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Introduction: Extra-uterine life support technology could provide a more physiologic alternative for the treatment of extremely premature infants, as it allows further fetal growth and development ex utero. Animal studies have been carried out which involved placing fetuses in a liquid-filled incubator, with oxygen supplied through an oxygenator connected to the umbilical vessels. Hence, by delaying lung exposure to air, further lung development and maturation can take place. This medical intervention requires adjustments to current obstetric procedures to maintain liquid-filled lungs through a so-called transfer procedure. Methods: Our objective was to develop obstetric device prototypes that allow clinicians to simulate this birth procedure to safely transfer the infant from the mother’s uterus to an extra-uterine life support system. To facilitate a usercentered design, implementation of medical simulation during early phase design of the prototype development was used. First, the requirements for the procedure and devices were established, by reviewing the literature and through interviewing direct stakeholders. The initial transfer device prototypes were tested on maternal and fetal manikins in participatory simulations with clinicians. Results & discussion: Through analysis of recordings of the simulations, the prototypes were evaluated on effectiveness, safety and usability with latent conditions being identified and improved. This medical simulation-based design process resulted in the development of a set of surgical prototypes and allowed for knowledge building on obstetric care in an extra-uterine life support context. [ABSTRACT FROM AUTHOR]

Several biomarkers of cardiovascular function are found to be increased in rheumatoid arthritis (RA), with some suggesting a relationship with disease activity and improvement with adequate anti-rheumatic treatment. Promising biomarkers include N-terminal pro-brain natriuretic peptide (NT-proBNP) and the soluble receptor form of advanced glycation end-products (sRAGE). The objective of this study was to investigate associations between NT-proBNP and sRAGE levels and markers of inflammation and disease activity in early RA patients and their changes during (effective) anti-rheumatic treatment. Data from 342 consecutive early RA patients participating in the 'Parelsnoer' cohort were used. At baseline and after 6 months' disease activity, NT-proBNP and sRAGE levels were assessed. After 6 months, NT-proBNP decreased from 83 pmol/L (mean) at baseline to 69 pmol/L at follow-up (p < 0.001), while sRAGE increased from 997 pg/mL to 1125 pg/mL (p < 0.001). A larger decrease in erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) was associated with larger changes in NT-proBNP and sRAGE. For every point decrease in ESR, there was a 1.7-point decrease in NT-proBNP and a 2.2-point increase in sRAGE. For CRP, these values were 1.7 and 2.7, respectively (p < 0.001). Suppressing inflammation, independently of achieving remission, increases sRAGE levels and decreases NT-proBNP levels significantly. Whether this translates into a decrease in incident cardiovascular disease remains to be elucidated. [ABSTRACT FROM AUTHOR]

To evaluate the relationship between reported coronavirus disease 2019 (COVID-19)-like symptoms and the presence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antibodies in patients with an immune-mediated inflammatory disorder or post-solid organ transplantation (IMIDT) with and without immunosuppressive medication (imed) and controls. The IENIMINI cohort was a prospective cohort study set up in the Netherlands in March 2020, with 2 monthly (paper) or weekly (online) questionnaires about COVID-19-like symptoms. Participants from this cohort who reported these symptoms between March 2020 and November 2020 were approached for this substudy. SARS-CoV-2 antibodies were tested using a total antibody assay. Of the 1203 participants approached, 629 agreed to participate and were sent a fingerprick test; 565 participants collected a capillary blood sample, of which 562 were usable. Analysis showed that 57/202 (28.2%) of the tested IMIDT group with imed, 48/16 3(29.4%) of the IMIDT group without imed, and 69/197 (35.0%) of the control group tested positive for SARS-CoV-2 antibodies. Seroprevalences of SARS-CoV-2 antibodies between males and females, biological disease-modifying anti-rheumatic drug users and non-users, and those who had had a serious disease period (defined as an episode with dyspnoea and fever) and those who had not, were not statistically different between the three groups. Approximately 30% of patients who had reported COVID-19-like symptoms had SARS-CoV-2 antibodies. The seroprevalence of SARS-CoV-2 antibodies after reported COVID-19-like symptoms was similar in IMIDT patients with and without imed compared to controls. [ABSTRACT FROM AUTHOR]

