Further development and validation of the Multimorbidity Treatment Burden Questionnaire (MTBQ).

OBJECTIVES: To undertake further psychometric testing of the Multimorbidity Treatment Burden Questionnaire (MTBQ) and examine whether reversing the scale reduced floor effects. DESIGN: Survey. SETTING: UK primary care. PARTICIPANTS: Adults (≥18 years) with three or more long-term conditions randomly selected from four general practices and invited by post. MEASURES: Baseline survey: sociodemographics, MTBQ (original or version with scale reversed), Treatment Burden Questionnaire (TBQ), four questions (from QQ-10) on ease of completing the questionnaires. Follow-up survey (1-4 weeks after baseline): MTBQ, TBQ and QQ-10. Anonymous data collected from electronic GP records: consultations (preceding 12 months) and long-term conditions. The proportion of missing data and distribution of responses were examined for the original and reversed versions of the MTBQ and the TBQ. Intraclass correlation coefficient (ICC) and Spearman's rank correlation (Rs) assessed test-retest reliability and construct validity, respectively. Ease of completing the MTBQ and TBQ was compared. Interpretability was assessed by grouping global MTBQ scores into 0 and tertiles (>0). RESULTS: 244 adults completed the baseline survey (consent rate 31%, mean age 70 years) and 225 completed the follow-up survey. Reversing the scale did not reduce floor effects or data skewness. The global MTBQ scores had good test-retest reliability (ICC for agreement at baseline and follow-up 0.765, 95% CI 0.702 to 0.816). Global MTBQ score was correlated with global TBQ score (Rs 0.77, p<0.001), weakly correlated with number of consultations (Rs 0.17, p=0.010), and number of different general practitioners consulted (Rs 0.23, p<0.001), but not correlated with number of long-term conditions (Rs -0.063, p=0.330). Most participants agreed that both the MTBQ and TBQ were easy to complete and included aspects they were concerned about. CONCLUSION: This study demonstrates test-retest reliability and ease of completion of the MTBQ and builds on a previous study demonstrating good content validity, construct validity and internal consistency reliability of the questionnaire.

Examining the biological pathways underlying clinical heterogeneity in Sjogren's syndrome: proteomic and network analysis.

OBJECTIVES: Stratification approaches are vital to address clinical heterogeneity in Sjogren's syndrome (SS). We previously described that the Newcastle Sjogren's Stratification Tool (NSST) identified four distinct clinical subtypes of SS. We performed proteomic and network analysis to analyse the underlying pathobiology and highlight potential therapeutic targets for different SS subtypes. METHOD: We profiled serum proteins using O-link technology of 180 SS subjects. We used 5 O-link proteomics panels which included a total of 454 unique proteins. Network reconstruction was performed using the ARACNE algorithm, with differential expression estimates overlaid on these networks to reveal the key subnetworks of differential expression. Furthermore, data from a phase III trial of tocilizumab in SS were reanalysed by stratifying patients at baseline using NSST. RESULTS: Our analysis highlights differential expression of chemokines, cytokines and the major autoantigen TRIM21 between the SS subtypes. Furthermore, we observe differential expression of several transcription factors associated with energy metabolism and redox balance namely APE1/Ref-1, FOXO1, TIGAR and BACH1. The differentially expressed proteins were inter-related in our network analysis, supporting the concept that distinct molecular networks underlie the clinical subtypes of SS. Stratification of patients at baseline using NSST revealed improvement of fatigue score only in the subtype expressing the highest levels of serum IL-6. CONCLUSIONS: Our data provide clues to the pathways contributing to the glandular and non-glandular manifestations of SS and to potential therapeutic targets for different SS subtypes. In addition, our analysis highlights the need for further exploration of altered metabolism and mitochondrial dysfunction in the context of SS subtypes.

Does a local Alcohol Health Champion programme have a measurable impact on health and crime outcomes? A natural experiment evaluation of Communities in Charge of Alcohol (CICA) based on triangulation of methods.

