Corrigendum: Serum D-dimer is not predictive of placenta-mediated complications in pregnancy at high risk: the multicentric prospective cohort AngioPred study.

[This corrects the article DOI: 10.3389/fcell.2023.1115622.].

Handling missing covariates in observational studies: an illustration with the assessment of prognostic factors of survival outcomes in soft-tissue or visceral sarcomas in irradiated fields (SIF).

Background: Missing covariates are common in observational research and can lead to bias and loss of statistical power. Limited data regarding prognostic factors of survival outcomes of sarcomas in irradiated fields (SIF) are available. Because of the long lag time between irradiation of first cancer and scarcity of SIF, missing data are a critical issue when analyzing long-term outcomes. We assessed prognostic factors of overall (OS), progression-free (PFS), and metastatic-progression-free (MPFS) survivals in SIF using three methods to account for missing covariates. Methods: We relied on the NETSARC French Sarcoma Group database, Cox (OS/PFS), and competitive hazards (MPFS) survival models. Covariates investigated were age, sex, histological subtype, tumor size, depth and grade, metastasis, surgery, surgical resection, surgeon's expertise, imaging, and neo-adjuvant treatment. We first applied multiple imputation (MI): observed data were used to estimate the missing covariate. With the missing-data modality approach, a category missing was created for qualitative variables. With the complete-case (CC) approach, analysis was restricted to patients without missing covariates. Results: CC subjects (N = 167; 33%) presented more often with soft-tissue sarcoma (versus visceral sarcoma) and grade I-II tumors as compared to the 504 eligible cases. With MI (N = 504), factors associated with the worst outcome included metastasis (p = 0.04) and R1/R2 resection (p < 0.001) for OS; higher grade/non-gradable tumors (p = 0.002) and R1/R2 resection (p < 0.001) for PFS; and metastasis (p = 0.01) for M-PFS. The 'missing-data modality' approach (N = 504) led to different associations, including significance reached due to variables with the modality 'missing'. The CC analysis led to different results and reduced precision. Conclusion: The CC population was not representative of the eligible population, introducing bias, in addition to worst precision. The 'missing-data modality method' results in biased estimates in non-randomized studies, as outcomes may be related to variables with missing values. Appropriate statistical methods for missing covariates, for example, MI, should therefore be considered.

Mean 3D Dispersion for Automatic General Movement Assessment of Preterm Infants.

The General Movement assessment (GMA) is a validated assessment of brain maturation primarily based on the qualitative analysis of the complexity and the variation of spontaneous motor activity. The GMA can identify preterm infants presenting an early abnormal developmental trajectory before term-equivalent age, which permits a personalized early developmental intervention. However, GMA is time-consuming and relies on a qualitative analysis; these limitations restrict the implementation of GMA in clinical practice. In this study based on a validated dataset of 183 videos from 92 premature infants (54 males, 38 females) born <33 weeks of gestational age (GA) and acquired between 32 and 40 weeks of GA, we introduce the mean 3D dispersion (M3D) for objective quantification and classification of normal and abnormal GMA. Moreover, we have created a new 3D representation of skeleton joints which allows an objective comparison of spontaneous movements of infants of different ages and sizes. Preterm infants with normal versus abnormal GMA had a distinct M3D distribution (p <0.001). The M3D has shown a good classification performance for GMA (AUC=0.7723) and presented an accuracy of 74.1%, a sensitivity of 75.8%, and a specificity of 70.1% when using an M3D of 0.29 as a classification threshold.Clinical relevance- Our study paves the way for the development of quantitative analysis of GMA within the Neonatal Unit.

EG-VEGF maternal levels predict spontaneous preterm birth in the second and third trimesters in pregnant women with risk factors for placenta-mediated complications.

