External validation of the Predicting Asthma Risk in Children tool in a clinical cohort

INTRODUCTION: The Predicting Asthma Risk in Children (PARC) tool uses questionnaire-based respiratory symptoms collected from preschool children to predict asthma risk 5 years later. The tool was developed and validated in population cohorts but not validated using a clinical cohort. We aimed to externally validate the PARC tool in a pediatric pulmonology clinic setting. METHODS: The Swiss Paediatric Airway Cohort (SPAC) is a prospective cohort of children seen in pediatric pulmonology clinics across Switzerland. We included children aged 1-6 years with cough or wheeze at baseline who completed the 2-year follow-up questionnaire. The outcome was defined as current wheeze plus use of asthma medication. We assessed performance using: sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV), area under the curve (AUC), scaled Brier's score, and Nagelkerke's R$^{2}$ scores. We compared performance in SPAC to that in the original population, the Leicester Respiratory Cohort (LRC). RESULTS: Among 346 children included, 125 (36%) reported the outcome after 2 years. At a PARC score of 4: sensitivity was higher (95% vs. 79%), specificity lower (14% vs. 57%), and NPV and PPV comparable (0.84 vs. 0.87 and 0.37 vs. 0.42) in SPAC versus LRC. AUC (0.71 vs. 0.78), R$^{2}$ (0.18 vs. 0.28) and Brier's scores (0.13 vs. 0.22) were lower in SPAC. CONCLUSIONS: The PARC tool shows some clinical utility, particularly for ruling out the development of asthma in young children, but performance limitations highlight the need for new prediction tools to be developed specifically for the clinical setting

Tofacitinib for ulcerative colitis:results of the prospective Dutch Initiative on Crohn and Colitis (ICC) registry

Background: Tofacitinib is a Janus kinase inhibitor approved for the treatment of ulcerative colitis (UC). Aim: To evaluate effectiveness, safety and use of tofacitinib in daily practice. Methods: UC patients initiating tofacitinib were prospectively enrolled in 15 hospitals in the Netherlands. Corticosteroid-free clinical remission (short clinical colitis activity index [SCCAI] ≤2), biochemical remission (faecal calprotectin level ≤250 µg/g), combined corticosteroid-free clinical and biochemical remission, predictors of remission, safety outcomes, treatment dose and effect on lipids were determined at weeks 12 and 24. Endoscopic outcomes were evaluated in centres with routine endoscopic evaluation. Results: In total, 123 UC patients (95% anti-TNF, 62% vedolizumab and 3% ustekinumab experienced) were followed for a median duration of 24 weeks (interquartile range 12-26). The proportion of patients in corticosteroid-free clinical, biochemical, and combined corticosteroid-free clinical and biochemical remission rate at week 24 was 29% (n: 22/77), 25% (n: 14/57), and 19% (n: 11/57) respectively. Endoscopic remission (Mayo = 0) was achieved in 21% of patients at week 12 (n: 7/33). Prior vedolizumab exposure was associated with reduced clinical remission (odds ratio 0.33, 95% confidence interval [CI] 0.11-0.94). At week 24, 33% (n: 14/42) of patients still on tofacitinib treatment used 10 mg twice daily. In total, 33 tofacitinib-related adverse events (89 per 100 patient years) occurred, 7 (6% of total cohort) resulted in discontinuation. Cholesterol, HDL and LDL levels increased during induction treatment by 18% (95% CI 9-26), 18% (95% CI 8-28) and 21% (95% CI 14-39) respectively. Conclusion: Tofacitinib is an effective treatment for UC after anti-TNF and vedolizumab failure. However, a relatively high rate of adverse events was observed resulting in discontinuation in 6% of patients

European Respiratory Society clinical practice guidelines for the diagnosis of asthma in children aged 5-16 years.

