Raising AWaRe-ness of Antimicrobial Stewardship Challenges in Pediatric Emergency Care: Results from the PERFORM Study Assessing Consistency and Appropriateness of Antibiotic Prescribing Across Europe.

BACKGROUND: Optimization of antimicrobial stewardship is key to tackling antimicrobial resistance, which is exacerbated by overprescription of antibiotics in pediatric emergency departments (EDs). We described patterns of empiric antibiotic use in European EDs and characterized appropriateness and consistency of prescribing. METHODS: Between August 2016 and December 2019, febrile children attending EDs in 9 European countries with suspected infection were recruited into the PERFORM (Personalised Risk Assessment in Febrile Illness to Optimise Real-Life Management) study. Empiric systemic antibiotic use was determined in view of assigned final "bacterial" or "viral" phenotype. Antibiotics were classified according to the World Health Organization (WHO) AWaRe classification. RESULTS: Of 2130 febrile episodes (excluding children with nonbacterial/nonviral phenotypes), 1549 (72.7%) were assigned a bacterial and 581 (27.3%) a viral phenotype. A total of 1318 of 1549 episodes (85.1%) with a bacterial and 269 of 581 (46.3%) with a viral phenotype received empiric systemic antibiotics (in the first 2 days of admission). Of those, the majority (87.8% in the bacterial and 87.0% in the viral group) received parenteral antibiotics. The top 3 antibiotics prescribed were third-generation cephalosporins, penicillins, and penicillin/ß-lactamase inhibitor combinations. Of those treated with empiric systemic antibiotics in the viral group, 216 of 269 (80.3%) received ≥1 antibiotic in the "Watch" category. CONCLUSIONS: Differentiating bacterial from viral etiology in febrile illness on initial ED presentation remains challenging, resulting in a substantial overprescription of antibiotics. A significant proportion of patients with a viral phenotype received systemic antibiotics, predominantly classified as WHO Watch. Rapid and accurate point-of-care tests in the ED differentiating between bacterial and viral etiology could significantly improve antimicrobial stewardship.

Treatment of Multisystem Inflammatory Syndrome in Children.

BACKGROUND: Evidence is urgently needed to support treatment decisions for children with multisystem inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2. METHODS: We performed an international observational cohort study of clinical and outcome data regarding suspected MIS-C that had been uploaded by physicians onto a Web-based database. We used inverse-probability weighting and generalized linear models to evaluate intravenous immune globulin (IVIG) as a reference, as compared with IVIG plus glucocorticoids and glucocorticoids alone. There were two primary outcomes: the first was a composite of inotropic support or mechanical ventilation by day 2 or later or death; the second was a reduction in disease severity on an ordinal scale by day 2. Secondary outcomes included treatment escalation and the time until a reduction in organ failure and inflammation. RESULTS: Data were available regarding the course of treatment for 614 children from 32 countries from June 2020 through February 2021; 490 met the World Health Organization criteria for MIS-C. Of the 614 children with suspected MIS-C, 246 received primary treatment with IVIG alone, 208 with IVIG plus glucocorticoids, and 99 with glucocorticoids alone; 22 children received other treatment combinations, including biologic agents, and 39 received no immunomodulatory therapy. Receipt of inotropic or ventilatory support or death occurred in 56 patients who received IVIG plus glucocorticoids (adjusted odds ratio for the comparison with IVIG alone, 0.77; 95% confidence interval [CI], 0.33 to 1.82) and in 17 patients who received glucocorticoids alone (adjusted odds ratio, 0.54; 95% CI, 0.22 to 1.33). The adjusted odds ratios for a reduction in disease severity were similar in the two groups, as compared with IVIG alone (0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids alone). The time until a reduction in disease severity was similar in the three groups. CONCLUSIONS: We found no evidence that recovery from MIS-C differed after primary treatment with IVIG alone, IVIG plus glucocorticoids, or glucocorticoids alone, although significant differences may emerge as more data accrue. (Funded by the European Union's Horizon 2020 Program and others; BATS ISRCTN number, ISRCTN69546370.).

Kallikrein directly interacts with and activates Factor IX, resulting in thrombin generation and fibrin formation independent of Factor XI.