BACKGROUND AND AIM: Drinking alcohol may cause harm to an individual's health and social relationships, while a drinking culture may harm societies as it may increase crime rates and make an area feel less safe. Local councils in Greater Manchester, UK, developed the Communities in Charge of Alcohol (CICA) intervention, in which volunteers were trained to give alcohol-related advice to the public and taught how to influence policies to restrict when, where and how alcohol is sold. As part of a larger study, the aim of the current project is to measure the impact of CICA on health and crime outcomes at the lower super output (LSOA) geographical aggregation. DESIGN: Quantitative evaluation using four time series analytic methods (stepped-wedge design, and comparisons to local controls, national controls and synthetic controls) with findings triangulated across these methods. A cost-benefit analysis was carried out alongside the effectiveness analysis. SETTING AND PARTICIPANTS: The general public in Greater Manchester, UK, between 2010 and 2020. MEASUREMENTS: The primary outcome of interest was alcohol-related hospital admissions. Secondary outcomes were accident and emergency (A&E) attendances, ambulance callouts, recorded crimes and anti-social behaviour incidents. FINDINGS: Triangulation of the results did not indicate any consistent effect on area-level alcohol-related hospital admissions, A&E attendances, ambulance callouts, reported crimes or anti-social behaviour associated with the implementation of CICA. The primary stepped-wedge analysis indicated an increase in alcohol-related hospital admissions following the implementation of CICA of 13.4% (95% confidence interval -3.3%, +30.1%), which was consistent with analyses based on other methods with point estimates ranging from +3.4% to 16.4%. CONCLUSION: There is no evidence of a measurable impact of the Communities in Charge of Alcohol (CICA) programme on area-level health and crime outcomes in Greater Manchester, UK, within 3 years of the programme start. The increase in alcohol-related hospital admissions was likely the result of other temporal trends rather than the CICA programme. Possible explanations include insufficient follow-up time, too few volunteers trained, volunteers being unwilling to get involved in licensing decisions or that the intervention has no direct impact on the selected outcomes.

Feline faces: Unraveling the social function of domestic cat facial signals.

Lately, there has been a growing interest in studying domestic cat facial signals, but most of this research has centered on signals produced during human-cat interactions or pain. The available research on intraspecific facial signaling with domesticated cats has largely focused on non-affiliative social interactions. However, the transition to intraspecific sociality through domestication could have resulted in a greater reliance on affiliative facial signals that aid with social bonding. Our study aimed to document the various facial signals that cats produce during affiliative and non-affiliative intraspecific interactions. Given the close relationship between the physical form and social function of mammalian facial signals, we predicted that affiliative and non-affiliative facial signals would have noticeable differences in their physical morphology. We observed the behavior of 53 adult domestic shorthair cats at CatCafé Lounge in Los Angeles, CA. Using Facial Action Coding Systems designed for cats, we compared the complexity and compositionality of facial signals produced in affiliative and non-affiliative contexts. To measure complexity and compositionality, we examined the number and types of facial muscle movements (AUs) observed in each signal. We found that compositionality, rather than complexity, was significantly associated with the social function of intraspecific facial signals. Our findings indicate that domestication likely had a significant impact on the development of intraspecific facial signaling repertoires in cats.

Antigen presentation by clonally diverse CXCR5+ B cells to CD4 and CD8 T cells is associated with durable response to immune checkpoint inhibitors.

Introduction: Increased T cell infiltration and interferon gamma (IFNγ) pathway activation are seen in tumors of melanoma patients who respond to ICI (immune checkpoint inhibitor) or MAPK pathway inhibitor (MAPKi) therapies. Yet, the rate of durable tumor control after ICI is almost twice that of MAPKi, suggesting that additional mechanisms may be present in patients responding to ICI therapy that are beneficial for anti-tumor immunity. Methods: We used transcriptional analysis and clinical outcomes from patients treated with ICI or MAPKi therapies to delineate immune mechanisms driving tumor response. Results: We discovered response to ICI is associated with CXCL13-driven recruitment of CXCR5+ B cells with significantly higher clonal diversity than MAPKi. Our in vitro data indicate that CXCL13 production was increased in human peripheral blood mononuclear cells by anti-PD1, but not MAPKi, treatment. Higher B cell infiltration and B cell receptor (BCR) diversity allows presentation of diverse tumor antigens by B cells, resulting in activation of follicular helper CD4 T cells (Tfh) and tumor reactive CD8 T cells after ICI therapy. Higher BCR diversity and IFNγ pathway score post-ICI are associated with significantly longer patient survival compared to those with either one or none. Conclusions: Response to ICI, but not to MAPKi, depends on the recruitment of CXCR5+ B cells into the tumor microenvironment and their productive tumor antigen presentation to follicular helper and cytotoxic, tumor reactive T cells. Our study highlights the potential of CXCL13 and B cell based strategies to enhance the rate of durable response in melanoma patients treated with ICI.

Advertisement of unhealthy commodities in Bristol and South Gloucestershire and rationale for a new advertisement policy.