Diagnosing asthma in children represents an important clinical challenge. There is no single gold standard test to confirm the diagnosis. Consequently, both over-, and under-diagnosis of asthma are frequent in children.A Task Force (TF) supported by the European Respiratory Society has developed these evidence-based clinical practice guidelines for the diagnosis of asthma in children aged 5-16 years using nine PICO (Population, Intervention, Comparator and Outcome) questions. The TF conducted systematic literature searches for all PICO questions and screened the outputs from these, including relevant full text articles. All TF members approved the final decision for inclusion of research papers. The TF assessed the quality of the evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach.The TF then developed a diagnostic algorithm based on the critical appraisal of the PICO questions, preferences expressed by lay members and test availability. Proposed cut-offs were determined based on the best available evidence. The TF formulated recommendations using the GRADE Evidence to Decision framework.Based on the critical appraisal of the evidence and the Evidence to Decision Framework the TF recommends spirometry, bronchodilator reversibility testing and FeNO as first line diagnostic tests in children under investigation for asthma. The TF recommends against diagnosing asthma in children based on clinical history alone or following a single abnormal objective test. Finally, this guideline also proposes a set of research priorities to improve asthma diagnosis in children in the future

Differentiation stage of myeloma plasma cells: biological and clinical significance

[EN] The notion that plasma cells (PCs) are terminally differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated in healthy individuals (n = 20) that the CD19 − CD81 expression axis identifies three bone marrow (BM)PC subsets with distinct age-prevalence, proliferation, replication-history, immunoglobulin-production, and phenotype, consistent with progressively increased differentiation from CD19+CD81+ into CD19 − CD81+ and CD19 − CD81 − BMPCs. Afterwards, we demonstrated in 225 newly diagnosed MM patients that, comparing to normal BMPC counterparts, 59% had fully differentiated (CD19 − CD81 −) clones, 38% intermediate-differentiated (CD19 − CD81+) and 3% less-differentiated (CD19+CD81+) clones. The latter patients had dismal outcome, and PC differentiation emerged as an independent prognostic marker for progression-free (HR: 1.7; P = 0.005) and overall survival (HR: 2.1; P = 0.006). Longitudinal comparison of diagnostic vs minimal-residual-disease samples (n = 40) unraveled that in 20% of patients, less-differentiated PCs subclones become enriched after therapy-induced pressure. We also revealed that CD81 expression is epigenetically regulated, that less-differentiated clonal PCs retain high expression of genes related to preceding B-cell stages (for example: PAX5), and show distinct mutation profile vs fully differentiated PC clones within individual patients. Together, we shed new light into PC plasticity and demonstrated that MM patients harbouring less-differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles

Clinical and organizational factors associated with mortality during the peak of first COVID-19 wave: the global UNITE-COVID study

Purpose: To accommodate the unprecedented number of critically ill patients with pneumonia caused by coronavirus disease 2019 (COVID-19) expansion of the capacity of intensive care unit (ICU) to clinical areas not previously used for critical care was necessary. We describe the global burden of COVID-19 admissions and the clinical and organizational characteristics associated with outcomes in critically ill COVID-19 patients. Methods: Multicenter, international, point prevalence study, including adult patients with SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR) and a diagnosis of COVID-19 admitted to ICU between February 15th and May 15th, 2020. Results: 4994 patients from 280 ICUs in 46 countries were included. Included ICUs increased their total capacity from 4931 to 7630 beds, deploying personnel from other areas. Overall, 1986 (39.8%) patients were admitted to surge capacity beds. Invasive ventilation at admission was present in 2325 (46.5%) patients and was required during ICU stay in 85.8% of patients. 60-day mortality was 33.9% (IQR across units: 20%–50%) and ICU mortality 32.7%. Older age, invasive mechanical ventilation, and acute kidney injury (AKI) were associated with increased mortality. These associations were also confirmed specifically in mechanically ventilated patients. Admission to surge capacity beds was not associated with mortality, even after controlling for other factors. Conclusions: ICUs responded to the increase in COVID-19 patients by increasing bed availability and staff, admitting up to 40% of patients in surge capacity beds. Although mortality in this population was high, admission to a surge capacity bed was not associated with increased mortality. Older age, invasive mechanical ventilation, and AKI were identified as the strongest predictors of mortality

Co-infection and ICU-acquired infection in COIVD-19 ICU patients: a secondary analysis of the UNITE-COVID data set