Kallikrein (PKa), generated by activation of its precursor prekallikrein (PK), plays a role in the contact activation phase of coagulation and functions in the kallikrein-kinin system to generate bradykinin. The general dogma has been that the contribution of PKa to the coagulation cascade is dependent on its action on FXII. Recently this dogma has been challenged by studies in human plasma showing thrombin generation due to PKa activity on FIX and also by murine studies showing formation of FIXa-antithrombin complexes in FXI deficient mice. In this study, we demonstrate high-affinity binding interactions between PK(a) and FIX(a) using surface plasmon resonance and show that these interactions are likely to occur under physiological conditions. Furthermore, we directly demonstrate dose- and time-dependent cleavage of FIX by PKa in a purified system by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis and chromogenic assays. By using normal pooled plasma and a range of coagulation factor-deficient plasmas, we show that this action of PKa on FIX not only results in thrombin generation, but also promotes fibrin formation in the absence of FXII or FXI. Comparison of the kinetics of either FXIa- or PKa-induced activation of FIX suggest that PKa could be a significant physiological activator of FIX. Our data indicate that the coagulation cascade needs to be redefined to indicate that PKa can directly activate FIX. The circumstances that drive PKa substrate specificity remain to be determined.

Polyspecific Intravenous Immunoglobulin in Clindamycin-treated Patients With Streptococcal Toxic Shock Syndrome: A Systematic Review and Meta-analysis.

We evaluated the effect of intravenous immunoglobulin (IVIG) on mortality in clindamycin-treated streptococcal toxic shock syndrome using a meta-analysis. In association with IVIG, mortality fell from 33.7% to 15.7% with remarkable consistency across the single randomized and four nonrandomized studies.

The interaction between fibrinogen and zymogen FXIII-A2B2 is mediated by fibrinogen residues γ390-396 and the FXIII-B subunits.

Coagulation transglutaminase factor XIII (FXIII) exists in circulation as heterotetrameric proenzyme FXIII-A2B2 Effectively all FXIII-A2B2 circulates bound to fibrinogen, and excess FXIII-B2 circulates in plasma. The motifs that mediate interaction of FXIII-A2B2 with fibrinogen have been elusive. We recently detected reduced binding of FXIII-A2B2 to murine fibrinogen that has γ-chain residues 390-396 mutated to alanines (Fibγ390-396A). Here, we evaluated binding features using human components, including recombinant fibrinogen variants, FXIII-A2B2, and isolated FXIII-A2 and -B2 homodimers. FXIII-A2B2 coprecipitated with wild-type (γA/γA), alternatively-spliced (γ'/γ'), and αC-truncated (Aα251) fibrinogens, whereas coprecipitation with human Fibγ390-396A was reduced by 75% (P <0001). Surface plasmon resonance showed γA/γA, γ'/γ', and Aα251 fibrinogens bound FXIII-A2B2 with high affinity (nanomolar); however, Fibγ390-396A did not bind FXIII-A2B2 These data indicate fibrinogen residues γ390-396 comprise the major binding motif for FXIII-A2B2 Compared with γA/γA clots, FXIII-A2B2 activation peptide release was 2.7-fold slower in Fibγ390-396A clots (P < .02). Conversely, activation of recombinant FXIII-A2 (lacking FXIII-B2) was similar in γA/γA and Fibγ390-396A clots, suggesting fibrinogen residues γ390-396 accelerate FXIII-A2B2 activation in a FXIII-B2-dependent mechanism. Recombinant FXIII-B2 bound γA/γA, γ'/γ', and Aα251 with similar affinities as FXIII-A2B2, but did not bind or coprecipitate with Fibγ390-396A FXIII-B2 also coprecipitated with fibrinogen from FXIII-A-deficient mouse and human plasmas. Collectively, these data indicate that FXIII-A2B2 binds fibrinogen residues γ390-396 via the B subunits, and that excess plasma FXIII-B2 is not free, but rather circulates bound to fibrinogen. These findings provide insight into assembly of the fibrinogen/FXIII-A2B2 complex in both physiologic and therapeutic situations.

Immobilized fibrinogen activates human platelets through glycoprotein VI.

