Objective
Adverse event (AE) monitoring is central to assessing therapeutic safety. The lack of a comprehensive framework to define and grade maternal and fetal AEs in pregnancy trials severely ...limits understanding risks in pregnant women. We created AE terminology to improve safety monitoring for developing pregnancy drugs, devices and interventions.
Method
Existing severity grading for pregnant AEs and definitions/indicators of ‘severe’ and ‘life‐threatening’ conditions relevant to maternal and fetal clinical trials were identified through a literature search. An international multidisciplinary group identified and filled gaps in definitions and severity grading using Medical Dictionary for Regulatory Activities (MedDRA) terms and severity grading criteria based on Common Terminology Criteria for Adverse Event (CTCAE) generic structure. The draft criteria underwent two rounds of a modified Delphi process with international fetal therapy, obstetric, neonatal, industry experts, patients and patient representatives.
Results
Fetal AEs were defined as being diagnosable in utero with potential to harm the fetus, and were integrated into MedDRA. AE severity was graded independently for the pregnant woman and her fetus. Maternal (n = 12) and fetal (n = 19) AE definitions and severity grading criteria were developed and ratified by consensus.
Conclusions
This Maternal and Fetal AE Terminology version 1.0 allows systematic consistent AE assessment in pregnancy trials to improve safety.
Key points
What's already known about this topic?
Adverse event (AE) monitoring is central to assessing therapeutic safety. The lack of a comprehensive AE framework in pregnancy trials severely limits understanding risks in pregnant women
What does this study add?
Through international consensus we systematically developed definitions and severity grading for maternal and foetal AEs: Maternal and Fetal AE Terminology Version 1.0. New fetal AE definitions were adopted by the Medical Dictionary for Regulatory Activities. This terminology should be used to monitor safety in pregnancy trials
Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe prothrombotic complication of adenoviral vaccines, including the ChAdOx1 nCoV-19 (Vaxzevria) vaccine. The putative mechanism ...involves formation of pathological anti–platelet factor 4 (PF4) antibodies that activate platelets via the low-affinity immunoglobulin G receptor FcγRIIa to drive thrombosis and thrombocytopenia. Functional assays are important for VITT diagnosis, as not all detectable anti-PF4 antibodies are pathogenic, and immunoassays have varying sensitivity. Combination of ligand binding of G protein–coupled receptors (protease-activated receptor-1) and immunoreceptor tyrosine–based activation motif–linked receptors (FcγRIIa) synergistically induce procoagulant platelet formation, which supports thrombin generation. Here, we describe a flow cytometry–based procoagulant platelet assay using cell death marker GSAO and P-selectin to diagnose VITT by exposing donor whole blood to patient plasma in the presence of a protease-activated receptor-1 agonist. Consecutive patients triaged for confirmatory functional VITT testing after screening using PF4/heparin ELISA were evaluated. In a development cohort of 47 patients with suspected VITT, plasma from ELISA-positive patients (n = 23), but not healthy donors (n = 32) or individuals exposed to the ChAdOx1 nCov-19 vaccine without VITT (n = 24), significantly increased the procoagulant platelet response. In a validation cohort of 99 VITT patients identified according to clinicopathologic adjudication, procoagulant flow cytometry identified 93% of VITT cases, including ELISA-negative and serotonin release assay–negative patients. The in vitro effect of intravenous immunoglobulin (IVIg) and fondaparinux trended with the clinical response seen in patients. Induction of FcγRIIa-dependent procoagulant response by patient plasma, suppressible by heparin and IVIg, is highly indicative of VITT, resulting in a sensitive and specific assay that has been adopted as part of a national diagnostic algorithm to identify vaccinated patients with platelet-activating antibodies.
•VITT plasma induces an FcγRIIa-dependent procoagulant response in donor platelets suppressible by heparin and IVIg.•Whole-blood procoagulant platelet flow cytometry has diagnostic potential to detect platelet-activating VITT antibodies.
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Predicting response to anti-tumour necrosis factor alpha (anti-TNFα) drugs at baseline remains an elusive goal in rheumatoid arthritis (RA) management. The purpose of this study was to determine if ...baseline genetic variants of PTPRC, AFF3, myD228, CHUK, MTHFR1, MTHFR2, CD226 and a number of KIR and HLA alleles could predict response to anti-TNF-α in rheumatoid arthritis patients.
