Positive Airway Pressure Treatment of Obstructive Sleep Apnea-Hypopnea in Hypertensive Disorders of Pregnancy: A Pilot Randomized Proof-of-Concept Clinical Trial.

Rationale: Maternal obstructive sleep apnea-hypopnea (OSAH) is associated with hypertensive disorders of pregnancy (HDP). OSAH treatment with positive airway pressure (PAP) in the general population lowers blood pressure (BP). However, there are limited data on the effects of PAP therapy in maternal OSAH. Objectives: Our primary objective was to assess the feasibility of recruitment to a pilot randomized trial and adherence to PAP therapy for OSAH in women with HDP. Secondary objectives included assessment of PAP effects on 24-h BP, arterial stiffness, and maternal and fetal outcomes. Methods: Women with singleton pregnancies at ⩾12 weeks' gestation and hypertension underwent home level 2 polysomnography; those with mild to moderate OSAH (apnea-hypopnea index ⩾ 5 events/h; women with severe OSAH with apnea-hypopnea index > 30 events/h and oxygen desaturation index > 30 were excluded) were randomized to either PAP or nasal dilator strip (NDS; control) therapy. After PAP education, adherence was monitored online with episodic phone or in-person support by research personnel. Twenty-four-hour BP and arterial stiffness were assessed at baseline and before delivery. Maternal and fetal outcomes were also recorded. Results: Of 105 potentially eligible participants, 67 agreed to undergo screening for OSAH over 38 months; 48 women meeting OSAH inclusion criteria were randomized to PAP (n = 27) or NDS (n = 21) therapy. Of these, 14 PAP (52%) and 13 NDS (62%) participants completed all predelivery measurements, with lack of completion due to urgent delivery (19% in the PAP group, 14% in the NDS group), PAP intolerance at initiation (19%), or other factors. Mean PAP use was 3.1 ± 2.5 h/night, with use ⩾4 h/night on 38.4 ± 33.7% of nights during 9.6 ± 4.0 weeks of treatment. BP was controlled within the target range in most participants. There were no differences in mean change in 24-hour BP or arterial stiffness measurements or in adverse maternal and fetal outcomes between the PAP and NDS groups in either intention-to-treat or per-protocol analyses. Conclusions: PAP adherence was suboptimal in this HDP cohort despite education and troubleshooting. Further work is required to identify optimal OSAH treatment strategies during pregnancy. Clinical trial registered with www.clinicaltrials.gov (NCT03309826).

Type of infertility and prevalence of congenital malformations.

BACKGROUND: Children conceived with assisted reproductive technologies (ART) or after a long waiting time have a higher prevalence of congenital malformations, but few studies have examined the contribution of type of infertility. OBJECTIVES: To quantify the association between causes of infertility and prevalence of malformations. METHODS: We compared the prevalence at birth of all and severe malformations diagnosed up to age 2 between 6656 children born in 1996-2017 to parents who had previously been assessed for infertility a an academic fertility clinic ("exposed") and 10,382 children born in the same period to parents with no recent medical history of infertility ("reference"). We estimated prevalence ratios (PR) and prevalence differences (PD), by infertility status, type of treatment (non-ART, ART), and infertility diagnosis, in all children and among singletons. RESULTS: Compared with children of parents with no infertility, children of parents with infertility had a higher prevalence of malformations (both definitions), particularly following ART conceptions. After accounting for treatment, ovulatory disorders were associated with a higher prevalence of both all (PR 1.49, 95% confidence interval (CI) 1.15, 1.93; PD 3.8, 95% CI 1.0, 6.6) and severe (PR 1.53, 95% CI 1.02, 2.29; PD 1.8, 95% CI -0.2, 3.7) malformations (the estimates refer to exposed children conceived without treatment). Unexplained and male factor infertility were associated with all and severe malformations, respectively. Estimates among singletons were similar. A diagnosis of ovulatory disorders was associated with all malformations also in analyses restricted to exposed children, regardless of treatment (we did not examine severe malformations, due to limited power). CONCLUSIONS: In this study, ovulatory disorders were consistently associated with a higher prevalence of congenital malformations (including severe malformations) among live births, regardless of mode of conception.

Perinatal morbidity among women with a previous caesarean delivery (PRISMA trial): a cluster-randomised trial.