BACKGROUND: Bristol City Council introduced a new advertisement policy in 2021/2022 which included prohibiting the advertising of unhealthy food and drink (HFSS), alcohol, gambling and payday loans across council-owned advertising spaces. This mixed methods study is part of the BEAR study, and aimed to explore the rationale and the barriers and facilitators to implementing the policy, and describe the perceived advertising environment prior to implementation. METHODS: Semi-structured interviews were carried out with seven stakeholders involved in the design and implementation of the advertising policy. A stakeholder topic guide was developed before interviews took place to help standardise the lines of inquiry between interviewees. A resident survey was developed to collect socio-demographic data and, for the purpose of this study, information regarding observations of advertising for HFSS products, alcohol and gambling. RESULTS: Fifty-eight percent of respondents residing in Bristol and South Gloucestershire reported seeing advertisements for unhealthy commodities in the week prior to completing the survey. This was highest for HFSS products (40%). 16% of residents reported seeing HFSS product advertisements specifically appealing to children. For HFSS products in particular, younger people were more likely to report seeing adverts than older people, as were those who were from more deprived areas. An advertisement policy that restricts the advertisement of such unhealthy commodities, and in particular for HFSS products, has the potential to reduce health inequalities. This rationale directly influenced the development of the advertisement policy in Bristol. Implementation of the policy benefitted from an existing supportive environment following the 'health in all policies' initiative and a focus on reducing health inequalities across the city. CONCLUSIONS: Unhealthy product advertisements, particularly for unhealthy food and drinks, were observed more by younger people and those living in more deprived areas. Policies that specifically restrict such advertisements, therefore, have the potential to reduce health inequalities, as was the hope when this policy was developed. Future evaluation of the policy will provide evidence of any public health impact.

Clonally expanded, thyrotoxic effector CD8+ T cells driven by IL-21 contribute to checkpoint inhibitor thyroiditis.

Autoimmune toxicity occurs in up to 60% of patients treated with immune checkpoint inhibitor (ICI) therapy for cancer and represents an increasing clinical challenge for expanding the use of these treatments. To date, human immunopathogenic studies of immune-related adverse events (IRAEs) have relied on sampling of circulating peripheral blood cells rather than affected tissues. Here, we directly obtained thyroid specimens from individuals with ICI-thyroiditis, one of the most common IRAEs, and compared immune infiltrates with those from individuals with spontaneous autoimmune Hashimoto's thyroiditis (HT) or no thyroid disease. Single-cell RNA sequencing revealed a dominant, clonally expanded population of thyroid-infiltrating cytotoxic CXCR6+ CD8+ T cells (effector CD8+ T cells) present in ICI-thyroiditis but not HT or healthy controls. Furthermore, we identified a crucial role for interleukin-21 (IL-21), a cytokine secreted by intrathyroidal T follicular (TFH) and T peripheral helper (TPH) cells, as a driver of these thyrotoxic effector CD8+ T cells. In the presence of IL-21, human CD8+ T cells acquired the activated effector phenotype with up-regulation of the cytotoxic molecules interferon-γ (IFN-γ) and granzyme B, increased expression of the chemokine receptor CXCR6, and thyrotoxic capacity. We validated these findings in vivo using a mouse model of IRAEs and further demonstrated that genetic deletion of IL-21 signaling protected ICI-treated mice from thyroid immune infiltration. Together, these studies reveal mechanisms and candidate therapeutic targets for individuals who develop IRAEs.

Assessing exposure to outdoor advertisement for products high in fat, salt and sugar (HFSS); is self-reported exposure a useful exposure metric?

BACKGROUND: Exposure to advertising of unhealthy commodities such as fast-food and gambling is recognised as a risk factor for developing non-communicable diseases. Assessment of the impact of such advertisement and the evaluation of the impact of any policies to restrict such advertisements on public health are reliant on the quality of the exposure assessment. A straightforward method for assessing exposure is to ask people whether they noticed any such advertisements in their neighbourhoods. However, the validity of this method is unclear. We assessed the associations between measured exposure to outdoor advertising, self-reported exposure, and self-reported consumption. METHODS: We collected exposure information in January-March 2022 using two methods: (i) through a resident survey investigating advertising and consumption of unhealthy products, distributed across Bristol and neighbouring South Gloucestershire, and (ii) through in-person auditing. Self-reported exposure was obtained from the resident survey (N = 2,560) and measured exposure from photos obtained for all Council owned advertisement sites (N = 973 bus stops). Both data sources were geographically linked at lower-super-output-area level. Reporting ratios (RRs), 95% confidence intervals (CIs), and Cohen's kappas, are presented. RESULTS: 24% of advertisements displayed food and/or drink advertising. Bristol respondents in neighbourhoods displaying food/drink adverts were more likely to also report seeing these adverts compared to those in neighbourhoods without food/drink adverts (59% vs. 51%, RR = 1.15, 95%CI 1.01-1.31). There was no such association in South Gloucestershire (26% vs. 32%, RR = 0.82, 95%CI 0.58-1.14). Respondents in both Bristol and South Gloucestershire who recalled seeing advertising for unhealthy food and drink products were more likely to consume them (e.g. for fast-food: 22% vs. 11%, RR = 2.01, 95%CI 1.68-2.42). There was no such association between measured food and drink adverts in respondents' local areas and self-reported consumption of HFSS product (90.1% vs. 90.7%, RR = 0.99, 95%CI 0.96-1.03). CONCLUSIONS: Self-reported outdoor advertisement exposure is correlated with measured exposure, making this a useful methodology for population studies. It has the added advantage that it correlates with consumption. However, given that measurement error can be significant and self-reported exposure is known to be susceptible to various biases, inferences from studies using this exposure metric should be made with caution.