Objectives: Two‐dimensional speckle‐tracking echocardiography (2D‐STE) is a promising technique which allows assessment of fetal cardiac function, and can be used in the evaluation of cardiac and non‐cardiac diseases in pregnancy. However, reliable fetal reference values for deformation parameters measured using 2D‐STE are needed before it can be introduced into clinical practice. This study aimed to obtain reference values for fetal global longitudinal strain (GLS) and GLS rate (GLSR) measured using 2D‐STE and compare right and left ventricular values. Methods: This was a prospective longitudinal cohort study of uncomplicated pregnancies that underwent echocardiography every 4 weeks from inclusion at 18–21 weeks until delivery to obtain four‐chamber loops of the fetal heart. Left and right ventricular GLS and GLSR were measured using 2D‐STE at each examination. Using Bayesian mixed‐effects models, reference values with lower and upper 5% prediction limits were calculated according to gestational age. Right and left ventricular GLS values according to gestational age were compared using the Wilcoxon signed‐rank test. Results: A total of 592 left ventricular and 566 right ventricular GLS and GLSR measurements were obtained from 124 women with uncomplicated pregnancy and non‐anomalous, appropriately grown fetuses. Reference values were obtained for both fetal ventricles according to gestational week. GLS and GLSR values of both ventricles increased (i.e. became less negative) significantly during pregnancy. Right ventricular GLS values were significantly higher (i.e. less negative) than the respective left ventricular values at every gestational week. Conclusions: Reference values were obtained for fetal GLS and GLSR measured using 2D‐STE. GLS and GLSR values increased significantly for both ventricles from the second trimester until delivery. GLS values were significantly higher for the right ventricle compared with the left ventricle. Future studies are needed to assess whether the obtained reference values are helpful in clinical practice in the assessment of pregnancy complications, such as fetal growth restriction or cardiac anomaly. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

4 DeVore GR, Satou G, Sklansky M. Comparing the Non-Quiver and Quiver Techniques for Identification of the Endocardial Borders Used for Speckle-Tracking Analysis of the Ventricles of the Fetal Heart. In this paper, we obtained reliable reference values for fetal global longitudinal strain (GLS) and strain rate (GLSR) using the 2D Cardiac Performance 1.2 software program by TOMTEC Imaging Systems GmbH (Munich, Germany). We thank Dr DeVore for his interest in our paper[1]. [Extracted from the article]

Background: Worldwide, hypertensive disorders of pregnancy (HDP), fetal growth restriction (FGR) and preterm birth remain the leading causes of maternal and fetal pregnancy-related mortality and (long-term) morbidity. Fetal cardiac deformation changes can be the first sign of placental dysfunction, which is associated with HDP, FGR and preterm birth. In addition, preterm birth is likely associated with changes in electrical activity across the uterine muscle. Therefore, fetal cardiac function and uterine activity can be used for the early detection of these complications in pregnancy. Fetal cardiac function and uterine activity can be assessed by two-dimensional speckle-tracking echocardiography (2D-STE), non-invasive fetal electrocardiography (NI-fECG), and electrohysterography (EHG). This study aims to generate reference values for 2D-STE, NI-fECG and EHG parameters during the second trimester of pregnancy and to investigate the diagnostic potential of these parameters in the early detection of HDP, FGR and preterm birth.Methods: In this longitudinal prospective cohort study, eligible women will be recruited from a tertiary care hospital and a primary midwifery practice. In total, 594 initially healthy pregnant women with an uncomplicated singleton pregnancy will be included. Recordings of NI-fECG and EHG will be made weekly from 22 until 28 weeks of gestation and 2D-STE measurements will be performed 4-weekly at 16, 20, 24 and 28 weeks gestational age. Retrospectively, pregnancies complicated with pregnancy-related diseases will be excluded from the cohort. Reference values for 2D-STE, NI-fECG and EHG parameters will be assessed in uncomplicated pregnancies. After, 2D-STE, NI-fCG and EHG parameters measured during gestation in complicated pregnancies will be compared with these reference values.Discussion: This will be the a large prospective study investigating new technologies that could potentially have a high impact on antepartum fetal monitoring.Trial Registration: Registered on 26 March 2020 in the Dutch Trial Register (NL8769) via https://www.trialregister.nl/trials and registered on 21 October 2020 to the Central Committee on Research Involving Human Subjects (NL73607.015.20) via https://www.toetsingonline.nl/to/ccmo_search.nsf/Searchform?OpenForm . [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Total vitamin B12 levels decrease significantly during pregnancy and recover to normal values within 8‐week postpartum. Holotranscobalamin (holoTC) reflects the active part of vitamin B12 and has been shown to remain constant during pregnancy and postpartum. A mechanism of redistribution of vitamin B12 is suggested, with a shift toward holoTC if there is insufficient total vitamin B12 available. Our objective was to examine vitamin B12 deficiency and the active vitamin B12 fraction in postpartum women. Methods: Total vitamin B12 and holoTC were measured in 171 women within 48 hours (T0) and at 5 weeks (T5) postpartum. Vitamin B12 deficiency was defined as total vitamin B12 < 180 pmol/L or holoTC <32 pmol/L. The active vitamin B12 fraction was defined as holoTC/total vitamin B12. Results: Without intervention, vitamin B12 deficiency based on both serum total vitamin B12 and holoTC changed from 75% and 60%, to respectively 10% and 6% at T5. The fraction of active vitamin B12 was significant higher in vitamin B12 deficient women at both time points and across time (P < .0001 and P = .002). A high fraction of active vitamin B12 was only present in women with total vitamin B12 deficiency at T0. At T5, no high vitamin B12 fraction was found. Conclusion: The changes in total vitamin B12 levels seem to be based on a physiological changes rather than vitamin B12 deficiency. The results of this study confirm the hypothesis that a shift toward the metabolic active vitamin B12 (holoTC) occurs in women with insufficient available total vitamin B12. [ABSTRACT FROM AUTHOR]