Glycoprotein VI, a major platelet activation receptor for collagen and fibrin, is considered a particularly promising, safe antithrombotic target. In this study, we show that human glycoprotein VI signals upon platelet adhesion to fibrinogen. Full spreading of human platelets on fibrinogen was abolished in platelets from glycoprotein VI- deficient patients suggesting that fibrinogen activates platelets through glycoprotein VI. While mouse platelets failed to spread on fibrinogen, human-glycoprotein VI-transgenic mouse platelets showed full spreading and increased Ca2+ signaling through the tyrosine kinase Syk. Direct binding of fibrinogen to human glycoprotein VI was shown by surface plasmon resonance and by increased adhesion to fibrinogen of human glycoprotein VI-transfected RBL-2H3 cells relative to mock-transfected cells. Blockade of human glycoprotein VI with the Fab of the monoclonal antibody 9O12 impaired platelet aggregation on preformed platelet aggregates in flowing blood independent of collagen and fibrin exposure. These results demonstrate that human glycoprotein VI binds to immobilized fibrinogen and show that this contributes to platelet spreading and platelet aggregation under flow.

Admission Plasma Troponin I Is Associated With Mortality in Pediatric Intensive Care.

OBJECTIVES: Assessment of whether admission plasma troponin I level is associated with mortality or requirement for vasoactive drugs in pediatric intensive care. DESIGN: Retrospective cohort study. SETTING: Single centre, tertiary referral general PICU, without a cardiac surgical program. PATIENTS: Three hundred and nineteen patients 0-18 years old in two cohorts. Cohort 1 was admitted between January 2009 and September 2012 and the cohort 2 between April 2014 and April 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma troponin I was measured in patients in cohort 1 only if the attending physician ordered the test due to clinical concern regarding myocardial injury. The second cohort had plasma troponin I routinely measured at admission. The primary outcome was death during PICU admission, and the secondary outcome was maximum inotrope requirement during PICU stay, measured by Vasoactive Inotrope Score. Plasma troponin I was a discriminator for mortality in both cohorts (area under the receiver-operating characteristic curve of 0.73 and 0.86 in cohorts 1 and 2, respectively). In an adjusted analysis using Cox regression, accounting for Pediatric Index of Mortality 2 risk of mortality and age, elevated plasma troponin I was significantly associated with death in both cohorts (hazard ratio, 4.99; p = 0.033; hazard ratio, 10.5; p = 0.026 in cohorts 1 and 2, respectively). Elevated plasma troponin I was only associated with increased Vasoactive Inotrope Score following multivariate analysis in the cohort 2. CONCLUSIONS: Detectable plasma troponin I at admission to PICU is independently associated with death. The utility of troponin I as a stratification biomarker requires further evaluation.

East London's Homeless: a retrospective review of an eye clinic for homeless people.

BACKGROUND: There is very little published work on the visual needs of homeless people. This paper is the first study to investigate the visual needs of homeless people in the UK. Although similar work has been done in other countries, this study is unique because the United Kingdom is the only country with a National Health Service which provides free healthcare at the point of access. This study analysed the refractive status of the sample used, determined the demographics of homeless people seeking eye care and established if there is a need for community eye health with access to free spectacle correction in East London. METHODS: This retrospective case study analysed the clinical records of 1,141 homeless people using the Vision Care for Homeless People services at one of their clinics in East London. All eye examinations were carried out by qualified optometrists and, where appropriate, spectacles were dispensed to patients. Data captured included age, gender, ethnicity and refractive error. Results were analysed using two-sample t-tests with Excel and Minitab. RESULTS: Demographics of age, gender and ethnicity are described. Spherical equivalents (SE) were calculated from prescription data available for 841 clinic users. Emmetropia was defined as SE-0.50DS to +1DS, myopia as SE < -0.50DS, and hyperopia as SE > +1DS. The majority of clinic users were male (79.2 %, n = 923). Approximately 80 % (n = 583) of clinic users were white, 10 % (n = 72) were 'black', 4 % (n = 29) 'Asian' and the remaining 5.6 % (n = 40) were of 'mixed ethnicity' and 'other' groups. The mean age of females attending the clinic was significantly lower than that of males (45.9 years, SD = 13.8 vs' 48.4 years, SD = 11.8) when analysed using a two-sample t-test (t (317) = 2.44, p = 0.02). One third of service users were aged between 50-59 years. Myopia and hyperopia prevalence rates were 37.0 % and 21.0 % respectively. A total of 34.8 % of homeless people were found to have uncorrected refractive error, and required spectacle correction. CONCLUSIONS: This study has identified a high proportion of uncorrected refractive error in this sample and therefore a need for regular eye examinations and provision of refractive correction for homeless people.