Prediction of spontaneous preterm birth in asymptomatic women remains a great challenge for the public health system. The aim of the study was to determine the informational value of EG-VEGF circulating levels for prediction of spontaneous preterm birth in the second and third trimesters in pregnant women at high risk for placenta-mediated complications. A prospective multicenter cohort study including 200 pregnant patients with five-serum sampling per patient. Women with spontaneous preterm birth have higher concentrations of serum EG-VEGF than uncomplicated patients at 24 weeks, 28 weeks and 32 weeks (p = 0.03, 0.02 and < 0.001). The areas under the curve reached 0.9 with 100% sensitivity at 32 weeks for the prediction of spontaneous preterm birth. Serum EG-VEGF concentrations could be considered as a reliable biomarker of spontaneous preterm birth in high-risk for placenta-mediated complications pregnant women.

Long-term developmental condition following neonatal arterial ischemic stroke: A systematic review.

BACKGROUND: Neonatal arterial ischemic stroke (NAIS) is the most frequent subtype of perinatal stroke. Its elusive pathophysiology, its abrupt and unexpected occurrence, and the uncertainty of the post-NAIS developmental condition may lead to parental emotional distress and psychological difficulties. The aim of this study was to summarize the current data on long-term developmental conditions following NAIS to support parental information given within the neonatal unit. METHODS: This systematic review included clinical studies of term infants with NAIS, who had a developmental assessment at ≥5 years of age. Studies were identified from the Medline and Embase databases on June 1, 2022. The Joanna Briggs Institute (JBI) appraisal tool was used to assess the risk of bias. Results were synthesized using a narrative approach. The 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was followed to report this work. RESULTS: Three cohort studies enrolling 205 children assessed from 5 to 7 years after NAIS were included. Most of the children presented long-term developmental conditions allowing them to be integrated into a regular school program, to participate in physical activities, and to have a good quality of life. Global intellectual deficiency and moderate-to-severe cerebral palsy occurred in less than 10% of the children. CONCLUSION: Physicians should not overestimate the incidence of moderate-to-severe developmental outcome following NAIS when discussing the prognosis with parents. A parental information sheet about NAIS and its long-term developmental conditions is provided.

From early motor ability to global cognitive development seven years after neonatal arterial ischemic stroke.

The developmental condition of children after neonatal arterial ischemic stroke (NAIS) is characterized by cognitive and motor impairments. We hypothesized that independent walking age would be a predictor of later global cognitive functioning in this population. Sixty-one children with an available independent walking age and full-scale IQ score seven years after NAIS were included in this study. Full-scale IQ was assessed using the fourth edition of the Wechsler Intelligence Scale for Children (WISC-IV). Independent walking age was negatively correlated with full-scale IQ score at seven years of age (Pearson correlation coefficient of -0.27; 95% confidence interval from 0.48 to -0.01; p <0.05). Early motor function is correlated with later global cognitive functioning in children after NAIS. Assessing and promoting early motor ability is essential in this population.

Deep learning predicts patients outcome and mutations from digitized histology slides in gastrointestinal stromal tumor.

Risk assessment of gastrointestinal stromal tumor (GIST) according to the AFIP/Miettinen classification and mutational profiling are major tools for patient management. However, the AFIP/Miettinen classification depends heavily on mitotic counts, which is laborious and sometimes inconsistent between pathologists. It has also been shown to be imperfect in stratifying patients. Molecular testing is costly and time-consuming, therefore, not systematically performed in all countries. New methods to improve risk and molecular predictions are hence crucial to improve the tailoring of adjuvant therapy. We have built deep learning (DL) models on digitized HES-stained whole slide images (WSI) to predict patients' outcome and mutations. Models were trained with a cohort of 1233 GIST and validated on an independent cohort of 286 GIST. DL models yielded comparable results to the Miettinen classification for relapse-free-survival prediction in localized GIST without adjuvant Imatinib (C-index=0.83 in cross-validation and 0.72 for independent testing). DL splitted Miettinen intermediate risk GIST into high/low-risk groups (p value = 0.002 in the training set and p value = 0.29 in the testing set). DL models achieved an area under the receiver operating characteristic curve (AUC) of 0.81, 0.91, and 0.71 for predicting mutations in KIT, PDGFRA and wild type, respectively, in cross-validation and 0.76, 0.90, and 0.55 in independent testing. Notably, PDGFRA exon18 D842V mutation, which is resistant to Imatinib, was predicted with an AUC of 0.87 and 0.90 in cross-validation and independent testing, respectively. Additionally, novel histological criteria predictive of patients' outcome and mutations were identified by reviewing the tiles selected by the models. As a proof of concept, our study showed the possibility of implementing DL with digitized WSI and may represent a reproducible way to improve tailoring therapy and precision medicine for patients with GIST.