The aim of this study was to systematically review the literature on fetal cardiac function, assessed with two-dimensional speckle-tracking echocardiography (2D-STE) in fetuses of mothers with diabetes in comparison to those of mothers without diabetes. RV-GLS values were increased (6 studies), decreased (1 study) or not different (1 study). In fetuses of mothers with diabetes versus mothers without diabetes, LV-GLS values were significantly increased (6 studies), decreased (1 study) or not significantly different (6 studies). [Extracted from the article]

Results The gynecology fellow showed a steep learning curve for both LV- and RV-GLS analysis. He achieved expert competency after 100 analyses for both LV-GLS (ICC 0.75) and RV-GLS (ICC 0.71). The gynecology resident started with a higher ICC value for LV-GLS analysis (ICC 0.55) and RV-GLS analysis (ICC 0.63) and showed a less steep learning curve. [Extracted from the article]

Objectives: In rheumatoid arthritis (RA), seropositive and seronegative disease may be two entities with different underlying pathophysiological mechanisms, long-term outcomes and disease presentations. However, the effect of the conjoint presence of multiple autoantibodies, as proxy for a more pronounced humoral autoimmune response, on clinical phenotype remains unclear. Therefore, this study investigates the association between the number of autoantibodies and initial clinical presentation in two independent cohorts of patients with early RA.Methods: Autoantibody status (rheumatoid factor, anticitrullinated protein antibodies and anticarbamylated protein antibodies) was determined at baseline in the Leiden Early Arthritis Cohort (n=828) and the Swedish BARFOT (Better Anti-Rheumatic Farmaco-Therapy, n=802) study. The association between the number of autoantibodies and baseline clinical characteristics was investigated using univariable and multivariable ordinal regression.Results: In both cohorts, the following independent associations were found in multivariable analysis: patients with a higher number of RA-associated antibodies were younger, more often smokers, had a longer symptom duration and a higher erythrocyte sedimentation rate at presentation compared with patients with few autoantibodies.Conclusions: The number of autoantibodies, reflecting the breadth of the humoral autoimmune response, is associated with the clinical presentation of RA. Predisease pathophysiology is thus reflected by the initial clinical phenotype. [ABSTRACT FROM AUTHOR]

Two-dimensional speckle-tracking echocardiography has been considered as an angle-independent modality. EP19.11: The effect of insonation angles on left and right ventricular global longitudinal strain in fetal speckle-tracking echocardiography However, a subgroup analysis, using only the highest quality ultrasound clips, revealed a significant difference in left ventricular GLS values between the oblique and perpendicular AoI compared to the up/down AoI. [Extracted from the article]