Peripheral blood samples were collected from 238 RA patients treated with anti-TNFα drugs. Genotyping was performed using biochip array technology by Randox Laboratories Ltd. and sequence specific polymerase chain reaction. Linear regression analysis was performed to investigate the role of these genotypes in predicting response to treatment, as defined by European League Against Rheumatism (EULAR) response classification and absolute change in disease activity score (DAS28).
Of 238 RA patients analysed, 50.4% received adalimumab, 29.7% received etanercept, 14.8% received infliximab, 3.4% certoluzimab and 1.7% golimumab. The MTHFR1 variant rs1801133 was significantly associated with the EULAR response, p=0.044. Patients with the HLA-DRB1*0404 allele displayed a significantly larger reduction in DAS28 compared to non-carriers (mean -2.22, -1.67 respectively, p=0.033). CD226 rs763361 was the only SNP variant significantly associated with ΔDAS28 (p=0.029).
This study has investigated individual allele associations with reductions in DAS28 across a range of anti-TNFα treatments. A combined predictive model indicates that patients with the HLA-DRB1*0404 allele and without the CD226 rs763361 polymorphism exhibit the largest reduction in DAS28 after anti-TNF-α treatment.
Abstract
Background
Clinical trials of anti-tumour necrosis factor alpha (TNF) have shown efficacy in 60–70% of rheumatoid arthritis patients (RA). Predicting response to anti-TNF drugs at baseline ...remains an elusive goal in RA management. The purpose of this study was to determine if baseline levels of circulating cytokines, soluble receptors, adhesion molecules and metabolic factors differentiate future responders.
Methods
RA patients (n=29) with active disease were recruited, who had failed on disease modifying drugs and were recommended for anti-TNF treatment. Peripheral blood samples were collected at baseline. Responders were identified by a ≥1.2 reduction in disease activity score (DAS28-ESR) at 6 months. Five protein arrays quantified 33 proteins in pre-treatment plasma (Cytokine I, III and IV; Metabolic I; Adhesion molecule; Randox Laboratories Ltd., UK). Data was analysed by Pearson ranked correlation and logistic regression to clinical measures of disease activity at baseline and six months anti-TNF treatment.
Results
Elevated levels of interleukin 8 (p=0.043), monocyte chemoattractant protein (p=0.027), granulocyte-macrophage colony-stimulating factor (p=0.020) and soluble interleukin 2α receptor (p=0.01) were associated with high TJC at baseline. No significant relationship with the protein array panels was recorded relative to baseline DAS28-ESR. Significant inverse correlations were observed between absolute change in DAS28-ESR after 6 months of anti-TNF therapy and baseline levels of interleukin 6 (p=0.026) and resistin (p=0.044).
Conclusions
These findings suggest that baseline levels of specific circulating proteins may help to differentiate RA patient responders to anti-TNF therapies.
Musculoskeletal diseases such as rheumatoid arthritis are complex multifactorial disorders that are chronic in nature and debilitating for patients. A number of drug families are available to ...clinicians to manage these disorders but few tests exist to target these to the most responsive patients. As a consequence, drug failure and switching to drugs with alternate modes of action is common. In parallel, a limited number of laboratory tests are available which measure biological indicators or 'biomarkers' of disease activity, autoimmune status, or joint damage. There is a growing awareness that assimilating the fields of drug selection and diagnostic tests into 'companion diagnostics' could greatly advance disease management and improve outcomes for patients. This review aims to highlight: the current applications of biomarkers in rheumatology with particular focus on companion diagnostics; developments in the fields of proteomics, genomics, microbiomics, imaging and bioinformatics and how integration of these technologies into clinical practice could support therapeutic decisions.
The internal mammary artery is regarded as the optimal conduit for coronary artery bypass grafting in adults. Use of this conduit in paediatric surgery is rare and has been reported mainly in ...patients with Kawasaki's disease. We report five patients who required internal mammary-coronary artery grafting due to adverse anatomical disposition of the coronary artery. In two cases an internal mammary graft was required during correction of transposition of the great arteries. The other cases involved correction of a left coronary artery arising anomalously from the pulmonary artery. Late angiography shows satisfactory growth and patency of the conduits.
