Clinical performance of an infliximab rapid quantification assay

Background: Therapeutic drug monitoring (TDM)-based algorithms can be used to guide infliximab (IFX) adjustments in inflammatory bowel disease (IBD) patients. This study aimed to explore a rapid IFX-quantification test from a clinical perspective. Methods: This manuscript describes a prospective cohort study involving 110 ulcerative colitis (UC) patients on the maintenance phase of IFX. IFX trough levels were quantified using a rapid quantification assay and a commonly-used reference kit. Results: Irrespective of the assay used to measure IFX, its through levels were statistically different between patients with and without endoscopic remission (Mayo endoscopic score = 0), as well as between patients stratified by their faecal calprotectin (FC) levels. Despite the fact that the two methods correlated well with each other [Spearman's rank correlation coefficient = 0.843, p < 0.001; intraclass correlation coefficients = 0.857, 95% confidence interval (CI): 0.791-0.903], there was a discernible systematic variation; values obtained with the reference kit were on average 2.62 units higher than those obtained with the rapid assay. Notwithstanding, 3 mu g/ml was shown to be an acceptable cut-off to assess endoscopic status and inflammatory burden levels using both assays. The percentage of patients that had a positive outcome when the IFX concentration measured by the rapid assay ranked above 3 mu g/ml was 88% both for a Mayo endoscopic score <= 1 and for an FC concentration <250 mu g/g. Conclusions: Based on this study, we concluded that using the rapid IFX assessment system with a 3 mu g/ml threshold is a reliable alternative to the time-consuming enzyme-linked immunosorbent assays in patients on the maintenance phase of IFX.Portuguese IBD Group (GEDII, Grupo de Estudo da Doenca Inflamatoria Intestinal)info:eu-repo/semantics/publishedVersio

In vitro and in vivo effects of SerpinA1 on the modulation of Transthyretin proteolysis

Transthyretin (TTR) proteolysis has been recognized as a complementary mechanism contributing to transthyretin-related amyloidosis (ATTR amyloidosis). Accordingly, amyloid deposits can be composed mainly of full-length TTR or contain a mixture of both cleaved and full-length TTR, particularly in the heart. The fragmentation pattern at Lys48 suggests the involvement of a serine protease, such as plasmin. The most common TTR variant, TTR V30M, is susceptible to plasmin-mediated proteolysis, and the presence of TTR fragments facilitates TTR amyloidogenesis. Recent studies revealed that the serine protease inhibitor, SerpinA1, was differentially expressed in hepatocyte-like cells (HLCs) from ATTR patients. In this work, we evaluated the effects of SerpinA1 on in vitro and in vivo modulation of TTR V30M proteolysis, aggregation, and deposition. We found that plasmin-mediated TTR proteolysis and aggregation are partially inhibited by SerpinA1. Furthermore, in vivo downregulation of SerpinA1 increased TTR levels in mice plasma and deposition in the cardiac tissue of older animals. The presence of TTR fragments was observed in the heart of young and old mice but not in other tissues following SerpinA1 knockdown. Increased proteolytic activity, particularly plasmin activity, was detected in mice plasmas. Overall, our results indicate that SerpinA1 modulates TTR proteolysis and aggregation in vitro and in vivo.This research was funded by COMPETE 2020 of PT2020 through the European Regional Development Fund (ERDF), “NETDIAMOND—New Targets in DIAstolic heart failure: from coMOrbidities to persoNalizeD medicine” project financed by the European Structural and Investment Funds (ESIF), through the Programa Operacional Regional (POCI-01-0145-FEDER-016385) and HEALTHUNORTE: Setting-up biobanks and regenerative medicine strategies to boost research in cardiovascular, musculoskeletal, neurological, oncological, immunological, and infectious diseases, NORTE- 01-0145-FEDER-000039. FB was supported by FCT—Fundação para a Ciência e Tecnologia/MEC— Ministério da Educação e Ciência with a PhD fellowship (SFRH/BD/123674/2016)