Introduction: To evaluate the use of reticulocyte hemoglobin content (CHr) and mean corpuscular volume (MCV) to identify truly iron-deficient women with postpartum anemia (PPA), in order to reduce unnecessary iron supplementation. Methods: Three hundred women with more than 500 mL of blood loss or clinical signs of anemia were divided in a control (Hb ≥ 10.5 g/dL, N = 150) and postpartum anemia group (PPA, Hb < 10.5 g/dL; N = 150). PPA women were given ferrous fumarate for a period of 4 weeks. Efficacy of the treatment was evaluated by comparing Hb, CHr, and MCV at baseline ( T0) and after 4 weeks ( T4). Using standard iron deficiency cut off values for MCV (80 fL) and CHr (28 pg) at T0, we divided the PPA group of both parameters into two subgroups, one suggestive for iron deficiency and one suggestive for noniron deficiency. Results: Irrespective of the parameter or the subdivision, delta Hb concentrations ( T4- T0) showed a similar increase in all PPA subgroups investigated. Both parameters in the PPA subgroups below their respective cut off value showed a significant improvement toward normalization, while the MCV and CHr in the PPA subgroups above their respective cut off value did not show any significant increase. Conclusion: Our data suggest that the etiology of the anemia in postpartum anemic women is not always iron deficiency. Using a combination of Hb, MCV and CHr, we increased the stringency to identify truly iron-deficient postpartum anemic women, thereby reducing unnecessary iron supplementation in those women with sufficient iron stores. [ABSTRACT FROM AUTHOR]

Objectives Anti-citrullinated protein antibodies (ACPA) are highly specific for rheumatoid arthritis (RA) and have been implicated in disease pathogenesis. Recent ongoing evidence indicates that the ACPA response broadens before precipitation of full-blown RA, as indicated by a more extensive isotype usage and an increased citrullinated epitope recognition profile. Nonetheless, the evolution of the ACPA response is still poorly understood and might intrinsically differ from the protective responses against pathogens. Methods The avidity and the avidity maturation of ACPA in relation to the avidity of antibodies against recall antigens were analysed. Results The avidity of ACPA was significantly lower than the avidity of antibodies to the recall antigens tetanus toxoid and diptheria toxoid. Moreover, ACPA did not show avidity maturation during longitudinal follow-up and ACPA avidity was also relatively low in patients who displayed extensive isotype switching. Conclusions These observations indicate that the natural evolution of ACPA differs from the development of antibodies against recall antigens. These data also indicate that ACPA avidity maturation and isotype switching are disconnected, whereby extensive isotype switching occurs in the setting of restricted avidity maturation. Intrinsic differences between the RA-specific autoantibody system and protective antibody responses against pathogens could be of relevance for designing novel B cell-targeted therapies for RA. [ABSTRACT FROM PUBLISHER]

OBJECTIVE: The protective effect of HLA-DRB1 alleles on the development of rheumatoid arthritis (RA) is poorly understood. The aim of this study was to perform a meta-analysis of 4 European populations to investigate which HLA-DRB1 alleles are associated with protection in anti-citrullinated protein antibody (ACPA)-positive RA and ACPA-negative RA. METHODS: Data for >2,800 patients and >3,000 control subjects for whom information on HLA-DRB1 typing and ACPA status was available were collected from 4 European countries: Norway, Sweden, The Netherlands, and Spain. The odds ratios (ORs) and 95% confidence intervals (95% CIs) associated with the different HLA-DRB1 alleles were analyzed in a combined meta-analysis focused on protective alleles and classifications. The analysis of ACPA-positive RA was stratified for the shared epitope (SE) alleles, to correct for skewing due to this association. RESULTS: In ACPA-positive RA, the only alleles that conveyed protection after stratification for SE were HLA-DRB1*13 alleles (OR 0.54 [95% CI 0.38-0.77]). The protective effect of the allele classifications based on the DERAA and D70 sequences was no longer present after exclusion of DRB1*13 (for D70, OR 0.97 [95% CI 0.75-1.25]), indicating that DRB1*13, rather than the DERAA or D70 sequence as such, is associated with protection. Among the DRB1*13 alleles, only DRB1*1301 was associated with protection (OR 0.24 [95% CI 0.09-0.59]). Protection appeared to follow a north-to-south gradient, with the strongest association in northern European countries. In ACPA-negative RA, there were no robust associations with HLA-DRB1 alleles. CONCLUSION: Our data do not support any of the classifications of protective alleles and indicate that protection against ACPA-positive RA is predominantly associated with HLA-DRB1*1301. [ABSTRACT FROM AUTHOR]