High dose (54 Gy) pre-operative helical tomotherapy for retroperitoneal liposarcoma: Results of a phase II multicenter study.

PURPOSE: To evaluate efficacy and feasibility of high-dose intensity-modulated radiotherapy (RT) with pre-operative helical tomotherapy, delivering 54 Gy/30 fractions in patients with retroperitoneal liposarcomas (RPLS). MATERIALS AND METHODS: Patients with operable, biopsy-proven, RPLS were included in this phase II multicenter study (ClinicalTrials.gov: NCT01841047). The primary objectives were to analyze loco-regional relapse free survival (LRFS), overall survival (OS) and toxicities, graded according to CTCAE V3.0. RESULTS: From April 2009 to September 2013, 48 patients were included. Histological types were: 20 well differentiated and 28 dedifferentiated liposarcomas. Median clinical target volume (CTV) was 2570 cc (range, 230-8734 cc). The radio-surgical schedule was completed as planned in all patients apart from one. A monobloc wide excision was achieved for all patients. Surgical margins were R0 (16; 34%), R1 (28; 60%), R2 (2; 4%) or missing (1, 2%).With a median follow-up of 5.5 years, 3-year LRFS rate was 74.2% (95%CI: [59.1%; 84.5%]). At 5 years, cumulative incidence of loco-regional relapse for well differentiated and dedifferentiated RPLS was 10% and 18%, respectively. The 5-year OS was 73.9% [95%CI: 58.7-84.3%]. During RT, the most common grade 3-4 adverse events were hematological (N = 20; 41.6%). After surgery and during follow-up, 17 patients (35.4%) presented a grade 3-4 toxicity. Two patients (4.1%) died due to a duodenal toxicity. Nine second cancers were observed. CONCLUSION: From this phase II trial of preoperative RT in RPLS patients, the dose level proposed cannot be considered safe, leading to non-negligible toxicity and second cancers rates. Our results, combined with STRASS-1 study, suggest that the ideal indication of RT for patients with RPLS still remains to be determined.

Prostatectomy Bed Image-guided Dose-escalated Salvage Radiotherapy (SPIDER): An International Multicenter Retrospective Study.

BACKGROUND: Management of macroscopic local recurrence (MLR) after radical prostatectomy is a challenging situation with no standardized approach. OBJECTIVE: The objective of our study was to assess the efficacy and safety of functional image-guided salvage radiotherapy (SRT) in patients with MLR in the prostate bed. DESIGN, SETTING, AND PARTICIPANTS: In this international multicenter retrospective study across 16 European centers, eligible patients were initially treated by radical prostatectomy (RP) with or without pelvic lymph node dissection for localized or locally advanced adenocarcinoma of the prostate. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Prostate-specific antigen (PSA) measured 4 wk after RP was <0.1 ng/ml. All patients presented a biochemical relapse after RP defined by an increase in PSA level of ≥0.2 ng/ml on two successive measures. Only patients with an MLR lesion in the prostatectomy bed visualized on functional imaging (multiparametric magnetic resonance imaging, positron emission tomography/computed tomography [PET/CT] choline, or PET/CT prostate-specific membrane antigen) were eligible. Patients with lymph node, bone, or visceral dissemination at restaging imaging (CT and/or bone scintigraphy and/or magnetic resonance imaging and/or PET) were excluded. Dose escalation was defined as a dose of >66 Gy prescribed to the prostate bed or to MLR. Toxicities were classified using the Common Terminology Criteria for Adverse Events scale, version 4.03. The primary endpoint was progression-free survival (PFS). Secondary outcomes were metastasis-free survival (MPFS), biochemical progression-free survival, and overall survival. Genitourinary (GU) and gastrointestinal (GI) toxicities were analyzed. RESULTS AND LIMITATIONS: Between January 2000 and December 2019, 310 patients received at least one dose escalation on MLR and 25 patients did not receive any dose escalation. The median PSA level before SRT was 0.63 ng/ml (interquartile range [IQR], 0.27-1.7). The median follow-up was 54 mo (IQR, 50-56). Five-year PFS and MPFS were 70% (95% confidence interval [CI]: [64; 75]) and 84% (95% CI: [78; 88]), respectively. Grade ≥2 GU and GI late toxicities were observed in 43 (12%) and 11 (3%) patients, respectively. When the prescribed dose on the MLR lesion was ≥72 Gy, an improvement in 5-yr PFS was found for patients received at least one dose escalation (73% [95% CI: 65-79]) vs 60% [95% CI: 48; 70]; p = 0.03). CONCLUSIONS: In this contemporary study integrating functional imaging data, we found potential efficacy of SRT with dose escalation ≥72 Gy for patients with MLR in the prostate bed and with an acceptable toxicity profile. Prospective data exploring this MLR dose escalation strategy are awaited. PATIENT SUMMARY: In this report, we looked at the outcomes from salvage radiotherapy for prostate cancer and macroscopic relapse in a large European population. We found that outcomes varied with prostate-specific antigen at relapse, Gleason score, and dose escalation. We found potential efficacy of salvage radiotherapy with dose escalation for macroscopic relapse in the prostate bed, with an acceptable toxicity profile.