BACKGROUND: Women with a previous caesarean delivery face a difficult choice in their next pregnancy: planning another caesarean or attempting vaginal delivery, both of which are associated with potential maternal and perinatal complications. This trial aimed to assess whether a multifaceted intervention, which promoted person-centred decision making and best practices, would reduce the risk of major perinatal morbidity among women with one previous caesarean delivery. METHODS: We conducted an open, multicentre, cluster-randomised, controlled trial of a multifaceted 2-year intervention in 40 hospitals in Quebec among women with one previous caesarean delivery, in which hospitals were the units of randomisation and women the units of analysis. Randomisation was stratified according to level of care, using blocked randomisation. Hospitals were randomly assigned (1:1) to the intervention group (implementation of best practices and provision of tools that aimed to support decision making about mode of delivery, including an estimation of the probability of vaginal delivery and an ultrasound estimation of the risk of uterine rupture), or the control group (no intervention). The primary outcome was a composite risk of major perinatal morbidity. This trial was registered with ISRCTN, ISRCTN15346559. FINDINGS: 21 281 eligible women delivered during the study period, from April 1, 2016 to Dec 13, 2019 (10 514 in the intervention group and 10 767 in the control group). None were lost to follow-up. There was a significant reduction in the rate of major perinatal morbidity from the baseline period to the intervention period in the intervention group as compared with the control group (adjusted odds ratio [OR] for incremental change over time, 0·72 [95% CI 0·52-0·99]; p=0·042; adjusted risk difference -1·2% [95% CI -2·0 to -0·1]). Major maternal morbidity was significantly reduced in the intervention group as compared with the control group (adjusted OR 0·54 [95% CI 0·33-0·89]; p=0·016). Minor perinatal and maternal morbidity, caesarean delivery, and uterine rupture rates did not differ significantly between groups. INTERPRETATION: A multifaceted intervention supporting women in their choice of mode of delivery and promoting best practices resulted in a significant reduction in rates of major perinatal and maternal morbidity, without an increase in the rate of caesarean or uterine rupture. FUNDING: Canadian Institutes of Health Research (CIHR, MOP-142448).

Activating Inducible T-cell Costimulator Yields Antitumor Activity Alone and in Combination with Anti-PD-1 Checkpoint Blockade.

In recent years, there has been considerable interest in mAb-based induction of costimulatory receptor signaling as an approach to combat cancer. However, promising nonclinical data have yet to translate to a meaningful clinical benefit. Inducible T-cell costimulator (ICOS) is a costimulatory receptor important for immune responses. Using a novel clinical-stage anti-ICOS immunoglobulin G4 mAb (feladilimab), which induces but does not deplete ICOS+ T cells and their rodent analogs, we provide an end-to-end evaluation of the antitumor potential of antibody-mediated ICOS costimulation alone and in combination with programmed cell death protein 1 (PD-1) blockade. We demonstrate, consistently, that ICOS is expressed in a range of cancers, and its induction can stimulate growth of antitumor reactive T cells. Furthermore, feladilimab, alone and with a PD-1 inhibitor, induced antitumor activity in mouse and humanized tumor models. In addition to nonclinical evaluation, we present three patient case studies from a first-time-in-human, phase I, open-label, dose-escalation and dose-expansion clinical trial (INDUCE-1; ClinicalTrials.gov: NCT02723955), evaluating feladilimab alone and in combination with pembrolizumab in patients with advanced solid tumors. Preliminary data showing clinical benefit in patients with cancer treated with feladilimab alone or in combination with pembrolizumab was reported previously; with example cases described here. Additional work is needed to further validate the translation to the clinic, which includes identifying select patient populations that will benefit from this therapeutic approach, and randomized data with survival endpoints to illustrate its potential, similar to that shown with CTLA-4 and PD-1 blocking antibodies. Significance: Stimulation of the T-cell activation marker ICOS with the anti-ICOS agonist mAb feladilimab, alone and in combination with PD-1 inhibition, induces antitumor activity across nonclinical models as well as select patients with advanced solid tumors.

Directive clinique no 439 : Diagnostic et prise en charge du vasa prævia.