Factors related to adverse long-term outcomes after mild traumatic brain injury in children: a scoping review.

OBJECTIVE: To identify demographic, premorbid and injury-related factors, or biomarkers associated with long-term (≥3 months) adverse outcomes in children after mild traumatic brain injury (mTBI). DESIGN: Scoping review of literature. PATIENTS: Children and adolescents with mTBI. RISK FACTORS: Any demographic, premorbid and injury-related factors, or biomarkers were included. We excluded genetic and treatment-related factors. MAIN OUTCOME MEASURES: Postconcussion syndrome (PCS), recovery. RESULTS: Seventy-three publications were included, reporting 12 long-term adverse outcomes, including PCS in 12 studies and recovery in 29 studies. Additional outcomes studied were symptom scores/severity (n=22), quality of life (n=9) and cognitive function (n=9). Forty-nine risk factors were identified across studies. Risk factors most often assessed were sex (n=28), followed by age (n=23), injury mechanism = (n=22) and prior mTBI (n=18). The influence of these and other risk factors on outcomes of mTBI were inconsistent across the reviewed literature. CONCLUSIONS: The most researched risk factors are sex, age and mechanism of injury, but their effects have been estimated inconsistently and did not show a clear pattern. The most studied outcomes are recovery patterns and symptom severity. However, these may not be the most important outcomes for clinicians and patients. Future primary studies in this area should focus on patient-important outcomes. Population-based prospective studies are needed that address prespecified hypotheses on the relationship of risk factors with given outcomes to enable reliable prediction of long-term adverse outcomes for childhood mTBI.

Educational interventions to prevent paediatric abusive head trauma in babies younger than one year old: A systematic review and meta-analyses.

BACKGROUND: Paediatric abusive head trauma (AHT) occurs in young children due to violent shaking or blunt impact. Educational and behavioural programmes modifying parent/infant interactions may aid primary prevention. This systematic review aims to assess the effectiveness of such interventions to prevent AHT in infants. METHODS: We searched Embase, MEDLINE, PsycINFO, The Cochrane library, CINAHL databases and trial registries to September 2021, for studies assessing the effectiveness of educational and behavioural interventions in preventing AHT. Eligible interventions had to include messaging about avoiding or dangers of infant shaking. Randomised controlled trials (RCTs) reporting results for primary (AHT, infant shaking) or secondary outcomes (including parental responses to infant crying, mental wellbeing), and non-randomised studies (NRSs) reporting primary outcomes were included. Evidence from combinable studies was synthesised using random-effects meta-analyses. Certainty of evidence was assessed using GRADE framework. PROSPERO registration CRD42020195644. FINDINGS: Of 25 identified studies, 16 were included in meta-analyses. Five NRSs reported results for AHT, of which four were meta-analysed (summary odds ratio [OR] 0.95, 95 % confidence intervals [CI] 0.80-1.13). Two studies assessed self-reported shaking (one cluster-RCT, OR 0.11, 95 % CI 0.02-0.53; one cohort study, OR 0.36, 95 % CI 0.20-0.64, not pooled). Meta-analyses of secondary outcomes demonstrated marginal improvements in parental response to inconsolable crying (summary mean difference 1.58, 95 % CI 0.11-3.06, on a 100-point scale) and weak evidence that interventions increased walking away from crying infants (summary incidence rate ratio 1.52, 95 % CI 0.94-2.45). No intervention effects were found in meta-analyses of parental mental wellbeing or other responses to crying. INTERPRETATION: Low certainty evidence suggests that educational programmes for AHT prevention are not effective in preventing AHT. There is low to moderate certainty evidence that educational interventions have no effect or only marginally improve some parental responses to infant crying.

Evaluating a pre-surgical health optimisation programme: a feasibility study.