Mode of delivery after labor induction with vaginal dinoprostone versus oral misoprostol for women with unfavorable cervix at term.

OBJECTIVE: To compare the delivery mode after labor induction with 10 mg vaginal dinoprostone insert versus oral misoprostol 50 µg/4 h for women with an unfavorable cervix. MATERIAL AND METHODS: This is a retrospective observational study comparing the before/after introduction of oral misoprostol for labor induction, conducted at the Saint-Étienne University Hospital on a cohort of 396 women with a Bishop score <6. One hundred and twelve women (28.3%) were treated with a 10 mg vaginal dinoprostone insert versus 284 (71.7%) with oral misoprostol 50 µg/4 h. The primary outcome was the cesarean section rate. RESULTS: Labor induction with vaginal dinoprostone was independently associated with an increased rate of cesarean sections compared to oral misoprostol (aOR = 2.44; CI95% from 1.35 to 4.40; p = 0.003). The use of vaginal dinoprostone increased the induction rate during more than 48 h (18.8% versus 9.9%; p = 0.02), and the occurrence of fetal heart rate changes (34.8% versus 21.1%; p = 0.005). The maternofetal morbidity was similar. CONCLUSION: Labor induction with vaginal dinoprostone was independently associated with an increased rate of cesarean sections compared to oral misoprostol in women with an unfavorable cervix.

Classification Performance of the Ages and Stages Questionnaire: Influence of Maternal Education Level.

(1) Background: The Ages and Stages Questionnaire-Third Edition (ASQ-3) is a parental screening questionnaire increasingly being used to evaluate the development of preterm children. We aimed to assess the classification performance of the ASQ-3 in preterm infant follow-up. (2) Methods: In this cross-sectional study, we included 185 children from the SEVE longitudinal cohort born <33 weeks of gestational age between November 2011 and January 2018, who had both an ASQ-3 score at 24 months of corrected age (CA) and a revised Brunet-Lézine (RBL) scale score at 30 months of CA. The ASQ-3 overall score and sub-scores were compared to the RBL developmental quotient (DQ) scores domain by domain. The diagnostic performance of the ASQ-3 was evaluated with the RBL as the reference method by calculating sensitivity, specificity, and positive and negative likelihood ratios. A multivariate analysis assessed the association between low maternal education level and incorrect evaluation with the ASQ-3. (3) Results: The ASQ-3 overall score had a specificity of 91%, a sensitivity of 34%, a positive likelihood ratio of 3.82, and a negative likelihood ratio of 0.72. Low maternal education level was a major risk factor for incorrectly evaluating children with the ASQ-3 (odds ratio 4.16, 95% confidence interval 1.47-12.03; p < 0.01). (4) Conclusions: Regarding the low sensitivity and the impact of a low maternal education level on the classification performance of the ASQ-3, this parental questionnaire should not be used alone to follow the development of preterm children.