Detection of anti-infliximab antibodies is impacted by antibody titer, infliximab level and IgG4 antibodies: a systematic comparison of three different assays

Background: There is scant information on the accuracy of different assays used to measure anti-infliximab antibodies (ADAs), especially in the presence of detectable infliximab (IFX). We thus aimed to evaluate and compare three different assays for the detection of IFX and ADAs and to clarify the impact of the presence of circulating IFX on the accuracy of the ADA assays.Methods: Blood samples from 79 ulcerative colitis (UC) patients treated with infliximab were assessed for IFX levels and ADAs using three different assays: an in-house assay and two commercial kits, Immundiagnostik and Theradiag. Sera samples with ADAs and undetectable levels of IFX were spiked with exogenous IFX and analyzed for ADAs.Results: The three assays showed 81-96% agreement for the measured IFX level. However, the in-house assay and Immundiagnostik assays detected ADAs in 34 out of 79 samples, whereas Theradiag only detected ADAs in 24 samples. Samples negative for ADAs with Theradiag, but ADA-positive in both the in-house and Immundiagnostik assays, were positive for IFX or IgG4 ADAs. In spiking experiments, a low concentration of exogenous IFX (5 mu g/ml) hampered ADA detection with Theradiag in sera samples with ADA levels of between 3 and 10 mu g/ml. In the Immundiagnostik assay detection interference was only observed at concentrations of exogenous IFX higher than 30 mu g/ml. However, in samples with high levels of ADAs (> 25 mu g/ml) interference was only observed at IFX concentrations higher than 100 mu g/ml in all three assays. Binary (IFX/ADA) stratification of the results showed that IFX+/ADA and IFX-/ADAs + were less influenced by the assay results than the double-positive (IFX+/ADAs+) and double-negative (IFX-/ADAs-) combination.Conclusions: All three methodologies are equally suitable for measuring IFX levels. However, erroneous therapeutic decisions may occur when patients show double-negative (IFX-/ADAs) or double-positive (IFX+/ADAs+) status, since agreement between assays is significantly lower in these circumstances

Qualidade de vida e fatores associados em mulheres sobreviventes ao câncer do colo do útero

The treatment for cervical cancer can lead to late adverse effects such as sexual, bowel or urinary dysfunction; early menopause and lymphedema in the lower limb, which may have a negative impact on quality of life. The objective was to assess the quality of life of cervical cancer survivors, their associated factors, and to compare quality of life with a control group of women with no history of cancer. Women undergoing treatment for cervical cancer from a minimum of three months were included in the cancer group (n = 37). In the control group, which is population-based, were included women without history of cancer (n = 37). The quality of life was evaluated using the WHOQOL-bref and the sexual function by the Female Sexual Function Index. Clinical, therapeutic and socioeconomic variables were evaluated by a questionnaire developed by the authors. In comparison to control group, the cancer group presented higher proportion of women who lived without a partner and who considered the relationship with their partner as poor / regular. In addition, cervical cancer survivors have urinary, intestinal and sexual dysfunctions. Besides, the cancer group exhibited poor score in the "Physical" and "Social Relations" domains of WHOQOL-bref (p = 0.03 and 0.01, respectively). The factors independently associated with "Physical" domain were lower limb lymphedema and urinary retention, and with "Social Relations" domain were social support of friends and vaginal stenosis / shortening. The results suggest negative impact of the disease and its treatment on quality of life of cervical cancer survivors. Thus, it should be investigated the quality of life and the factors associated with it in order to improve patient’s care, which should be performed by multiprofessional team.O tratamento para o câncer do colo do útero pode levar à ocorrência de efeitos adversos tardios, como disfunções sexuais, intestinais ou urinárias; menopausa precoce e linfedema em membro inferior, os quais podem ter impacto negativo na qualidade de vida. O objetivo do estudo foi avaliar a qualidade de vida de sobreviventes ao câncer do colo do útero, seus fatores associados e comparar a qualidade de vida com um grupo controle de mulheres sem história de câncer. O grupo câncer foi composto por mulheres com término do tratamento há três meses (n= 37). O grupo controle, de base populacional, foi composto por mulheres sem história de câncer (n= 37). A qualidade de vida foi avaliada pelo WHOQOL-bref e a função sexual pelo Female Sexual Function Índex. Variáveis clínicas, terapêuticas e socioeconômicas foram avaliadas por questionário desenvolvido pelos autores. Em comparação ao controle, o grupo câncer apresentou maior percentual de mulheres que viviam sem companheiro, que consideravam o relacionamento com o companheiro como ruim/regular e que apresentavam disfunções urinárias, intestinais e sexuais. Além disso, o grupo câncer apresentou piores escores nos domínios “Físico” e “Relações Sociais” do WHOQOL-bref (p=0,03 e 0,01, respectivamente). Foram fatores independentemente associados ao domínio “Físico”: linfedema de membros inferiores e retenção urinária; e ao domínio “Relações Sociais”: apoio social de amigos e estenose/encurtamento vaginal. Os resultados sugerem impacto negativo da doença e de seu tratamento sobre a qualidade de vida das sobreviventes. Deve-se investigar a qualidade de vida e os fatores que a influenciam, visando um atendimento mais integral, direcionado às necessidades das pacientes, por meio de equipe multiprofissional