BACKGROUND: Health optimisation programmes are increasingly popular and aim to support patients to lose weight or stop smoking ahead of surgery, yet there is little published evidence about their impact. This study aimed to assess the feasibility of evaluating a programme introduced by a National Health Service (NHS) clinical commissioning group offering support to smokers/obese patients in an extra 3 months prior to the elective hip/knee surgery pathway. METHODS: Feasibility study mapping routinely collected data sources, availability and completeness for 502 patients referred to the hip/knee pathway in February-July 2018. RESULTS: Data collation across seven sources was complex. Data completeness for smoking and ethnicity was poor. While 37% (184) of patients were eligible for health optimisation, only 28% of this comparatively deprived patient group accepted referral to the support offered. Patients who accepted referral to support and completed the programme had a larger median reduction in BMI than those who did not accept referral (- 1.8 BMI points vs. - 0.5). Forty-nine per cent of patients who accepted support were subsequently referred to surgery, compared to 61% who did not accept referral to support. CONCLUSIONS: Use of routinely collected data to evaluate health optimisation programmes is feasible though demanding. Indications of the positive effects of health optimisation interventions from this study and existing literature suggest that the challenge of programme evaluation should be prioritised; longer-term evaluation of costs and outcomes is warranted to inform health optimisation policy development.

Supraglottic airway device versus tracheal intubation in the initial airway management of out-of-hospital cardiac arrest: the AIRWAYS-2 cluster RCT.

BACKGROUND: When a cardiac arrest occurs, cardiopulmonary resuscitation should be started immediately. However, there is limited evidence about the best approach to airway management during cardiac arrest. OBJECTIVE: The objective was to determine whether or not the i-gel® (Intersurgical Ltd, Wokingham, UK) supraglottic airway is superior to tracheal intubation as the initial advanced airway management strategy in adults with non-traumatic out-of-hospital cardiac arrest. DESIGN: This was a pragmatic, open, parallel, two-group, multicentre, cluster randomised controlled trial. A cost-effectiveness analysis accompanied the trial. SETTING: The setting was four ambulance services in England. PARTICIPANTS: Patients aged ≥ 18 years who had a non-traumatic out-of-hospital cardiac arrest and were attended by a participating paramedic were enrolled automatically under a waiver of consent between June 2015 and August 2017. Follow-up ended in February 2018. INTERVENTION: Paramedics were randomised 1 : 1 to use tracheal intubation (764 paramedics) or i-gel (759 paramedics) for their initial advanced airway management and were unblinded. MAIN OUTCOME MEASURES: The primary outcome was modified Rankin Scale score at hospital discharge or 30 days after out-of-hospital cardiac arrest, whichever occurred earlier, collected by assessors blinded to allocation. The modified Rankin Scale, a measure of neurological disability, was dichotomised: a score of 0-3 (good outcome) or 4-6 (poor outcome/death). The primary outcome for the economic evaluation was quality-adjusted life-years, estimated using the EuroQol-5 Dimensions, five-level version. RESULTS: A total of 9296 patients (supraglottic airway group, 4886; tracheal intubation group, 4410) were enrolled [median age 73 years; 3373 (36.3%) women]; modified Rankin Scale score was known for 9289 patients. Characteristics were similar between groups. A total of 6.4% (311/4882) of patients in the supraglottic airway group and 6.8% (300/4407) of patients in the tracheal intubation group had a good outcome (adjusted difference in proportions of patients experiencing a good outcome: -0.6%, 95% confidence interval -1.6% to 0.4%). The supraglottic airway group had a higher initial ventilation success rate than the tracheal intubation group [87.4% (4255/4868) vs. 79.0% (3473/4397), respectively; adjusted difference in proportions of patients: 8.3%, 95% confidence interval 6.3% to 10.2%]; however, patients in the tracheal intubation group were less likely to receive advanced airway management than patients in the supraglottic airway group [77.6% (3419/4404) vs. 85.2% (4161/4883), respectively]. Regurgitation rate was similar between the groups [supraglottic airway group, 26.1% (1268/4865); tracheal intubation group, 24.5% (1072/4372); adjusted difference in proportions of patients: 1.4%, 95% confidence interval -0.6% to 3.4%], as was aspiration rate [supraglottic airway group, 15.1% (729/4824); tracheal intubation group, 14.9% (647/4337); adjusted difference in proportions of patients: 0.1%, 95% confidence interval -1.5% to 1.8%]. The longer-term outcomes were also similar between the groups (modified Rankin Scale: at 3 months, odds ratio 0.89, 95% confidence interval 0.69 to 1.14; at 6 months, odds ratio 0.91, 95% confidence interval 0.71 to 1.16). Sensitivity analyses did not alter the overall findings. There were no unexpected serious adverse events. Mean quality-adjusted life-years to 6 months were 0.03 in both groups (supraglottic airway group minus tracheal intubation group difference -0.0015, 95% confidence interval -0.0059 to 0.0028), and total costs were £157 (95% confidence interval -£270 to £583) lower in the tracheal intubation group. Although the point estimate of the incremental cost-effectiveness ratio suggested that tracheal intubation may be cost-effective, the huge uncertainty around this result indicates no evidence of a difference between groups. LIMITATIONS: Limitations included imbalance in the number of patients in each group, caused by unequal distribution of high-enrolling paramedics; crossover between groups; and the fact that participating paramedics, who were volunteers, might not be representative of all paramedics in the UK. Findings may not be applicable to other countries. CONCLUSION: Among patients with out-of-hospital cardiac arrest, randomisation to the supraglottic airway group compared with the tracheal intubation group did not result in a difference in outcome at 30 days. There were no notable differences in costs, outcomes and overall cost-effectiveness between the groups. FUTURE WORK: Future work could compare alternative supraglottic airway types with tracheal intubation; include a randomised trial of bag mask ventilation versus supraglottic airways; and involve other patient populations, including children, people with trauma and people in hospital. TRIAL REGISTRATION: This trial is registered as ISRCTN08256118. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and supported by the NIHR Comprehensive Research Networks and will be published in full in Health Technology Assessment; Vol. 26, No. 21. See the NIHR Journals Library website for further project information.