Background: The COVID-19 pandemic presented major challenges for critical care facilities worldwide. Infections which develop alongside or subsequent to viral pneumonitis are a challenge under sporadic and pandemic conditions; however, data have suggested that patterns of these differ between COVID-19 and other viral pneumonitides. This secondary analysis aimed to explore patterns of co-infection and intensive care unit-acquired infections (ICU-AI) and the relationship to use of corticosteroids in a large, international cohort of critically ill COVID-19 patients.Methods: This is a multicenter, international, observational study, including adult patients with PCR-confirmed COVID-19 diagnosis admitted to ICUs at the peak of wave one of COVID-19 (February 15th to May 15th, 2020). Data collected included investigator-assessed co-infection at ICU admission, infection acquired in ICU, infection with multi-drug resistant organisms (MDRO) and antibiotic use. Frequencies were compared by Pearson's Chi-squared and continuous variables by Mann-Whitney U test. Propensity score matching for variables associated with ICU-acquired infection was undertaken using R library MatchIT using the "full" matching method.Results: Data were available from 4994 patients. Bacterial co-infection at admission was detected in 716 patients (14%), whilst 85% of patients received antibiotics at that stage. ICU-AI developed in 2715 (54%). The most common ICU-AI was bacterial pneumonia (44% of infections), whilst 9% of patients developed fungal pneumonia; 25% of infections involved MDRO. Patients developing infections in ICU had greater antimicrobial exposure than those without such infections. Incident density (ICU-AI per 1000 ICU days) was in considerable excess of reports from pre-pandemic surveillance. Corticosteroid use was heterogenous between ICUs. In univariate analysis, 58% of patients receiving corticosteroids and 43% of those not receiving steroids developed ICU-AI. Adjusting for potential confounders in the propensity-matched cohort, 71% of patients receiving corticosteroids developed ICU-AI vs 52% of those not receiving corticosteroids. Duration of corticosteroid therapy was also associated with development of ICU-AI and infection with an MDRO.Conclusions: In patients with severe COVID-19 in the first wave, co-infection at admission to ICU was relatively rare but antibiotic use was in substantial excess to that indication. ICU-AI were common and were significantly associated with use of corticosteroids

Direct association between pharyngeal viral secretion and host cytokine response in severe pandemic influenza

<p>Abstract</p> <p>Background</p> <p>Severe disease caused by 2009 pandemic influenza A/H1N1virus is characterized by the presence of hypercytokinemia. The origin of the exacerbated cytokine response is unclear. As observed previously, uncontrolled influenza virus replication could strongly influence cytokine production. The objective of the present study was to evaluate the relationship between host cytokine responses and viral levels in pandemic influenza critically ill patients.</p> <p>Methods</p> <p>Twenty three patients admitted to the ICU with primary viral pneumonia were included in this study. A quantitative PCR based method targeting the M1 influenza gene was developed to quantify pharyngeal viral load. In addition, by using a multiplex based assay, we systematically evaluated host cytokine responses to the viral infection at admission to the ICU. Correlation studies between cytokine levels and viral load were done by calculating the Spearman correlation coefficient.</p> <p>Results</p> <p>Fifteen patients needed of intubation and ventilation, while eight did not need of mechanical ventilation during ICU hospitalization. Viral load in pharyngeal swabs was 300 fold higher in the group of patients with the worst respiratory condition at admission to the ICU. Pharyngeal viral load directly correlated with plasma levels of the pro-inflammatory cytokines IL-6, IL-12p70, IFN-γ, the chemotactic factors MIP-1β, GM-CSF, the angiogenic mediator VEGF and also of the immuno-modulatory cytokine IL-1ra (p < 0.05). Correlation studies demonstrated also the existence of a significant positive association between the levels of these mediators, evidencing that they are simultaneously regulated in response to the virus.</p> <p>Conclusions</p> <p>Severe respiratory disease caused by the 2009 pandemic influenza virus is characterized by the existence of a direct association between viral replication and host cytokine response, revealing a potential pathogenic link with the severe disease caused by other influenza subtypes such as H5N1.</p

Premolis semirufa (Walker, 1856) Envenomation, Disease Affecting Rubber Tappers of the Amazon: Searching for Caterpillar-Bristles Toxic Components

