Unsupervised denoising of the non-invasive fetal electrocardiogram with sparse domain Kalman filtering and vectorcardiographic loop alignment.

Objective.Even though the electrocardiogram (ECG) has potential to be used as a monitoring or diagnostic tool for fetuses, the use of non-invasive fetal ECG is complicated by relatively high amounts of noise and fetal movement during the measurement. Moreover, machine learning-based solutions to this problem struggle with the lack of clean reference data, which is difficult to obtain. To solve these problems, this work aims to incorporate fetal rotation correction with ECG denoising into a single unsupervised end-to-end trainable method.Approach.This method uses the vectorcardiogram (VCG), a three-dimensional representation of the ECG, as an input and extends the previously introduced Kalman-LISTA method with a Kalman filter for the estimation of fetal rotation, applying denoising to the rotation-corrected VCG.Main results.The resulting method was shown to outperform denoising auto-encoders by more than 3 dB while achieving a rotation tracking error of less than 33∘. Furthermore, the method was shown to be robust to a difference in signal to noise ratio between electrocardiographic leads and different rotational velocities.Significance.This work presents a novel method for the denoising of non-invasive abdominal fetal ECG, which may be trained unsupervised and simultaneously incorporates fetal rotation correction. This method might prove clinically valuable due the denoised fetal ECG, but also due to the method's objective measure for fetal rotation, which in turn might have potential for early detection of fetal complications.

Histological evidence of MAPK pathway activation across subtypes of adult orbital xanthogranulomatous disease irrespective of the detection of oncogenic mutations.

Adult orbital xanthogranulomatous disease (AOXGD) is a spectrum of histiocytoses with four subtypes. Mitogen-activated protein kinase (MAPK) pathway mutations have been detected in various histiocytic neoplasms, little is known about this in AOXGD. Targeted regions of cancer- and histiocytosis-related genes were analyzed and immunohistochemical staining of phosphorylated ERK (pERK), cyclin D1 and PU.1 was performed in 28 AOXGD and 10 control xanthelasma biopsies to assess MAPK pathway activation. Mutations were detected in 7/28 (25%) patients. Positive staining for pERK and/or cyclin D1 was found across all subtypes in 17/27 (63%) patients of whom 12/17 (71%) did not harbour a mutation. Xanthelasma tissue stained negative for pERK and cyclin D1. Relapse occurred in 5/7 (71%) patients with a MAPK pathway mutation compared to 8/21 (38%) patients in whom no mutation could be detected. Molecular analysis and evaluation for systemic disease is warranted to identify patients at risk of recurrent xanthomatous disease.

Porto-sinusoidal vascular disorder and nephrotic-range proteinuria due to venous vasculitis in Behçet's disease.

Behçet's disease (BD) is an autoinflammatory disease with multifactorial and polygenic etiology, potentially involving arteries and veins of any size resulting in variable vessel vasculitis. We report a case of an Iranian male who presented with porto-sinusoidal vascular disorder due to venous vasculitis as initial manifestation of BD. Despite immunosuppression, anticoagulation and venous recanalization, he subsequently developed severe nephrotic-range proteinuria mimicking a primary renal disease which was completely and immediately ameliorated by stenting of the vena cava. This demonstrates that the proteinuria was caused by increased intraglomerular pressure due to venous outflow obstruction as a consequence of venous vasculitis. To our knowledge, this is the first report of massive proteinuria caused by venous obstruction of the caval vein in the context of BD. Altogether, this case demonstrates the extensive spectrum of vascular disease in BD.

Deep Learing for Sparse Domain Kalman Filtering With Applications on ECG Denoising and Motility Estimation.

OBJECTIVE: The reconstruction of an input based on a sparse combination of signals, known as sparse coding, has found widespread use in signal processing. In this work, the combination of sparse coding with Kalman filtering is explored and its potential is shown on two use-cases. METHODS: This work extends the Iterative Shrinkage and Thresholding Algorithm with a Kalman filter in the sparse domain. The resulting method may be implemented as a deep unfolded neural network and may be applied to any signal which has a sparse representation and a known or assumed relation between consecutive measurements. This method is evaluated on the use cases of noise reduction in the electrocardiogram (ECG) and the estimation of object motility. RESULTS: For ECG denoising, the proposed method achieved an improvement in Signal-to-Noise ratio of 18.6 dB, which is comparable to state-of-the-art. In motility estimation, a correlation of 0.84 with ground truth simulations was found. CONCLUSION: The proposed method was shown to have advantages over sparse coding and Kalman filtering alone. Due to the low complexity and high generalizability of the proposed method, the implementation of context-specific knowledge or an extension to other applications can be readily made. SIGNIFICANCE: The presented Kalman-ISTA algorithm is a resource-efficient method combining the promise of both sparse coding and Kalman filtering, making it well-suited for various applications.