BACKGROUND: Cardiac arrest is a serious medical emergency in which the heartbeat and breathing stop suddenly. Every year in the UK, a large number of patients (around 123 per 100,000) suffer a cardiac arrest outside hospital. Only 7­9% of these patients survive to leave hospital. The best initial treatment in cardiac arrest is cardiopulmonary resuscitation (commonly known as CPR), during which it is vital to give chest compressions and maintain a clear airway. Two main techniques are used to keep the airway clear: tracheal intubation (inserting a breathing tube into the windpipe) and a supraglottic airway device (a newer device that is inserted less deeply and sits just above the voicebox). Both techniques are used routinely by paramedics in the UK when treating a cardiac arrest, but there is no evidence about which technique is best. The AIRWAYS-2 trial aimed to find out whether or not a supraglottic airway device is better than tracheal intubation. WHO PARTICIPATED AND WHAT WAS INVOLVED?: Paramedics from four UK ambulance services were put into one of two groups at random. One group was randomly chosen to use tracheal intubation and the other group was randomly chosen to use a supraglottic airway device at all adult cardiac arrests they attended for approximately 2 years. Paramedics were able to apply their clinical judgement and use a different device if they felt that this would be best for the patient. A total of 1523 paramedics took part and enrolled 9296 patients. Following cardiac arrest, a patient's recovery was assessed as good or poor (including patients who did not survive). WHAT DID THE TRIAL FIND?: A similar percentage of patients in both groups had a good recovery. There was no evidence to suggest that the supraglottic airway device was any better than tracheal intubation for treating a cardiac arrest.

Prognostic value of National Early Warning Scores (NEWS2) and component physiology in hospitalised patients with COVID-19: a multicentre study.

BACKGROUND: National Early Warning Scores (NEWS2) are used to detect all-cause deterioration. While studies have looked at NEWS2, the use of virtual consultation and remote monitoring of patients with COVID-19 mean there is a need to know which physiological observations are important. AIM: To investigate the relationship between outcome and NEWS2, change in NEWS2 and component physiology in COVID-19 inpatients. METHODS: A multi-centre retrospective study of electronically recorded, routinely collected physiological measurements between March and June 2020. First and maximum NEWS2, component scores and outcomes were recorded. Areas under the curve (AUCs) for 2-day, 7-day and 30-day mortality were calculated. RESULTS: Of 1263 patients, 26% died, 7% were admitted to intensive care units (ICUs) before discharge and 67% were discharged without ICU. Of 1071 patients with initial NEWS2, most values were low: 50% NEWS2=0-2, 27% NEWS2=3-4, 14% NEWS2=5-6 and 9% NEWS2=7+. Maximum scores were: 14% NEWS2=0-2, 22% NEWS2=3-4, 17% NEWS2=5-6 and 47% NEWS2=7+. Higher first and maximum scores were predictive of mortality, ICU admission and longer length of stay. AUCs based on 2-day, 7-day, 30-day and any hospital mortality were 0.77 (95% CI 0.70 to 0.84), 0.70 (0.65 to 0.74), 0.65 (0.61 to 0.68) and 0.65 (0.61 to 0.68), respectively. The AUCs for 2-day mortality were 0.71 (0.65 to 0.77) for supplemental oxygen, 0.65 (0.56 to 0.73) oxygen saturation and 0.64 (0.56 to 0.73) respiratory rate. CONCLUSION: While respiratory parameters were most predictive, no individual parameter was as good as a full NEWS2, which is an acceptable predictor of short-term mortality in patients with COVID-19. This supports recommendation to use NEWS2 alongside clinical judgement to assess patients with COVID-19.