Geoeconomic variations in epidemiology, ventilation management, and outcomes in invasively ventilated intensive care unit patients without acute respiratory distress syndrome: a pooled analysis of four observational studies

Background: Geoeconomic variations in epidemiology, the practice of ventilation, and outcome in invasively ventilated intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) remain unexplored. In this analysis we aim to address these gaps using individual patient data of four large observational studies. Methods: In this pooled analysis we harmonised individual patient data from the ERICC, LUNG SAFE, PRoVENT, and PRoVENT-iMiC prospective observational studies, which were conducted from June, 2011, to December, 2018, in 534 ICUs in 54 countries. We used the 2016 World Bank classification to define two geoeconomic regions: middle-income countries (MICs) and high-income countries (HICs). ARDS was defined according to the Berlin criteria. Descriptive statistics were used to compare patients in MICs versus HICs. The primary outcome was the use of low tidal volume ventilation (LTVV) for the first 3 days of mechanical ventilation. Secondary outcomes were key ventilation parameters (tidal volume size, positive end-expiratory pressure, fraction of inspired oxygen, peak pressure, plateau pressure, driving pressure, and respiratory rate), patient characteristics, the risk for and actual development of acute respiratory distress syndrome after the first day of ventilation, duration of ventilation, ICU length of stay, and ICU mortality. Findings: Of the 7608 patients included in the original studies, this analysis included 3852 patients without ARDS, of whom 2345 were from MICs and 1507 were from HICs. Patients in MICs were younger, shorter and with a slightly lower body-mass index, more often had diabetes and active cancer, but less often chronic obstructive pulmonary disease and heart failure than patients from HICs. Sequential organ failure assessment scores were similar in MICs and HICs. Use of LTVV in MICs and HICs was comparable (42·4% vs 44·2%; absolute difference -1·69 [-9·58 to 6·11] p=0·67; data available in 3174 [82%] of 3852 patients). The median applied positive end expiratory pressure was lower in MICs than in HICs (5 [IQR 5-8] vs 6 [5-8] cm H2O; p=0·0011). ICU mortality was higher in MICs than in HICs (30·5% vs 19·9%; p=0·0004; adjusted effect 16·41% [95% CI 9·52-23·52]; p&lt;0·0001) and was inversely associated with gross domestic product (adjusted odds ratio for a US$10 000 increase per capita 0·80 [95% CI 0·75-0·86]; p&lt;0·0001). Interpretation: Despite similar disease severity and ventilation management, ICU mortality in patients without ARDS is higher in MICs than in HICs, with a strong association with country-level economic status