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"Morton, Ben"
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Multicentre evaluation of two multiplex PCR platforms for the rapid microbiological investigation of nosocomial pneumonia in UK ICUs: the INHALE WP1 study
BackgroundCulture-based microbiological investigation of hospital-acquired or ventilator-associated pneumonia (HAP or VAP) is insensitive, with aetiological agents often unidentified. This can lead to excess antimicrobial treatment of patients with susceptible pathogens, while those with resistant bacteria are treated inadequately for prolonged periods. Using PCR to seek pathogens and their resistance genes directly from clinical samples may improve therapy and stewardship.MethodsSurplus routine lower respiratory tract samples were collected from intensive care unit patients about to receive new or changed antibiotics for hospital-onset lower respiratory tract infections at 15 UK hospitals. Testing was performed using the BioFire FilmArray Pneumonia Panel (bioMérieux) and Unyvero Pneumonia Panel (Curetis). Concordance analysis compared machine and routine microbiology results, while Bayesian latent class (BLC) analysis estimated the sensitivity and specificity of each test, incorporating information from both PCR panels and routine microbiology.FindingsIn 652 eligible samples; PCR identified pathogens in considerably more samples compared with routine microbiology: 60.4% and 74.2% for Unyvero and FilmArray respectively vs 44.2% by routine microbiology. PCR tests also detected more pathogens per sample than routine microbiology. For common HAP/VAP pathogens, FilmArray had sensitivity of 91.7%–100.0% and specificity of 87.5%–99.5%; Unyvero had sensitivity of 50.0%–100.0%%, and specificity of 89.4%–99.0%. BLC analysis indicated that, compared with PCR, routine microbiology had low sensitivity, ranging from 27.0% to 69.4%.InterpretationConventional and BLC analysis demonstrated that both platforms performed similarly and were considerably more sensitive than routine microbiology, detecting potential pathogens in patient samples reported as culture negative. The increased sensitivity of detection realised by PCR offers potential for improved antimicrobial prescribing.
Journal Article
Comprehensive review of safety in Experimental Human Pneumococcal Challenge
Experimental Human Pneumococcal Challenge (EHPC) involves the controlled exposure of adults to a specific antibiotic-sensitive Streptococcus pneumoniae serotype, to induce nasopharyngeal colonisation for the purpose of vaccine research. The aims are to review comprehensively the safety profile of EHPC, explore the association between pneumococcal colonisation and frequency of safety review and describe the medical intervention required to undertake such studies.
A single-centre review of all EHPC studies performed 2011-2021. All recorded serious adverse events (SAE) in eligible studies are reported. An unblinded meta-analysis of collated anonymised individual patient data from eligible EHPC studies was undertaken to assess the association between experimental pneumococcal colonisation and the frequency of safety events following inoculation.
In 1416 individuals (median age 21, IQR 20-25), 1663 experimental pneumococcal inoculations were performed. No pneumococcal-related SAE have occurred. 214 safety review events were identified with 182 (12.85%) participants presenting with symptoms potentially in keeping with pneumococcal infection, predominantly in pneumococcal colonised individuals (colonised = 96/658, non-colonised = 86/1005, OR 1.81 (95% CI 1.28-2.56, P = <0.001). The majority were mild (pneumococcal group = 72.7% [120/165 reported symptoms], non-pneumococcal = 86.7% [124/143 reported symptoms]). 1.6% (23/1416) required antibiotics for safety.
No SAEs were identified directly relating to pneumococcal inoculation. Safety review for symptoms was infrequent but occurred more in experimentally colonised participants. Most symptoms were mild and resolved with conservative management. A small minority required antibiotics, notably those serotype 3 inoculated.
Outpatient human pneumococcal challenge can be conducted safely with appropriate levels of safety monitoring procedures in place.
Journal Article
Socioeconomic status and 30-day mortality after minor and major trauma: A retrospective analysis of the Trauma Audit and Research Network (TARN) dataset for England
Socioeconomic status (SES) is associated with rate and severity of trauma. However, it is unclear whether there is an independent association between SES and mortality after injury. Our aim was to assess the relationship between SES and mortality from trauma.
We conducted a secondary analysis of the Trauma Audit and Research Network dataset. Participants were patients admitted to NHS hospitals for trauma between January 2015 and December 2015, and resident in England. Analyses used multivariate logistic regression with thirty-day mortality as the main outcome. Co-variates include SES derived from area-level deprivation, age, injury severity and comorbidity. All analyses were stratified into minor and major trauma.
There were 48,652 admissions (68% for minor injury, ISS<15) included, and 3,792 deaths. Thirty-day mortality was 10% for patients over 85 with minor trauma, which was higher than major trauma for all age groups under 65. Deprivation was not significantly associated with major trauma mortality. For minor trauma, patients older than 40 had significantly higher aORs than the 0-15 age group. Both the most and second most deprived had significantly higher aORs (1.35 and 1.28 respectively).