Why, when and how to assess autonomic nervous system maturation in neonatal care units: A practical overview.

The evaluation of the autonomic reactivity of newborns by heart rate variability (HRV) analysis is a simple and essential aid to identifying pathological situations of dysautonomia. Thanks to this relatively simple and reproducible analytic tool, the pediatrician can identify and target children at high risk of life-threatening events, i.e., those with insufficient intrinsic capacity for cardiorespiratory self-regulation, who should benefit from close cardiorespiratory monitoring. Different mathematical algorithms integrate delayed or real-time variations in the length of the RR interval to better understand the state of autonomic maturation of the newborn. HRV analysis, as a non-invasive tool for assessing autonomic balance, is essential to assess the functioning of the autonomic nervous system and, more specifically, parasympathetic/sympathetic balance. Despite many recognized diagnostic and therapeutic implications, its application to neonatal medicine is not yet well understood.

Serum D-dimer is not predictive of placenta-mediated complications in pregnancy at high risk: The multicentric prospective cohort AngioPred study.

Background: The theory that D-dimer level might has a predictive or diagnostic role in preeclampsia needs to be explored. Aim of the study was to evaluate the association between serum D-dimer level and the occurrence of placenta-mediated complications (PMC) in a pregnant population at high risk. Methods: A prospective multicenter cohort study including 200 pregnant women was conducted. Results: Serum D-dimer increases throughout pregnancy, with the highest levels at the end of gestation. Serum D-dimer level was similar for women with PMC and with no complication. Serum D-dimer level was not different in women with preeclampsia versus uncomplicated women. Serum D-dimer level was not different in women with early or late preeclampsia versus uncomplicated women. Conclusion: This result suggests that serum D-dimer level was not predictive of the PMC occurrence. This corroborates the fact that the origin of PMC based more on immunity than in hemostasis.

Perinatal inflammation exposure and developmental outcomes 7 years after neonatal arterial ischaemic stroke.

AIM: To test the association between perinatal inflammation exposure and Full-Scale IQ (FSIQ) score 7 years after neonatal arterial ischaemic stroke (NAIS). METHOD: We conducted a cross-sectional ancillary study nested in a multicentric longitudinal French cohort of infants born at term with NAIS between November 2003 and October 2006. Seventy-three children were included (45 males, 28 females). The a priori defined primary outcome measure was the FSIQ score assessed with the Wechsler Intelligence Scale for Children, Fourth Edition at 7 years of age. RESULTS: Seventeen (23%) of the included children were exposed to perinatal inflammation. Exposure to perinatal inflammation was independently associated with an increase of FSIQ score (coefficient 13.4, 95% confidence interval 1.3-25.4; p = 0.03). Children exposed to perinatal inflammation had a higher median cerebral volume, a lower median lesion volume, and less extensive lesion distributions compared to non-exposed children. INTERPRETATION: We propose the existence of two NAIS categories: arteritis-associated NAIS in children exposed to perinatal inflammation and embolism-associated NAIS in children non-exposed to perinatal inflammation. Identifying these two NAIS categories would open the possibility for specific curative strategies: anti-inflammatory strategy in arteritis-associated NAIS and recanalization strategy in embolism-associated NAIS.

Pain and satisfaction in women induced by vaginal dinoprostone, double balloon catheter and oral misoprostol.