Systematic review with meta-analysis: the accuracy of serological tests to support the diagnosis of coeliac disease.

BACKGROUND: There is growing support for a biopsy avoidant approach to diagnose coeliac disease in both children and adults, using a serological diagnosis instead. AIMS: To assess the diagnostic accuracy of serological tests for coeliac disease in adults and children. METHODS: Seven electronic databases were searched between January 1990 and August 2020. Eligible diagnostic studies evaluated the accuracy of serological tests for coeliac disease against duodenal biopsy. Risk of bias assessment was performed using QUADAS-2. Bivariate random-effects meta-analyses were used to estimate serology sensitivity and specificity at the most commonly reported thresholds. RESULTS: 113 studies (n = 28,338) were included, all in secondary care populations. A subset of studies were included in meta-analyses due to variations in diagnostic thresholds. Summary sensitivity and specificity of immunoglobulin A (IgA) anti-tissue transglutaminase were 90.7% (95% confidence interval: 87.3%, 93.2%) and 87.4% (84.4%, 90.0%) in adults (5 studies) and 97.7% (91.0%, 99.4%) and 70.2% (39.3%, 89.6%) in children (6 studies); and of IgA endomysial antibodies were 88.0% (75.2%, 94.7%) and 99.6% (92.3%, 100%) in adults (5 studies) and 94.5% (88.9%, 97.3%) and 93.8% (85.2%, 97.5%) in children (5 studies). CONCLUSIONS: Anti-tissue transglutaminase sensitivity appears to be sufficient to rule out coeliac disease in children. The high specificity of endomysial antibody in adults supports its use to rule in coeliac disease. This evidence underpins the current development of clinical guidelines for a serological diagnosis of coeliac disease. Studies in primary care are needed to evaluate serological testing strategies in this setting.

Regression discontinuity analysis for pharmacovigilance: statin example reflected trial findings showing little evidence of harm.

OBJECTIVES: The study aims to explore the use of regression discontinuity analysis (RDA) to examine effects of prescription of statins on total cholesterol and adverse outcomes (type 2 diabetes, rhabdomyolysis and myopathy, myalgia and myositis, liver disease, CVD, and mortality). STUDY DESIGN AND SETTING: We conducted a prospective cohort study using the Clinical Practice Research Datalink including patients with QRISK scores of 10 to 30 in 2010 to 2013 who were last followed-up in October 2016. Comparing patients with QRISK≥20 and QRISK<20, we explored RDA assumptions, provided proof of concept analyses (total cholesterol as outcome), and investigated the effect of statins prescription on adverse outcomes. RESULT: RDA confirmed statin prescription reduced total cholesterol (Mean difference (MD) -1.33 mmol/L, 95%Confidence Interval (CI) -1.93 to -0.73). RDA provided little evidence for adverse effects on diabetes, myalgia and myositis, liver disease, CVD, or mortality. The RDA analysis findings are similar to RCT results. Findings from non-RDA analysis agree with published observational studies. CONCLUSION: RDA can be used with large routine clinical datasets to provide evidence on effects of medications which are prescribed according to a threshold. Testable RDA assumptions were satisfied, but confidence intervals were wide, partly due to the low compliance with the prescribing threshold.

Automated Machine Learning Pipeline Framework for Classification of Pediatric Functional Nausea Using High-Resolution Electrogastrogram.

OBJECTIVE: Pediatric functional nausea is challenging for patients to manage and for clinicians to treat since it lacks objective diagnosis and assessment. A data-driven non-invasive diagnostic screening tool that distinguishes the electro-pathophysiology of pediatric functional nausea from healthy controls would be an invaluable aid to support clinical decision-making in diagnosis and management of patient treatment methodology. The purpose of this paper is to present an innovative approach for objectively classifying pediatric functional nausea using cutaneous high-resolution electrogastrogram data. METHODS: We present an Automated Electrogastrogram Data Analytics Pipeline framework and demonstrate its use in a 3x8 factorial design to identify an optimal classification model according to a defined objective function. Low-fidelity synthetic high-resolution electrogastrogram data were generated to validate outputs and determine SOBI-ICA noise reduction effectiveness. RESULTS: A 10 parameter support vector machine binary classifier with a radial basis function kernel was selected as the overall top-performing model from a pool of over 1000 alternatives via maximization of an objective function. This resulted in a 91.6% test ROC AUC score. CONCLUSION: Using an automated machine learning pipeline approach to process high-resolution electrogastrogram data allows for clinically significant objective classification of pediatric functional nausea. SIGNIFICANCE: To our knowledge, this is the first study to demonstrate clinically significant performance in the objective classification of pediatric nausea patients from healthy control subjects using experimental high-resolution electrogastrogram data. These results indicate a promising potential for high-resolution electrogastrography to serve as a data-driven screening tool for the objective diagnosis of pediatric functional nausea.