The impact of healthy pregnancy on features of heart rate variability and pulse wave morphology derived from wrist-worn photoplethysmography.

Due to the association between dysfunctional maternal autonomic regulation and pregnancy complications, tracking non-invasive features of autonomic regulation derived from wrist-worn photoplethysmography (PPG) measurements may allow for the early detection of deteriorations in maternal health. However, even though a plethora of these features-specifically, features describing heart rate variability (HRV) and the morphology of the PPG waveform (morphological features)-exist in the literature, it is unclear which of these may be valuable for tracking maternal health. As an initial step towards clarity, we compute comprehensive sets of HRV and morphological features from nighttime PPG measurements. From these, using logistic regression and stepwise forward feature elimination, we identify the features that best differentiate healthy pregnant women from non-pregnant women, since these likely capture physiological adaptations necessary for sustaining healthy pregnancy. Overall, morphological features were more valuable for discriminating between pregnant and non-pregnant women than HRV features (area under the receiver operating characteristics curve of 0.825 and 0.74, respectively), with the systolic pulse wave deterioration being the most valuable single feature, followed by mean heart rate (HR). Additionally, we stratified the analysis by sleep stages and found that using features calculated only from periods of deep sleep enhanced the differences between the two groups. In conclusion, we postulate that in addition to HRV features, morphological features may also be useful in tracking maternal health and suggest specific features to be included in future research concerning maternal health.

Accidental rupture of membranes and neonatal infection after labor induction with silicone or latex balloon catheters: A retrospective cohort study.

OBJECTIVE(S): Accidental rupture of membranes (acROM), an insertion-related complication of the balloon catheter for labor induction, may prolong the duration of ruptured membranes. Prolonged rupture of membranes is associated with an increased risk of intra-uterine infection with possibly neonatal infection as result. Little is known about safety profiles of different catheters regarding the occurrence of these complications. This study compares the incidence of neonatal early-onset sepsis (EOS) and acROM in women receiving either silicone or latex balloon catheters. STUDY DESIGN: A retrospective cohort study was performed including 2200 women (silicone balloon catheter, n = 1100 vs. latex balloon catheter, n = 1100). The primary outcomes were the incidence of acROM, and suspected and proven neonatal EOS. Secondary outcomes were: prolonged rupture of membranes, intrapartum fever, pre- or postnatal neonatal exposure to antibiotics, and perinatal outcomes. A subgroup analysis was performed between women with and without acROM. RESULTS: No statistically significant difference with regard to suspected or proven EOS was seen between the silicone and latex groups. The acROM rate was significantly higher in the silicone group compared to the latex group (2.9 % and 0.3 %, p < 0.01). Prolonged rupture of membranes was significantly more common in the silicone group compared to the latex group (5.0 % and 2.4 %, p < 0.01), as was the use of intrapartum antibiotics (12.7 % and 9.6 %, p = 0.02). Neonates were significantly more often exposed to pre- or postnatal antibiotics in the silicone group compared to the latex group (17.6 % and 13.6 %, p = 0.01). Subgroup analysis showed significantly more suspected and proven neonatal EOS when catheter-insertion was complicated with acROM (11.4 % and 20.0 %), compared to cases without acROM (3.8 % and 2.5 %), irrespective of the type of catheter used. CONCLUSION(S): The use of silicone balloon catheters for labor induction results in higher rates of acROM, prolonged rupture of membranes and use of intrapartum antibiotics, compared to latex balloon catheters. No statistically significant differences were found in the occurrence of suspected or proven neonatal EOS, however neonates from the silicone group were more often exposed to pre- or postnatal antibiotics. When acROM occurs, irrespective of type of catheter used, suspected and proven neonatal EOS was seen more often.

Long-term data on efficacy and safety of adalimumab in Behçet's disease.