OBJECTIVE: The aim of this study was to evaluate the pain experience of women induced by intravaginal dinoprostone (Propess®), oral misoprostol (Angusta®) or double balloon catheter (Cook®). METHODS: This single-center prospective study was carried out in the obstetric gynecology department of the university hospital of Saint-Etienne from March 2018 to April 2021 in women requiring cervical ripening for the purpose of artificial labor induction. RESULTS: We included 82 women in the oral misoprostol group, 35 in the vaginal dinoprostone group and 58 in the balloon group. The overall pain, assessed by a numerical scale from 0 to 10, was similar for the different methods of induction (p = 0.253). Pain at insertion was greater with the double balloon catheter compared to the vaginal dinoprostone (3.67 versus 5.75 p = 0.001). Pain in the 2 h prior to the delivery room was greater with vaginal dinoprostone and oral misoprostol compared with the double balloon catheter (7.91 and 7.4 versus 5.47 respectively, p = <0.0001). Women induced by balloon catheter would more often have preferred to be induced by another method compared to those induced by oral misoprostol or vaginal dinoprostone (p = 0.004). Adjusting for previous cesarian section, gestational age at delivery, need for oxytocin augmentation and indication for induction, women induced by balloon were five times more risk to prefer another induction method (OR 5.01 95% CI [1.09-23.03], p = 0.038). There was no significant difference in stress and overall experience of induction depending on the method. CONCLUSION: In order to improve the women experience, information, consent and participation in the decisions and choices of their induction method are essential.

Heart Rate Variability Analysis to Evaluate Autonomic Nervous System Maturation in Neonates: An Expert Opinion.

While heart rate variability (HRV) is a relevant non-invasive tool to assess the autonomic nervous system (ANS) functioning with recognized diagnostic and therapeutic implications, the lack of knowledge on its interest in neonatal medicine is certain. This review aims to briefly describe the algorithms used to decompose variations in the length of the RR interval and better understand the physiological autonomic maturation data of the newborn. Assessing newborns' autonomous reactivity can identify dysautonomia situations and discriminate children with a high risk of life-threatening events, which should benefit from cardiorespiratory monitoring at home. Targeted monitoring of HRV should provide an objective reflection of the newborn's intrinsic capacity for cardiorespiratory self-regulation.

Animal Models of Chorioamnionitis: Considerations for Translational Medicine.

Preterm birth is defined as any birth occurring before 37 completed weeks of gestation by the World Health Organization. Preterm birth is responsible for perinatal mortality and long-term neurological morbidity. Acute chorioamnionitis is observed in 70% of premature labor and is associated with a heavy burden of multiorgan morbidities in the offspring. Unfortunately, chorioamnionitis is still missing effective biomarkers and early placento- as well as feto-protective and curative treatments. This review summarizes recent advances in the understanding of the underlying mechanisms of chorioamnionitis and subsequent impacts on the pregnancy outcome, both during and beyond gestation. This review also describes relevant and current animal models of chorioamnionitis used to decipher associated mechanisms and develop much needed therapies. Improved knowledge of the pathophysiological mechanisms underpinning chorioamnionitis based on preclinical models is a mandatory step to identify early in utero diagnostic biomarkers and design novel anti-inflammatory interventions to improve both maternal and fetal outcomes.

The impact of perinatal inflammation on the electroencephalogram in preterm infants: a systematic review.

BACKGROUND: To summarise the association between perinatal inflammation (PI) exposure and electroencephalography (EEG) features in preterm infants. METHODS: This systematic review included clinical studies of preterm infants born <37 weeks of gestational age (GA), who had both a PI exposure and an EEG assessment performed during the neonatal period. Studies were identified from Medline and Embase databases on the 15th of September 2021. PI was defined by histological chorioamnionitis, clinical chorioamnionitis, or early-onset neonatal infection (EONI). The risk of bias in included studies was assessed using the Joanna Briggs Institute (JBI) appraisal tool. A narrative approach was used to synthesise results. This review followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 statement. RESULTS: Two cross-sectional studies enrolling 130 preterm children born <32 weeks of GA assessed with one-channel amplitude-integrated EEG (aEEG) during the first four days of life were included. A PI exposure was described in 39 (30%) infants and was associated with a decrease in amplitude and a reduced incidence of sleep-wake cycling patterns. CONCLUSION: These results should be interpreted with caution because of the small number of included studies and their heterogeneity. Further clinical studies evaluating the association of PI with EEG findings are needed. IMPACT: A method to assess developmental trajectories following perinatal inflammation is required. Insufficient data exist to determine EEG features associated with perinatal inflammation. Further clinical studies evaluating this association are needed.