 80%, and aim to keep specificity above 70%. Optimal threshold for the hospital population will maximise specificity, minimum 80%, and aim to keep sensitivity above 70%. DISCUSSION: The results from this study will determine how accurately the SMARTChip purine assay test can identify stroke mimic conditions within the suspected stroke population. If acceptable performance is confirmed, deployment of the test in ambulances or emergency departments could enable more appropriate direction of patients to stroke or non-stroke services. TRIAL REGISTRATION: Registered with ISRCTN (identifier: ISRCTN22323981) on 13/02/2019 http://www.isrctn.com/ISRCTN22323981.

A Novel Combination of Blood Biomarkers and Clinical Stroke Scales Facilitates Detection of Large Vessel Occlusion Ischemic Strokes.

Acute ischemic stroke caused by large vessel occlusions (LVOs) is a major contributor to stroke deaths and disabilities; however, identification for emergency treatment is challenging. We recruited two separate cohorts of suspected stroke patients and screened a panel of blood-derived protein biomarkers for LVO detection. Diagnostic performance was estimated by using blood biomarkers in combination with NIHSS-derived stroke severity scales. Multivariable analysis demonstrated that D-dimer (OR 16, 95% CI 5-60; p-value < 0.001) and GFAP (OR 0.002, 95% CI 0-0.68; p-value < 0.05) comprised the optimal panel for LVO detection. Combinations of D-dimer and GFAP with a number of stroke severity scales increased the number of true positives, while reducing false positives due to hemorrhage, as compared to stroke scales alone (p-value < 0.001). A combination of the biomarkers with FAST-ED resulted in the highest accuracy at 95% (95% CI: 87-99%), with sensitivity of 91% (95% CI: 72-99%), and specificity of 96% (95% CI: 90-99%). Diagnostic accuracy was confirmed in an independent cohort, in which accuracy was again shown to be 95% (95% CI: 87-99%), with a sensitivity of 82% (95% CI: 57-96%), and specificity of 98% (95% CI: 92-100%). Accordingly, the combination of D-dimer and GFAP with stroke scales may provide a simple and highly accurate tool for identifying LVO patients, with a potential impact on time to treatment.

Utility of Routine Laboratory Biomarkers to Detect COVID-19: A Systematic Review and Meta-Analysis.

No routine laboratory biomarkers perform well enough in diagnosing COVID-19 in isolation for them to be used as a standalone diagnostic test or to help clinicians prioritize patients for treatment. Instead, other diagnostic tests are needed. The aim of this work was to statistically summarise routine laboratory biomarker measurements in COVID-19-positive and -negative patients to inform future work. A systematic literature review and meta-analysis were performed. The search included names of commonly used, routine laboratory tests in the UK NHS, and focused on research papers reporting laboratory results of patients diagnosed with COVID-19. A random effects meta-analysis of the standardized mean difference between COVID-19-positive and -negative groups was conducted for each biomarker. When comparing reported laboratory biomarker results, we identified decreased white blood cell, neutrophil, lymphocyte, eosinophil, and platelet counts; while lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase were elevated in COVID-19-positive compared to COVID-19-negative patients. Differences were identified across a number of routine laboratory biomarkers between COVID-19-positive and -negative patients. Further research is required to identify whether routine laboratory biomarkers can be used in the development of a clinical scoring system to aid with triage of patients.

High Variability in Sepsis Guidelines in UK: Why Does It Matter?

It is recommended that developers of Point Of Care Tests (POCTs) assess the care pathway of the patient population of interest in order to understand if the POCT fits within the pathway and has the potential to improve it. If the variation of the pathway across potential hospitals is large, then it is likely that the evaluation of effectiveness is harder and the route towards large-scale takes adoption longer. Evaluating care pathways can be a time-consuming activity when conducted through clinical audits or interviews with healthcare professionals. We have developed a more rapid methodology which extrapolates the care pathway from local hospital guidelines and assesses their variation. Sepsis kills 46,000 people per year in the UK with societal costs of up to £10 billion. Therefore, there is a clinical need for an optimized pathway. By applying our method in this field, we were able to assess the variation in current hospital guidelines for sepsis and infer the potential impact this may have on the evidence development on innovations in this applications. We obtained 15 local sepsis guidelines. Two independent reviewers extracted: use of the national early warning score (NEWS), signs and risk factors informing the decision to prescribe antibiotics, and the number of decisional steps up to this point. Considerable variation was observed in all the variables, which is likely to have an impact on future clinical and economic evaluations and adoption of POCT for the identification of patients with sepsis.