INTRODUCTION: Behçet's disease (BD) is a systemic, inflammatory disorder affecting multiple organ systems, frequently treated with TNF-α blocking agents, as infliximab and adalimumab. Insights about long-term use of adalimumab are lacking. Therefore, we conducted a study into the long-term efficacy and safety of adalimumab in BD. METHODS: A retrospective cohort study from patients with BD treated with adalimumab in the Erasmus Medical Center was performed. Patients included were at least 18 years of age, diagnosed according to ISG criteria, and uninterruptedly used adalimumab for at least 36 months. RESULTS: In a population of 39 BD patients using adalimumab, 29 patients persisted treatment >36 months (range 37-206 months). Indications for treatment were uveitis (n = 15) 51.7%, mucocutaneous involvement (n = 9) 31%, arthritis (n = 2) 6.9%, intestinal disease (n = 3) 10.3%. Overall, adalimumab decreased the occurrence of flares from 0.64 to 0.17 flares per year and BCVA improved subsequently. Also, a steady decline in BDCAF is reported over the course of at least 5 years. Subsequently, 79% was able to reduce their use of immunosuppressive agents aside from adalimumab. Adverse effects were reported in, (n = 15) 51.7% of which (n = 13) 86.6% were infectious complications. Two of those required inpatient hospital care. CONCLUSION: Our study illustrates durable long-term efficacy of adalimumab treatment in patients with BD. In our patient cohort long-term adalimumab treatment is safe, with a low incidence of serious adverse events.

NT-proBNP and sRAGE levels in early rheumatoid arthritis.

OBJECTIVE: 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. METHOD: 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. RESULTS: 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). CONCLUSION: 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.

Adult orbital xanthogranuloma: long-term follow-up of treated cases.

BACKGROUND: Adult orbital xanthogranulomatous disease (AOXGD) is a group of rare disorders. Four subtypes are identified: adult-onset xanthogranuloma (AOX), adult-onset asthma and periocular xanthogranuloma (AAPOX), necrobiotic xanthogranuloma (NBX), and Erdheim-Chester disease (ECD). Therapy options vary and little is known about the long-term effect of the treatment. In this study, we will describe the clinical behaviour, effect of treatment, and long-term outcome in a consecutive series of patients with AOXGD. METHODS: This is a descriptive, retrospective study with a long follow-up term of 21 patients with histologically proven AOXGD, treated between 1989 and 2021 in the Rotterdam Eye Hospital and Erasmus MC University Medical Center. RESULTS: Twenty-one patients with histologically proven AOXGD were included. The follow-up ranged from 2-260 months (median of 67 months). Six of the nine patients with AOX were treated with surgery alone, with recurrence in two. Three received systemic therapy, with recurrence in one. All four patients with AAPOX received systemic treatment, the disease recurred in two. Two patients with NBX were treated with surgery alone, with recurrence in one. Four required additional therapy with recurrence in two. Both patients with ECD required systemic therapy. CONCLUSIONS: Recognition of AOXGD is important, in particular, because of the potential severe systemic locations in the different subtypes. Surgical excision might be a sufficient therapy for patients with AOX. Patients with AAPOX, NBX, and ECD warrant systemic therapy. Currently, there is no conclusive evidence for a superior treatment strategy, but further studies are necessary to investigate treatment options.

Characterizing the effect of demographics, cardiorespiratory factors, and inter-subject variation on maternal heart rate variability in pregnancy with statistical modeling: a retrospective observational analysis.

Pregnancy complications are associated with insufficient adaptation of the maternal autonomic nervous system to the physiological demands of pregnancy. Consequently, assessing maternal heart rate variability (mHRV)-which reflects autonomic regulation-is a promising tool for detecting early deterioration in maternal health. However, before mHRV can be used to screen for complications, an understanding of the factors influencing mHRV during healthy pregnancy is needed. In this retrospective observational study, we develop regression models to unravel the effects of maternal demographics (age, body mass index (BMI), gestational age (GA), and parity), cardiorespiratory factors (heart rate and breathing rate), and inter-subject variation on mHRV. We develop these models using two datasets which are comprised of, respectively, single measurements in 290 healthy pregnant women and repeated measurements (median = 8) in 29 women with healthy pregnancies. Our most consequential finding is that between one-third and two-thirds of the variation in mHRV can be attributed to inter-subject variability. Additionally, median heart rate dominantly affects mHRV (p < 0.001), while BMI and parity have no effect. Moreover, we found that median breathing rate, age, and GA all impact mHRV (p < 0.05). These results suggest that personalized, long-term monitoring would be necessary for using mHRV for obstetric screening.

The electrical heart axis in fetuses with congenital heart disease, measured with non-invasive fetal electrocardiography.