OBJECTIVE: It has been suggested that anti-citrullinated protein antibodies (ACPAs) play an important role in the pathogenesis of rheumatoid arthritis (RA). To exert their pathologic effects, ACPAs must recruit immune effector mechanisms such as activation of the complement system. Mouse models of RA have shown that, surprisingly, arthritogenic antibodies activate the alternative pathway of complement rather than the expected classical pathway. This study was undertaken to investigate whether human anti-cyclic citrullinated peptide (anti-CCP) antibodies activate the complement system in vitro and, if so, which pathways of complement activation are used. METHODS: We set up novel assays to analyze complement activation by anti-CCP antibodies, using cyclic citrullinated peptide-coated plates, specific buffers, and normal and complement-deficient sera as a source of complement. RESULTS: Anti-CCP antibodies activated complement in a dose-dependent manner via the classical pathway of complement, and, surprisingly, via the alternative pathway of complement. The lectin pathway was not activated by anti-CCP antibodies. Complement activation proceeded in vitro up to the formation of the membrane attack complex, indicating that all activation steps, including the release of C5a, took place. CONCLUSION: Our findings indicate that anti-CCP antibodies activate the complement system in vitro via the classical and alternative pathways but not via the lectin pathway. These findings are relevant for the design of interventions aimed at inhibition of complement-mediated damage in RA. [ABSTRACT FROM AUTHOR]

Objective: Anti-citrullinated protein antibodies (ACPAs) display high association with rheumatoid arthritis (RA) and are implicated in its pathogenesis. The presence of ACPAs is known to precede the onset of RA. In order to identify the features that could confer its pathogenicity, we extensively characterized this antibody response in a unique North American native population of patients with RA and their unaffected relatives.Methods: The levels of IgA, IgM, and IgG ACPAs, as well as IgM and IgA rheumatoid factor (RF), were measured in serum samples obtained from 81 patients with RA and 195 of their unaffected relatives. The isotype distribution, the fine specificity of the ACPA response, and its association with RF were compared in health and disease.Results: ACPA positivity was observed in 19% of the healthy relatives and ~91% of the patients with RA. ACPA isotype usage was strikingly lower in unaffected relatives than in patients with RA (1-2 versus 5-6 isotypes). Fine specificity studies showed that reactivity to citrullinated fibrinogen and vimentin was present in sera from patients with RA, while it was virtually absent in their unaffected relatives. Finally, the ACPA and RF responses were associated in patients with RA but were discordant in their healthy relatives. Extended analyses revealed that the presence of ACPAs was associated with RA irrespective of RF status, while the association of RF with disease relied on its interaction with ACPAs.Conclusion: The fine specificity and isotype usage of the ACPA response are qualitatively different in health and disease. Epitope spreading and expansion of the isotype repertoire might be necessary for development of RA, and this could be facilitated by the presence of RF antibodies. [ABSTRACT FROM AUTHOR]

The Stokes flow inside a two-dimensional rectangular cavity |x|≼a, |y|≼b is analyzed for a highly viscous, incompressible fluid flow, driven by a single rotlet placed at position (0,c). Specifically, a rigorous solution of the governing two-dimensional biharmonic equation for the stream function is constructed analytically by means of the superposition principle. With this solution, multicellular flow patterns can be described for narrow cavities, in which the number of flow cells is directly related to the value of the aspect ratio A=b/a. The solution also shows that for a certain rotlet position (0,c0), which depends on a and b, the flow has a stagnation point (0,-c0) symmetrically placed inside the rectangle. As the flow would not be affected by placing a second (inactive) rotlet in this stagnation point, this allows us to construct a blinking rotlet model for the rectangular cavity, with the inactive rotlet in the stagnation point of the flow induced by the active rotlet. For rectangular cavities, it holds that more than one of these special rotlet positions can be found for cavities that are elongated to sufficiently large aspect ratios. The blinking rotlet model is applied to illustrate several aspects of stirring in a Stokes flow in a rectangular domain. [ABSTRACT FROM AUTHOR]