Pararama, the popular name of the larval form of the moth Premolis semirufa inhabits rubber plantations in the Amazon region and the accidental contact of the skin with the caterpillar's bristles or cocoons results in immediate and intense heat, pain, edema, and itching. In many cases a chronic inflammatory reaction with immobilization of the joints occurs. The current study has evaluated the biological and immunochemical characteristics of the Pararama caterpillar bristles extract. Electrophoretic analysis showed the presence of several components, including a very intense 82 kDa band. This latter component was endowed with intense gelatinolytic activity, as observed in zymography assays. Further analysis revealed that the extract also contained hyaluronidase activity but is devoid of phospholipase A2 activity. In vivo assays, using mice, showed that the extract was not lethal, but caused significant edema and induced intense infiltration of inflammatory cells to the envenomation site. The extract also induced high specific antibody titers, but no autoantibodies were detected. The data obtained, so far, demonstrate the existence of a mixture of different enzymes in the bristles of Premolis semirufa caterpillar, which can act together in the generation and development of the clinical manifestations of the Pararama envenomation

Divergent Genomic and Epigenomic Landscapes of Lung Cancer Subtypes Underscore the Selection of Different Oncogenic Pathways during Tumor Development

For therapeutic purposes, non-small cell lung cancer (NSCLC) has traditionally been regarded as a single disease. However, recent evidence suggest that the two major subtypes of NSCLC, adenocarcinoma (AC) and squamous cell carcinoma (SqCC) respond differently to both molecular targeted and new generation chemotherapies. Therefore, identifying the molecular differences between these tumor types may impact novel treatment strategy. We performed the first large-scale analysis of 261 primary NSCLC tumors (169 AC and 92 SqCC), integrating genome-wide DNA copy number, methylation and gene expression profiles to identify subtype-specific molecular alterations relevant to new agent design and choice of therapy. Comparison of AC and SqCC genomic and epigenomic landscapes revealed 778 altered genes with corresponding expression changes that are selected during tumor development in a subtype-specific manner. Analysis of >200 additional NSCLCs confirmed that these genes are responsible for driving the differential development and resulting phenotypes of AC and SqCC. Importantly, we identified key oncogenic pathways disrupted in each subtype that likely serve as the basis for their differential tumor biology and clinical outcomes. Downregulation of HNF4α target genes was the most common pathway specific to AC, while SqCC demonstrated disruption of numerous histone modifying enzymes as well as the transcription factor E2F1. In silico screening of candidate therapeutic compounds using subtype-specific pathway components identified HDAC and PI3K inhibitors as potential treatments tailored to lung SqCC. Together, our findings suggest that AC and SqCC develop through distinct pathogenetic pathways that have significant implication in our approach to the clinical management of NSCLC

Pediatric drug safety signal detection: a new drug-event reference set for performance testing of data-mining methods and systems

BACKGROUND: Better evidence regarding drug safety in the pediatric population might be generated from existing data sources such as spontaneous reporting systems and electronic healthcare records. The Global Research in Paediatrics (GRiP)-Network of Excellence aims to develop pediatric-specific methods that can be applied to these data sources. A reference set of positive and negative drug-event associations is required. OBJECTIVE: The aim of this study was to develop a pediatric-specific reference set of positive and negative drug-event associations. METHODS: Considering user patterns and expert opinion, 16 drugs that are used in individuals aged 0-18 years were selected and evaluated against 16 events, regarded as important safety outcomes. A cross-table of unique drug-event pairs was created. Each pair was classified as potential positive or negative control based on information from the drug's Summary of Product Characteristics and Micromedex. If both information sources consistently listed the event as an adverse event, the combination was reviewed as potential positive control. If both did not, the combination was evaluated as potential negative control. Further evaluation was based on published literature. RESULTS: Selected drugs include ibuprofen, flucloxacillin, domperidone, methylphenidate, montelukast, quinine, and cyproterone/ethinylestradiol. Selected events include bullous eruption, aplastic anemia, ventricular arrhythmia, sudden death, acute kidney injury, psychosis, and seizure. Altogether, 256 unique combinations were reviewed, yielding 37 positive (17 with evidence from the pediatric population and 20 with evidence from adults only) and 90 negative control pairs, with the remainder being unclassifiable. CONCLUSION: We propose a drug-event reference set that can be used to compare different signal detection methods in the pediatric population