OBJECTIVES: To determine if the electrical heart axis in different types of congenital heart defects (CHD) differs from that of a healthy cohort at mid-gestation. METHODS: Non-invasive fetal electrocardiography (NI-fECG) was performed in singleton pregnancies with suspected CHD between 16 and 30 weeks of gestation. The mean electrical heart axis (MEHA) was determined from the fetal vectorcardiogram after correction for fetal orientation. Descriptive statistics were used to determine the MEHA with corresponding 95% confidence intervals (CI) in the frontal plane of all fetuses with CHD and the following subgroups: conotruncal anomalies (CTA), atrioventricular septal defects (AVSD) and hypoplastic right heart syndrome (HRHS). The MEHA of the CHD fetuses as well as the subgroups was compared to the healthy control group using a spherically projected multivariate linear regression analysis. Discriminant analysis was applied to calculate the sensitivity and specificity of the electrical heart axis for CHD detection. RESULTS: The MEHA was determined in 127 fetuses. The MEHA was 83.0° (95% CI: 6.7°; 159.3°) in the total CHD group, and not significantly different from the control group (122.7° (95% CI: 101.7°; 143.6°). The MEHA was 105.6° (95% CI: 46.8°; 164.4°) in the CTA group (n = 54), -27.4° (95% CI: -118.6°; 63.9°) in the AVSD group (n = 9) and 26.0° (95% CI: -34.1°; 86.1°) in the HRHS group (n = 5). The MEHA of the AVSD and the HRHS subgroups were significantly different from the control group (resp. p = 0.04 and p = 0.02). The sensitivity and specificity of the MEHA for the diagnosis of CHD was 50.6% (95% CI 47.5% - 53.7%) and 60.1% (95% CI 57.1% - 63.1%) respectively. CONCLUSION: The MEHA alone does not discriminate between healthy fetuses and fetuses with CHD. However, the left-oriented electrical heart axis in fetuses with AVSD and HRHS was significantly different from the control group suggesting altered cardiac conduction along with the structural defect. TRIAL REGISTRATION: Clinical trial registration number: NL48535.015.14.

Corrigendum to "Hydroxychloroquine Use in Lupus Patients during Pregnancy Is Associated with Longer Pregnancy Duration in Preterm Births".

[This corrects the article DOI: 10.1155/2017/2810202.].

The association between uterine contraction frequency and fetal scalp pH in women with suspicious or pathological fetal heart rate tracings: A retrospective study.

OBJECTIVE: Current guidelines provide little supporting literature for the definition of uterine tachysystole during labour and no distinction is made for optimal contraction frequency depending on the clinical situation. We hypothesize that fetal hypoxia is frequently caused by uterine tachysystole and that high uterine contraction frequencies are especially harmful when fetal heart rate (FHR) abnormalities are present. We studied the association between contraction frequency and fetal scalp pH values in women with an indication for fetal blood sampling (FBS) based on FHR abnormalities. STUDY DESIGN: A retrospective study including 762 women was performed in a tertiary teaching hospital in the Netherlands from January 2015 until January 2020. Women with a singleton pregnancy with a gestational age ≥ 34+0 weeks were included when FBS was performed because of suspicious or pathological FHR tracings. Exclusion criteria were maternal age < 18 years, failed fetal scalp pH values, lack of thirty minute registration by tocodynamometry prior to FBS, poor quality of uterine monitoring, intrauterine resuscitation in the thirty minutes prior to FBS, maternal body mass index ≥ 30 kg/m2 and neonatal birth weight < 10th percentile. Uterine contractions in the thirty minutes prior to FBS were manually annotated by a researcher who was blinded to FBS values, FHR and other obstetrical data. Linear and logistic analysis were used to explore the association between uterine contraction frequency and FBS results. RESULTS: Low fetal scalp pH values were significantly associated with contraction frequency prior to FBS. Fetuses of women with four to five contractions per ten minutes prior to FBS were 2.4 times more likely to have hypoxia as compared to fetuses of women with two to three contractions per ten minutes (aOR 2.4, 95% CI 1.1-5.4). With increasing contraction frequency, the risk of fetal hypoxia further increased. CONCLUSIONS: Contraction frequency above four per ten minutes prior to FBS is significantly associated with fetal hypoxia in women with FHR abnormalities. We suggest to aim for a maximum contraction frequency of four per ten minutes in these women.

Immunopathogenesis of Behçet's disease and treatment modalities.