Maintaining face-to-face contact during the COVID-19 pandemic: a longitudinal qualitative investigation in UK primary care.

BACKGROUND: In March 2020, the COVID-19 pandemic required a rapid reconfiguration of UK general practice to minimise face-to-face contact with patients to reduce infection risk. However, some face-to-face contact remained necessary and practices needed to ensure such contact could continue safely. AIM: To examine how practices determined when face-to-face contact was necessary and how face-to-face consultations were reconfigured to reduce COVID-19 infection risk. DESIGN & SETTING: Qualitative interview study in general practices in Bristol, North Somerset, and South Gloucestershire. METHOD: Longitudinal semi-structured interviews with clinical and managerial practice staff were undertaken at four timepoints between May and July 2020. RESULTS: Practices worked flexibly within general national guidance to determine when face-to-face contact with patients was necessary, influenced by knowledge of the patient, experience, and practice resilience. For example, practices prioritised patients according to clinical need using face-to-face contact to resolve clinician uncertainty or provide adequate reassurance to patients. To make face-to-face contact as safe as possible and keep patients separated, practices introduced a heterogeneous range of measures that exploited features of their indoor and outdoor spaces, and altered their appointment processes. As national restrictions eased in June and July, the number and proportion of patients seen face to face generally increased. However, the reconfiguration of buildings and processes reduced the available capacity and put increased pressure on practices. CONCLUSION: Practices responded rapidly and creatively to the initial lockdown restrictions. The variety of ways practices organised face-to-face contact to minimise infection highlights the need for flexibility in guidance.

Cost-effectiveness of the i-gel supraglottic airway device compared to tracheal intubation during out-of-hospital cardiac arrest: Findings from the AIRWAYS-2 randomised controlled trial.

AIM: Optimal airway management during out-of-hospital cardiac arrest (OHCA) is uncertain. Complications from tracheal intubation (TI) may be avoided with supraglottic airway (SGA) devices. The AIRWAYS-2 cluster randomised controlled trial (ISRCTN08256118) compared the i-gel SGA with TI as the initial advanced airway management (AAM) strategy by paramedics treating adults with non-traumatic OHCA. This paper reports the trial cost-effectiveness analysis. METHODS: A within-trial cost-effectiveness analysis of the i-gel compared with TI was conducted, with a six-month time horizon, from the perspective of the UK National Health Service (NHS) and personal social services. The primary outcome measure was quality-adjusted life years (QALYs), estimated using the EQ-5D-5L questionnaire. Multilevel linear regression modelling was used to account for clustering by paramedic when combining costs and outcomes. RESULTS: 9296 eligible patients were attended by 1382 trial paramedics and enrolled in the AIRWAYS-2 trial (4410 TI, 4886 i-gel). Mean QALYs to six months were 0.03 in both groups (i-gel minus TI difference -0.0015, 95% CI -0.0059 to 0.0028). Total costs per participant up to six months post-OHCA were £3570 and £3413 in the i-gel and TI groups respectively (mean difference £157, 95% CI -£270 to £583). Based on mean difference point estimates, TI was more effective and less costly than i-gel; however differences were small and there was great uncertainty around these results. CONCLUSION: The small differences between groups in QALYs and costs shows no difference in the cost-effectiveness of the i-gel and TI when used as the initial AAM strategy in adults with non-traumatic OHCA.

Quantifying interfacial substrate interactions via surface energy analyses.

Determination of a substrate's surface energy profile is a facile and inexpensive method to indicate the substrate's interfacial thermodynamics with another substance (e.g., microorganisms, biomacromolecules, medical devices, etc). The following protocol details a goniometric method to calculate a substrate's surface energy profile which (1) directly correlates to a substrate's interfacial Gibbs energy (ΔG) and (2) predicts the interfacial interactions with other substances. We also provide a calculation template using advanced mathematics to expedite surface energy profile determination. For complete details on the use and execution of this protocol, please refer to Cavitt et al. (2020).