In the 13-month period between June 1985 and July 1986, 27 children were found to be HIV positive in the Princess Margaret Hospital in Nassau. Nineteen of the children had clinical AIDS, four were in ...the prodromal phase and four were symptom free. The clinical course of these infants is presented. Of the 18 mothers 16 were screened and were all seropositive and asymptomatic. They remained healthy in spite of subsequent pregnancies in nine of them (56%) during a follow-up period of between 13 and 65 months (mean 40 months). Fifteen of the 18 mothers were Haitian but only three had other risk factors, throwing doubt on the value of selective screening in Afro-Caribbean countries.
La forêt, en plus de ses fonctions économiques reconnues par tous les acteurs du milieu rural tels que le développement de l'emploi rural et le marché local du bois pour la transformation ou pour ...l'énergie, rend de nombreux autres services.Cependant, de multiples risques sont identifiables et doivent être gérés dans et pourront éventuellement être aggravés par les changements climatiques: futures sécheresses favorables aux pathogènes et ravageurs ainsi qu'à la propagation des incendies, et le risque de la modification du vent.Le projet FORRISK se focalisera ainsi sur les risques en forêt dont l'intensité est modulée par le changement climatique. L'histoire des forêts du sud de l'Europe nous rappelle que pour de nombreux problèmes, une approche seulement nationale n'a pas de sens. C'est-à-dire, les risques concernés, les réponses à apporter peuvent être soit au niveau technique soit au niveau de l'organisation des institutions. Pour cette raison, FORRISK vise à coordonner et mettre en réseau trois communautés différentes que sont les acteurs politiques, les gestionnaires et les scientifiques, dans le but d'obtenir quela gestion des risques soit partie intégrante des décisions prises à tous les niveaux du secteur forestier. Cela permettra d'initier une plateforme européenne sur les risques forestiers en facilitant des recommandations et des informations pertinentes à tous les niveaux.Pour y parvenir, le projet analysera et comparera les outils institutionnels, les systèmes et organisations liés à la gestion de risques dans les régions étudiées. Ensuite, FORRISK développera sur le terrain des techniques de lutte écologique, génétique et sylvicole, dont les résultats feront l'objet de guides de bonne pratique. Les outils produits consisteront à des cartes de risques à l'échelle régionale ou subrégionale, ainsi que à des modèles informatiques permettant de faire des diagnostics sur le terrain et de modéliser la propagation du fomès dans les peuplements de pin maritime. Ainsi, décideurs politiques, gestionnaires et scientifiques auront entre leurs mains des outils adaptés à la gestion de nombreux risques menaçant la forêt dans leurs régions.
La forêt, en plus de ses fonctions économiques reconnues par tous les acteurs du milieu rural tels que le développement de l'emploi rural et le marché local du bois pour la transformation ou pour ...l'énergie, rend de nombreux autres services.Cependant, de multiples risques sont identifiables et doivent être gérés dans et pourront éventuellement être aggravés par les changements climatiques: futures sécheresses favorables aux pathogènes et ravageurs ainsi qu'à la propagation des incendies, et le risque de la modification du vent.Le projet FORRISK se focalisera ainsi sur les risques en forêt dont l'intensité est modulée par le changement climatique. L'histoire des forêts du sud de l'Europe nous rappelle que pour de nombreux problèmes, une approche seulement nationale n'a pas de sens. C'est-à-dire, les risques concernés, les réponses à apporter peuvent être soit au niveau technique soit au niveau de l'organisation des institutions. Pour cette raison, FORRISK vise à coordonner et mettre en réseau trois communautés différentes que sont les acteurs politiques, les gestionnaires et les scientifiques, dans le but d'obtenir quela gestion des risques soit partie intégrante des décisions prises à tous les niveaux du secteur forestier. Cela permettra d'initier une plateforme européenne sur les risques forestiers en facilitant des recommandations et des informations pertinentes à tous les niveaux.Pour y parvenir, le projet analysera et comparera les outils institutionnels, les systèmes et organisations liés à la gestion de risques dans les régions étudiées. Ensuite, FORRISK développera sur le terrain des techniques de lutte écologique, génétique et sylvicole, dont les résultats feront l'objet de guides de bonne pratique. Les outils produits consisteront à des cartes de risques à l'échelle régionale ou subrégionale, ainsi que à des modèles informatiques permettant de faire des diagnostics sur le terrain et de modéliser la propagation du fomès dans les peuplements de pin maritime. Ainsi, décideurs politiques, gestionnaires et scientifiques auront entre leurs mains des outils adaptés à la gestion de nombreux risques menaçant la forêt dans leurs régions.
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