A chemical potentiator of copper-accumulation used to investigate the iron-regulons of Saccharomyces cerevisiae.

The extreme resistance of Saccharomyces cerevisiae to copper is overcome by 2-(6-benzyl-2-pyridyl)quinazoline (BPQ), providing a chemical-biology tool which has been exploited in two lines of discovery. First, BPQ is shown to form a red (BPQ)2 Cu(I) complex and promote Ctr1-independent copper-accumulation in whole cells and in mitochondria isolated from treated cells. Multiple phenotypes, including loss of aconitase activity, are consistent with copper-BPQ mediated damage to mitochondrial iron-sulphur clusters. Thus, a biochemical basis of copper-toxicity in S. cerevisiae is analogous to other organisms. Second, iron regulons controlled by Aft1/2, Cth2 and Yap5 that respond to mitochondrial iron-sulphur cluster status are modulated by copper-BPQ causing iron hyper-accumulation via upregulated iron-import. Comparison of copper-BPQ treated, untreated and copper-only treated wild-type and fra2Δ by RNA-seq has uncovered a new candidate Aft1 target-gene (LSO1) and paralogous non-target (LSO2), plus nine putative Cth2 target-transcripts. Two lines of evidence confirm that Fra2 dominates basal repression of the Aft1/2 regulons in iron-replete cultures. Fra2-independent control of these regulons is also observed but CTH2 itself appears to be atypically Fra2-dependent. However, control of Cth2-target transcripts which is independent of CTH2 transcript abundance or of Fra2, is also quantified. Use of copper-BPQ supports a substantial contribution of metabolite repression to iron-regulation.

Fluid overload in a South African pediatric intensive care unit.

OBJECTIVE: Fluid resuscitation is integral to resuscitation guidelines and critical care. However, fluid overload (FO) yields increased morbidity. METHODS: Prospective observational study of Red Cross War Memorial Children's Hospital pediatric intensive care unit admissions (February to March 2013). FO % = (fluid in minus fluid out) [liters]/weight [kg] × 100%. PRIMARY OUTCOMES: FO ≥ 10%, 28 day mortality. RESULTS: Median [interquartile range (IQR)] age: 9.5 (2.0-39.0) months, median (IQR) admission weight: 7.9 (3.6-13.7) kg. Median (IQR) FO with admission weight: 3.5 (2.1-4.9)%; three patients had FO ≥ 10%. The 28 day mortality was 10% (n = 10). Patients who died had higher mean (IQR) FO using admission weight [4.9 (2.9-9.3)% vs. 3.4 (1.9-4.8)%; p = 0.04]. CONCLUSIONS: Low FO ≥ 10% prevalence with 28 day mortality 10%. Higher FO% with admission weight associated with mortality (p = 0.04). We advocate further investigation of FO% as a simple bedside tool.

Self-compassion and self-coldness and their relationship with psychological distress and subjective well-being among community-based Hazaras in Australia.

Hazaras are a newly emerging community in Australia and limited research has explored their mental health. The first aim of this study was to explore levels of psychological distress and subjective well-being reported by Hazaras in Australia, and whether scores on psychosocial variables (self-compassion, self-coldness, acculturation, resilience, spirituality), psychological distress and domains of subjective well-being differed by sociodemographic groups. The second aim had two parts: (a) to examine bivariate relationships between the psychosocial variables, psychological distress and subjective well-being; and (b) to examine whether the psychosocial predictor variables independently contributed to subjective well-being and psychological distress when controlling for sociodemographic characteristics. Seventy-two Hazaras (58 men and 14 women), with a mean age of 28.82 years (SD = 8.84) and average length of time residing in Australia of 10.17 years (SD = 4.11), completed an online survey. There were sociodemographic differences in relation to key variables of interest; for example, participants who did not have family members in Australia reported lower levels of global life satisfaction. Moderate negative relationships were found between self-compassion and psychological distress and between self-coldness and subjective well-being. Self-coldness, self-compassion, resilience and acculturation contributed uniquely to psychological distress and subjective well-being when controlling for sociodemographic variables. Although migration programmes that provide permanent residency and allow family members to join refugees in Australia are limited, they appear important. Many of the difficulties facing Hazaras are ongoing, external and beyond their control (e.g. visa status); however, there is a possibility that self-compassion can play a role as a protective factor.