This study provides evidence of an independent relationship between SES and mortality after minor trauma, but not for major trauma. Our results identify that, for less severe trauma, older patients and patients with low SES with have an increased risk of 30-day mortality. Policy makers and service providers should consider extending the provision of 'major trauma' healthcare delivery to this at-risk population.
Journal Article
Diagnostic accuracy of combined thoracic and cardiac sonography for the diagnosis of pulmonary embolism: A systematic review and meta-analysis
Computed tomography pulmonary angiography (CTPA) is the diagnostic standard for pulmonary embolism (PE), but is unavailable in many low resource settings. We evaluated the evidence for point of care ultrasound as an alternative diagnostic. Using a PROSPERO-registered, protocol-driven strategy (https://www.crd.york.ac.uk/PROSPERO, ID = CRD42018099925), we searched MEDLINE, EMBASE, and CINHAL for observational and clinical trials of cardiopulmonary ultrasound (CPUS) for PE. We included English-language studies of adult patients with acute breathlessness, reported according to PRISMA guidelines published in the last two decades (January 2000 to February 2020). The primary outcome was diagnostic accuracy of CPUS compared to reference standard CTPA for detection of PE in acutely breathless adults. We identified 260 unique publications of which twelve met all inclusion criteria. Of these, seven studies (N = 3872) were suitable for inclusion in our meta-analysis for diagnostic accuracy (two using CTPA and five using clinically derived diagnosis criterion). Meta-analysis of data demonstrated that using cardiopulmonary ultrasound (CPUS) was 91% sensitive and 81% specific for pulmonary embolism diagnosis compared to diagnostic standard CTPA. When compared to clinically derived diagnosis criterion, CPUS was 52% sensitive and 92% specific for PE diagnosis. We observed substantial heterogeneity across studies meeting inclusion criteria (I.sup.2 = 73.5%). Cardiopulmonary ultrasound may be useful in areas where CTPA is unavailable or unsuitable. Interpretation is limited by study heterogeneity. Further methodologically rigorous studies comparing CPUS and CTPA are important to inform clinical practice.
Journal Article
Long term outcomes for elderly patients after emergency intensive care admission: A cohort study
Elderly patients (≥ 80 years of age) surviving an episode of critical illness suffer long-term morbidity and risk of mortality. Identifying high risk groups could assist in informing discussions with patients and families.
To determine factors associated with long-term survival following ICU admission.
A cohort study of patients aged ≥ 80 years of age admitted to the ICU as an emergency.
Patients admitted from January 2010 to December 2018 were included in the study. Primary outcome was five year survival. Mortality was assessed using a multivariable flexible parametric survival analysis adjusted for demographics, and clinically relevant covariates.
There were 828 patients. Mean age was 84 years (SD 3.2) and 419 (51%) were male. Patients were categorised into medical (423 (51%)) and surgical (405 (49%)) admissions. Adjusted hazard ratios (aHR) for mortality were highest for serum lactate (>8 mmol/l aHR 2.56 (C.I. 1.79-3.67)), lowest systolic blood pressure (< 70 mmHg aHR 2.04 (C.I. 1.36-3.05)) and pH (< 7.05 aHR 4.70 (C.I 2.67-8.21)). There were no survivors beyond one year with severe abnormalities of pH and lactate (< 7.05 and > 8 mmol/l respectively). Relative survival for medical patients was below that expected for the general population for the duration of the study.
Overall five-year survival was 27%. For medical and surgical patients it was 19% and 35% respectively. Survival at 30 days and one year was 61% and 46%. The presence of features of circulatory shock predicted poor short and long term survival.
Journal Article
First Human Challenge Testing of a Pneumococcal Vaccine. Double-Blind Randomized Controlled Trial
New vaccines are urgently needed to protect the vulnerable from bacterial pneumonia. Clinical trials of pneumonia vaccines are slow and costly, requiring tens of thousands of patients. Studies of pneumococcal vaccine efficacy against colonization have been proposed as a novel method to down-select between vaccine candidates.
Using our safe and reproducible experimental human pneumococcal colonization model, we aimed to determine the effect of 13-valent pneumococcal conjugate vaccine (PCV) on colonization.
A total of 100 healthy participants aged 18-50 years were recruited into this double-blind randomized placebo-controlled trial. They were randomly assigned to PCV (n = 49) or hepatitis A (control, n = 50) vaccination and inoculated with 80,000 CFU/100 μl of Streptococcus pneumoniae (6B) per naris.
Participants were followed up for 21 days to determine pneumococcal colonization by culture of nasal wash. The PCV group had a significantly reduced rate of 6B colonization (10% [5 of 48]) compared with control subjects (48% [23 of 48]) (risk ratio, 0.22; confidence interval, 0.09-0.52; P < 0.001). Density of colonization was reduced in the PCV group compared with the control group following inoculation. The area under the curve (density vs. day) was significantly reduced in the PCV compared with control group (geometric mean, 259 vs. 11,183; P = 0.017).