INTRODUCTION: Behçet's disease (BD) is an auto-inflammatory disease, primarily characterized by recurrent painful mucocutaneous ulcerations. METHODS: A literature search was performed to write a narrative review into the pathogenesis and current treatment options of BD. RESULTS: The pathogenesis of BD remains to be elucidated, but is considered a genetically primed disease in which an external trigger causes immune activation resulting in inflammatory symptoms. GWAS data show an association between multiple genetic polymorphisms (HLA-B51, ERAP1, IL10 and IL23R-IL12RB2) and increased susceptibility to BD. Bacteria as streptococci, an unbalanced microbiome or molecular mimicry trigger the inflammation in BD. Increased production or responsiveness of pro-inflammatory components of the innate immune response (TLR, neutrophils, NK-cells or γδ T-cells) to these triggers may be a crucial step in the pathogenesis of BD. Additionally to an increased autoinflammatory response there is evidence of a dysregulated adaptive immune system, with a disturbed Th1/Th2 balance, expansion of Th17 cells and possibly a decrease in regulatory T cells, resulting in a surplus in pro-inflammatory cytokines. The inflammation causes a typical clinical phenotype including orogenital ulcerations, uveitis and skin lesions. Treatment is aimed at the aberrations found in the innate (neutrophils and γδ-T cells) and adaptive immune system (TNF-α, INF-γ, IL-1), directed at organ involvement and individualized based on patient characteristics. CONCLUSION: We presented an extensive review into the pathogenesis and treatment options of BD.

New possibilities for ST analysis - A post-hoc analysis on the Dutch STAN RCT.

BACKGROUND: The diagnostic value of ST analysis of the fetal electrocardiogram (fECG) during labor is uncertain. False alarms (ST events) may be explained by physiological variation of the fetal electrical heart axis. Adjusted ST events, based on a relative rather than an absolute rise from baseline, correct for this variation and may improve the diagnostic accuracy of ST analysis. AIMS: Determine the optimal cut-off for relative ST events in fECG to detect fetal metabolic acidosis. STUDY DESIGN: Post-hoc analysis on fECG tracings from the Dutch STAN trial (STAN+CTG branch). SUBJECTS: 1328 term singleton fetuses with scalp ECG tracing during labor, including 10 cases of metabolic acidosis. OUTCOME MEASURES: Cut-off value for relative ST events at the point closest to (0,1) in the receiver operating characteristic (ROC) curve with corresponding sensitivity and specificity. RESULTS: Relative baseline ST events had an optimal cut-off at an increment of 85% from baseline. Relative ST events had a sensitivity of 90% and specificity of 80%. CONCLUSIONS: Adjusting the current definition of ST events may improve ST analysis, making it independent of CTG interpretation.

Fetal myocardial deformation measured with two-dimensional speckle-tracking echocardiography: longitudinal prospective cohort study of 124 healthy fetuses.

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.

Non-invasive fetal electrocardiography, electrohysterography and speckle-tracking echocardiography in the second trimester: study protocol of a longitudinal prospective cohort study (BEATS-study).

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 .

Autologous stem-cell transplantation in systemic sclerosis-associated interstitial lung disease: early action in selected patients rather than escalation therapy for all.

Systemic sclerosis (SSc) is a rare rheumatic disease characterised by inflammation, vasculopathy and fibrosis of skin and internal organs. A common complication and a leading cause of death in SSc is interstitial lung disease (ILD). The current armamentarium of treatments in SSc-ILD mainly includes immunosuppressive therapies and has recently been expanded with anti-fibrotic agent nintedanib. Autologous stem cell transplantation (SCT) is increasingly used in progressive diffuse cutaneous SSc. This intensive treatment has been studied in three randomised trials and demonstrated to improve survival and quality of life. In the subsets of patients with SSc-ILD, SCT resulted in stabilisation and modest improvement of lung volumes and disease extent on high resolution computed tomography, but less impact was seen on diffusion capacity. Comparison of SCT outcomes with results from SSc-ILD trials is difficult though, as lung involvement per se was not an inclusion criterion in all SCT trials. Also, baseline characteristics differed between studies. The risk of severe treatment-related complications from SCT is still considerable and patients with extensive lung disease are particularly at risk of complications during transplantation. Therefore SCT should only be provided by experienced multidisciplinary teams in carefully selected patients. Future research needs to include comprehensive pulmonary evaluation and establish whether SCT early in the disease might prevent irreversible pulmonary damage and reduce treatment-related complications. Also, more insight in mechanisms of action of SCT in the lung and predictors for response will improve the use of this treatment in SSc-ILD. In this review the role of SCT in the treatment of SSc-ILD is summarised.