Host gene expression signatures to identify infection type and organ dysfunction in children evaluated for sepsis: a multicentre cohort study.

BACKGROUND: Sepsis is defined as dysregulated host response to infection that leads to life-threatening organ dysfunction. Biomarkers characterising the dysregulated host response in sepsis are lacking. We aimed to develop host gene expression signatures to predict organ dysfunction in children with bacterial or viral infection. METHODS: This cohort study was done in emergency departments and intensive care units of four hospitals in Queensland, Australia, and recruited children aged 1 month to 17 years who, upon admission, underwent a diagnostic test, including blood cultures, for suspected sepsis. Whole-blood RNA sequencing of blood was performed with Illumina NovaSeq (San Diego, CA, USA). Samples with completed phenotyping, monitoring, and RNA extraction by March 31, 2020, were included in the discovery cohort; samples collected or completed thereafter and by Oct 27, 2021, constituted the Rapid Paediatric Infection Diagnosis in Sepsis (RAPIDS) internal validation cohort. An external validation cohort was assembled from RNA sequencing gene expression count data from the observational European Childhood Life-threatening Infectious Disease Study (EUCLIDS), which recruited children with severe infection in nine European countries between 2012 and 2016. Feature selection approaches were applied to derive novel gene signatures for disease class (bacterial vs viral infection) and disease severity (presence vs absence of organ dysfunction 24 h post-sampling). The primary endpoint was the presence of organ dysfunction 24 h after blood sampling in the presence of confirmed bacterial versus viral infection. Gene signature performance is reported as area under the receiver operating characteristic curves (AUCs) and 95% CI. FINDINGS: Between Sept 25, 2017, and Oct 27, 2021, 907 patients were enrolled. Blood samples from 595 patients were included in the discovery cohort, and samples from 312 children were included in the RAPIDS validation cohort. We derived a ten-gene disease class signature that achieved an AUC of 94·1% (95% CI 90·6-97·7) in distinguishing bacterial from viral infections in the RAPIDS validation cohort. A ten-gene disease severity signature achieved an AUC of 82·2% (95% CI 76·3-88·1) in predicting organ dysfunction within 24 h of sampling in the RAPIDS validation cohort. Used in tandem, the disease class and disease severity signatures predicted organ dysfunction within 24 h of sampling with an AUC of 90·5% (95% CI 83·3-97·6) for patients with predicted bacterial infection and 94·7% (87·8-100·0) for patients with predicted viral infection. In the external EUCLIDS validation dataset (n=362), the disease class and disease severity predicted organ dysfunction at time of sampling with an AUC of 70·1% (95% CI 44·1-96·2) for patients with predicted bacterial infection and 69·6% (53·1-86·0) for patients with predicted viral infection. INTERPRETATION: In children evaluated for sepsis, novel host transcriptomic signatures specific for bacterial and viral infection can identify dysregulated host response leading to organ dysfunction. FUNDING: Australian Government Medical Research Future Fund Genomic Health Futures Mission, Children's Hospital Foundation Queensland, Brisbane Diamantina Health Partners, Emergency Medicine Foundation, Gold Coast Hospital Foundation, Far North Queensland Foundation, Townsville Hospital and Health Services SERTA Grant, and Australian Infectious Diseases Research Centre.

Adverse psychological effects and costs associated with waiting for radiofrequency ablation.

BACKGROUND: Radiofrequency ablation (RFA) is undertaken as a potentially curative treatment for a variety of heart rhythm disturbances. Previous studies have demonstrated improved quality of life and reduced symptoms after ablation. In many health care environments waiting lists exist for scheduling of procedures. However, the psychological effects of waiting for radiofrequency ablation have not previously been assessed. We hypothesized that waiting for this intervention may be associated with increased psychological morbidity and health care costs. METHODS: Ninety-two patients scheduled for elective RFA completed repeated questionnaires comprising the Medical Outcomes Short Form 36, Hospital Anxiety and Depression Scale, and an in-house questionnaire designed to assess the burden of symptoms related to arrhythmia (arrhythmia-related burden score). Mean scores were generated and compared at time points while waiting, before and after the procedure. Regression analyses were carried out to identify predictors of increased psychological morbidity while waiting and immediately prior to the procedure. Health care costs during the waiting period as a consequence of arrhythmia were quantified. RESULTS: Mean scores for parameters of psychological morbidity worsened during the period of waiting and improved after the procedure. Predictors of adverse effects within the cohort varied according to the time point assessed for each of the measures of psychological morbidity. A conservative estimate of the health care cost incurred while waiting exceeds £ 181 per patient. CONCLUSIONS: Waiting for radiofrequency ablation appears to be associated with adverse psychological effects and health care costs. These results may support strategies to reduce waiting times and prioritize resource allocation.