PCV reduced pneumococcal colonization rate, density, and duration in healthy adults. The experimental human pneumococcal colonization model is a safe, cost-effective, and efficient method to determine the protective efficacy of new vaccines on pneumococcal colonization; PCV provides a gold standard against which to test these novel vaccines. Clinical trial registered with
45340436.
Journal Article
Becoming the temporary surgeon: A grounded theory examination of anaesthetists performing emergency front of neck access in inter-disciplinary simulation-based training
The time-critical ‘can’t intubate, can’t oxygenate’ [CICO] emergency post-induction of anaesthesia is rare, but one which, should it occur, requires Anaesthetists to perform rapid emergency front of neck access [FONA] to the trachea, restoring oxygenation, and preventing death or brain hypoxia. The UK Difficult Airway Society [DAS] has directed all Anaesthetists to be trained with surgical cricothyroidotomy [SCT] as the primary emergency FONA method, sometimes referred to as ‘Cric’ as a shorthand. We present a longitudinal analysis using a classical approach to Grounded Theory methodology of ten Specialist Trainee Anaesthetists’ data during a 6-month training programme delivered jointly by Anaesthetists and Surgeons. We identified with a critical realist ontology and an objectivist epistemology meaning data interpretation was driven by participants’ narratives and accepted as true accounts of their experience. Our theory comprises three themes: ‘Identity as an Anaesthetist’; ‘The Role of a Temporary Surgeon’; and ‘Training to Reconcile Identities’, whereby training facilitated the psychological transition from a ‘bloodless Doctor’ (Anaesthetist) to becoming a ‘temporary Surgeon’. The training programme enabled Specialist Trainees to move between the role of control and responsibility (Identity as an Anaesthetist), through self-described ‘failure’ and into a role of uncertainty about one’s own confidence and competence (The Role of a Temporary Surgeon), and then return to the Anaesthetist’s role once the airway had been established. Understanding the complexity of an intervention and providing a better insight into the training needs of Anaesthetic trainees, via a Grounded Theory approach, allows us to evaluate training programmes against the recognised technical and non-technical needs of those being trained.
Journal Article
Health systems strengthening through surgical and perioperative care pathways: a changing paradigm
Global health has traditionally focused on the primary health development with disease-specific focus such as HIV, malaria and non-communicable diseases (NCDs). As such, surgery has traditionally been neglected in global health as investment in them is often expensive, relative to these other priorities. Therefore, efforts to improve surgical care have remained on the periphery of initiatives in health system strengthening. However, today, many would argue that global health should focus on universal health coverage with primary health and surgery and perioperative care integrated as a part of this. In this article, we discuss the past developments and future-looking solutions on how surgery can contribute to the delivery of effective and equitable healthcare across the world. These include bidirectional integration of surgical and chronic disease pathways and better understanding financing initiatives. Specifically, we focus on access to safe elective and emergency surgery for NCDs and an integrated approach towards the rising multimorbidity from chronic disease in the population. Underpinning these, data-driven solutions from high-quality research from clinical trials and cohort studies through established surgical research networks are needed. Although challenges will remain around financing, we propose that development of surgical services will strengthen and improve performance of whole health systems and contribute to improvement in population health across the world.
Journal Article
A Retrospective Evaluation of Critical Care Blood Culture Yield – Do Support Services Contribute to the “Weekend Effect”?
The \"weekend effect\" describes an increase in adverse outcomes for patients admitted at the weekend. Critical care units have moved to higher intensity working patterns to address this with some improved outcomes. However, support services have persisted with traditional working patterns. Blood cultures are an essential diagnostic tool for patients with sepsis but yield is dependent on sampling technique and processing. We therefore used blood culture yield as a surrogate for the quality of support service provision. We hypothesized that blood culture yields would be lower over the weekend as a consequence of reduced support services.
We performed a retrospective observational study examining 1575 blood culture samples in a university hospital critical care unit over a one-year period.
Patients with positive cultures had, on average, higher APACHE II scores (p = 0.015), longer durations of stay (p = 0.03), required more renal replacement therapy (p<0.001) and had higher mortality (p = 0.024). Blood culture yield decreased with repeated sampling with an increased proportion of contaminants. Blood cultures were 26.7% less likely to be positive if taken at the weekend (p = 0.0402). This effect size is the equivalent to the impact of sampling before and after antibiotic administration.
Our study demonstrates that blood culture yield is lower at the weekend. This is likely caused by delays or errors in incubation and processing, reflecting the reduced provision of support services at the weekend. Reorganization of services to address the \"weekend effect\" should acknowledge the interdependent nature of healthcare service delivery.
Journal Article