The Clinical Need for New Diagnostics in the Identification and Management of Patients with Suspected Sepsis in UK NHS Hospitals: A Survey of Healthcare Professionals.

Development of a new diagnostic is ideally driven by an understanding of the clinical need that the test addresses and the optimal role the test will have within a care pathway. This survey aimed to understand the clinical need for new sepsis diagnostics and to identify specific clinical scenarios that could be improved by testing. An electronic, cross-sectional survey was circulated to UK National Health Service (NHS) doctors and nurses who care for patients with suspected sepsis in hospitals. Two hundred and sixty-five participants completed the survey, representing 64 NHS Trusts in England. Sixty-seven percent of respondents suggested that the major cause of delay was during the initial identification of sepsis and the subsequent recognition of patients who were deteriorating. Existing blood tests did not enhance the confidence of consultants making their diagnoses. Those surveyed identified a role for a near-patient test to "rule out" suspected sepsis and, thereby, stop or postpone use of antibiotics. Current diagnostic tests are slow, non-specific, and do not reliably identify patients with a high suspicion of sepsis. As a result, they have a limited use in patient management and antibiotic stewardship. Future development of sepsis diagnostics should focus on overcoming these limitations.

Asymmetrical Bioimpedance in the Anterior Circulation for Urgent Stratification of suspected Stroke (ABACUS Stroke): study protocol for a diagnostic accuracy study.

BACKGROUND: Early identification and treatment of stroke improve outcome. Ischaemic stroke due to large vessel occlusion (LVO) benefits from time-critical thrombectomy but this is only available in highly specialised healthcare services. Cerebral Bioimpedance Asymmetry (CBA) measurement obtained with the portable and rapid Cerebrotech Visor™ System device may be able to identify certain types of stroke including LVO. This test could be deployed pre-hospital and used to immediately direct patients to the most appropriate healthcare service for treatment. This study is evaluating the diagnostic accuracy of CBA measurements obtained from a real-world population of suspected stroke. METHODS: Study design: Prospective observational cohort study.Setting: A hyperacute stroke unit and neuroscience centre in North East England.Participants: Adults with a paramedic assigned diagnosis of suspected stroke arriving at hospital within 6 hours of symptom onset.Index Test: Cerebral Bioimpedance Asymmetry measurement performed using the Cerebrotech Visor™ System. Measurement values produce continuous data (range 0 -100); pre-defined threshold for positive state ≥ 10.Reference Standard Tests: Standard CT brain +/- CT/MR angiography, and expert clinician opinion will establish the following clinical outcomes which constitute the suspected stroke population: ischaemic stroke +/- large vessel occlusion; symptomatic severe anterior vessel stenosis; large (≥60ml) and small (<60mls) vessel intracerebral haemorrhage; transient ischaemic attack; stroke mimic conditions; prior territorial stroke.Analyses: Sensitivity, specificity, negative and positive predictive values, area under the Receiver Operating Characteristic curve for identification of i) "complex stroke" (ischaemic stroke with large vessel occlusion or symptomatic severe anterior vessel stenosis or intracerebral haemorrhage ≥60ml or prior territorial stroke) and ii) ischaemic stroke with large vessel occlusion in isolation.Sample size: 124 participants. DISCUSSION: The results from this study will determine how accurately CBA measurement using the Cerebrotech Visor™ System can identify key stroke types within the suspected stroke population. Acceptable diagnostic performance would be an important step forwards for access to time-critical treatments. TRIAL REGISTRATION: Registered with ISRCTN (identifier: ISRCTN79169844) on 06/08/2018.