Seeing you through London 2012: eye care at the Olympics.

BACKGROUND: Provision of eye care services for competitors and their support teams has become an integral part of the modern Olympic Games. AIM: To describe the organisation of the eye clinic at London 2012 over a 4-week period and provide outline audit data. METHODS: The clinic employed multidisciplinary eye care professionals and utilised state-of-the-art instrumentation to provide the highest level of eye care. RESULTS: A total of 1406 patients from 154 countries attended the clinic over the Olympic Games, of which, 276 were competitors. All individuals received a comprehensive refractive and ocular health examination. Minor ocular injuries, glaucoma, diabetic retinopathy and macular degeneration were among the conditions detected and managed. Most patients attended the clinic to have their refractive status checked: 973 spectacles and 50 pairs of contact lenses were dispensed. CONCLUSIONS: It is hoped that this account of the provision of eye care at London 2012 will assist with the planning of this service at future events.

Seeing you through London 2012: eye care at the Paralympics.

BACKGROUND: The provision of eye care services for competitors and support teams is integral to the modern Olympic Games. The eye clinic for the London 2012 Paralympic Games employed a multidisciplinary team of eye care professionals using state-of-the-art instrumentation to provide the highest level of eye care. The detailed organisation of the eye care clinic at London 2012 is described in a companion paper which summarises the eye care clinic during the London 2012 Olympic Games. These two reports will aid in planning eye care clinics at future Games. AIM: This paper summarises the organisation of the eye clinic and provides outline audit data relating to eye conditions encountered during the Paralympic Games. RESULTS: A total of 870 patients representing 102 countries attended the eye clinic. 274 (31.5%) were competitors; the remainder were trainers and support staff. No serious ocular injuries resulted from competitor injury in the field of play during the Paralympic Games, although seven patients were referred urgently to hospital eye services for conditions including orbital cellulitis, retinal detachment, exudative macular degeneration, corneal ulcer, Stevens-Johnson syndrome and macular oedema. A total of 749 spectacles, 14 pairs of contact lenses and 7 low vision aids were dispensed. CONCLUSIONS: By combining excellent facilities and equipment with a multidisciplinary team of eye care professionals, we feel we provided the highest level of eye care, providing a legacy for future Games.

Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study.

Background: Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments. Methods: The Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-weighted cohort study, clinical and outcome data from children with suspected or proven MIS-C were collected onto a web-based Research Electronic Data Capture database. After excluding neonates and incomplete or duplicate records, inverse probability weighting was used to compare primary treatments with intravenous immunoglobulin, intravenous immunoglobulin plus glucocorticoids, or glucocorticoids alone, using intravenous immunoglobulin as the reference treatment. Primary outcomes were a composite of inotropic or ventilator support from the second day after treatment initiation, or death, and time to improvement on an ordinal clinical severity scale. Secondary outcomes included treatment escalation, clinical deterioration, fever, and coronary artery aneurysm occurrence and resolution. This study is registered with the ISRCTN registry, ISRCTN69546370. Findings: We enrolled 2101 children (aged 0 months to 19 years) with clinically diagnosed MIS-C from 39 countries between June 14, 2020, and April 25, 2022, and, following exclusions, 2009 patients were included for analysis (median age 8·0 years [IQR 4·2-11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White). 680 (33·8%) patients received primary treatment with intravenous immunoglobulin, 698 (34·7%) with intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) with glucocorticoids alone; 59 (2·9%) patients received other combinations, including biologicals, and 85 (4·2%) patients received no immunomodulators. There were no significant differences between treatments for primary outcomes for the 1586 patients with complete baseline and outcome data that were considered for primary analysis. Adjusted odds ratios for ventilation, inotropic support, or death were 1·09 (95% CI 0·75-1·58; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids and 0·93 (0·58-1·47; corrected p value=1·00) for glucocorticoids alone, versus intravenous immunoglobulin alone. Adjusted average hazard ratios for time to improvement were 1·04 (95% CI 0·91-1·20; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids, and 0·84 (0·70-1·00; corrected p value=0·22) for glucocorticoids alone, versus intravenous immunoglobulin alone. Treatment escalation was less frequent for intravenous immunoglobulin plus glucocorticoids (OR 0·15 [95% CI 0·11-0·20]; p<0·0001) and glucocorticoids alone (0·68 [0·50-0·93]; p=0·014) versus intravenous immunoglobulin alone. Persistent fever (from day 2 onward) was less common with intravenous immunoglobulin plus glucocorticoids compared with either intravenous immunoglobulin alone (OR 0·50 [95% CI 0·38-0·67]; p<0·0001) or glucocorticoids alone (0·63 [0·45-0·88]; p=0·0058). Coronary artery aneurysm occurrence and resolution did not differ significantly between treatment groups. Interpretation: Recovery rates, including occurrence and resolution of coronary artery aneurysms, were similar for primary treatment with intravenous immunoglobulin when compared to glucocorticoids or intravenous immunoglobulin plus glucocorticoids. Initial treatment with glucocorticoids appears to be a safe alternative to immunoglobulin or combined therapy, and might be advantageous in view of the cost and limited availability of intravenous immunoglobulin in many countries. Funding: Imperial College London, the European Union's Horizon 2020, Wellcome Trust, the Medical Research Foundation, UK National Institute for Health and Care Research, and National Institutes of Health.

Diagnosis of childhood febrile illness using a multi-class blood RNA molecular signature.

BACKGROUND: Appropriate treatment and management of children presenting with fever depend on accurate and timely diagnosis, but current diagnostic tests lack sensitivity and specificity and are frequently too slow to inform initial treatment. As an alternative to pathogen detection, host gene expression signatures in blood have shown promise in discriminating several infectious and inflammatory diseases in a dichotomous manner. However, differential diagnosis requires simultaneous consideration of multiple diseases. Here, we show that diverse infectious and inflammatory diseases can be discriminated by the expression levels of a single panel of genes in blood. METHODS: A multi-class supervised machine-learning approach, incorporating clinical consequence of misdiagnosis as a "cost" weighting, was applied to a whole-blood transcriptomic microarray dataset, incorporating 12 publicly available datasets, including 1,212 children with 18 infectious or inflammatory diseases. The transcriptional panel identified was further validated in a new RNA sequencing dataset comprising 411 febrile children. FINDINGS: We identified 161 transcripts that classified patients into 18 disease categories, reflecting individual causative pathogen and specific disease, as well as reliable prediction of broad classes comprising bacterial infection, viral infection, malaria, tuberculosis, or inflammatory disease. The transcriptional panel was validated in an independent cohort and benchmarked against existing dichotomous RNA signatures. CONCLUSIONS: Our data suggest that classification of febrile illness can be achieved with a single blood sample and opens the way for a new approach for clinical diagnosis. FUNDING: European Union's Seventh Framework no. 279185; Horizon2020 no. 668303 PERFORM; Wellcome Trust (206508/Z/17/Z); Medical Research Foundation (MRF-160-0008-ELP-KAFO-C0801); NIHR Imperial BRC.

'In sight, out of mind': the experiences of the compliantly engaged community psychiatric out-patient.

Research on engagement within community-based psychiatric services in the UK has mainly focussed on factors related to those 'at risk' of non-attendance or non-compliance, with the tacit assumption that those in regular attendance are largely content and hence not a priority. The present study systematically explored the experiences and views of 25 people with severe and enduring mental illness who had regularly attended out-patient settings for more than 5 years. Regular attendance at consultations was not synonymous with satisfaction-in fact it masked varying levels of unmet needs and 'de-humanisation'. In order to establish and maintain non-coercive community services that prioritise 'recovery' above illness and 'risk' containment, it is essential that the experiences of people in established and apparently 'less troublesome' therapeutic relationships are also taken into account and integrated into policy and practice.

Infections strain UK hospitals.

High numbers of patients with covid-19 in wards have a serious impact on health services, even if it they are in hospital for a different reason, reports Clare Wilson.

How quickly can you catch covid-19 again?

A prior infection appears to offer some protection, but it is unclear for how long, or whether reinfections are guaranteed to be mild, finds Clare Wilson.