OBJECTIF: Résumer les données probantes actuelles et énoncer des recommandations pour le diagnostic et la classification du vasa prævia et pour la prise en charge des femmes ayant reçu ce diagnostic. POPULATION CIBLE: Femmes enceintes présentant un vasa prævia ou des vaisseaux ombilicaux péricervicaux. OPTIONS: En cas de diagnostic soupçonné ou confirmé de vasa prævia ou de vaisseaux ombilicaux péricervicaux, prendre en charge la patiente à l'hôpital ou à domicile, puis pratiquer une césarienne avant terme ou à terme ou entreprendre une épreuve de travail. RéSULTATS: Hospitalisation prolongée, accouchement prématuré, césarienne et morbidité et mortalité néonatales. BéNéFICES, RISQUES ET COûTS: Les femmes ayant un vasa prævia ou des vaisseaux ombilicaux péricervicaux présentent un risque accru d'issues défavorables maternelles, fœtales ou postnatales, à savoir un diagnostic potentiellement erroné, un besoin d'hospitalisation, une restriction inutile des activités, un accouchement précoce et une césarienne inutile. L'optimisation des protocoles de diagnostic et de prise en charge peut améliorer les issues maternelles, fœtales et postnatales. DONNéES PROBANTES: Des recherches ont été effectuées dans les bases de données Medline, PubMed, Embase et Cochrane Library, de leur création jusqu'à mars 2022, à partir de termes MeSH et de mots clés liés à la grossesse, au vasa prævia, aux vaisseaux prævia, à l'hémorragie ante partum, au col court, au travail prématuré et à la césarienne. Le présent document est un résumé des données probantes et non pas une revue méthodologique. MéTHODES DE VALIDATION: Les auteurs ont évalué la qualité des données probantes et la force des recommandations en utilisant le cadre méthodologique GRADE (Grading of Recommendations Assessment, Development and Evaluation). Voir l'annexe A en ligne (tableau A1 pour les définitions et tableau A2 pour l'interprétation des recommandations fortes et faibles). PROFESSIONNELS CONCERNéS: Fournisseurs de soins obstétricaux, y compris obstétriciens, médecins de famille, infirmières, sages-femmes, spécialistes en médecine fœto-maternelle et radiologistes. RéSUMé POUR TWITTER: En cas de cordon et de vaisseaux ombilicaux non protégés dans les membranes près du col (vasa prævia y compris), une caractérisation échographique et une prise en charge avisée s'imposent pour réduire les risques pour le bébé et la mère pendant la grossesse et l'accouchement. DÉCLARATIONS SOMMAIRES: RECOMMANDATIONS.

Guideline No. 439: Diagnosis and Management of Vasa Previa.

OBJECTIVE: To summarize the current evidence and to make recommendations for diagnosis and classification of vasa previa and for management of women with this diagnosis. TARGET POPULATION: Pregnant women with vasa previa or low-lying fetal vessels. OPTIONS: To manage vasa previa in hospital or at home, and to perform a cesarean delivery preterm or at term, or to allow a trial of labour when a diagnosis of vasa previa or low-lying fetal vessels is suspected or confirmed. OUTCOMES: Prolonged hospitalization, preterm birth, rate of cesarean delivery, and neonatal morbidity and mortality. BENEFITS, HARMS, AND COSTS: Women with vasa previa or low-lying fetal vessels are at an increased risk of maternal and fetal or postnatal adverse outcomes. These outcomes include a potentially incorrect diagnosis, need for hospitalization, unnecessary restriction of activities, an early delivery, and an unnecessary cesarean delivery. Optimization of diagnostic and management protocols can improve maternal and fetal or postnatal outcomes. EVIDENCE: Medline, Pubmed, Embase, and the Cochrane Library were searched from inception to March 2022, using medical subject headings (MeSH) and keywords related to pregnancy, vasa previa, low-lying fetal vessels, antepartum hemorrhage, short cervix, preterm labour, and cesarean delivery. This document presents an abstraction of the evidence rather than a methodological review. VALIDATION METHODS: The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and weak recommendations). INTENDED AUDIENCE: Obstetric care providers, including obstetricians, family physicians, nurses, midwives, maternal-fetal medicine specialists, and radiologists. TWEETABLE ABSTRACT: Unprotected fetal vessels in placental membranes and cord that are close to the cervix, including vasa previa, need careful characterization by sonographic examination and evidence-based management to reduce risks to the baby and the mother during pregnancy and delivery. SUMMARY STATEMENTS: RECOMMENDATIONS.

Adherence and efficacy of mandibular advancement splint treatment of sleep-disordered breathing during pregnancy: a pilot study.

PURPOSE: Sleep-disordered breathing (SDB) is common in pregnancy and is associated with adverse health consequences for both mother and child. Mandibular advancement splints (MAS) have been shown to improve sleep quality, daytime sleepiness and snoring in non-pregnant women. The effectiveness of MAS for treating SDB in pregnancy is unknown. This pilot study aimed to evaluate the efficacy and adherence to MAS in pregnant women with SDB. METHODS: Women with mild-moderate SDB (apnea-hypopnea index (AHI) 10-29/h) on level 2 polysomnography (PSG) performed at 22.0 ± 5.5 weeks' gestation were treated with a MAS during pregnancy to 6 months postpartum. An embedded micro-recorder measured adherence. PSG was repeated while on titrated treatment, and off treatment in the postpartum period. RESULTS: Among 17 women completing the study, MAS was worn ≥ 4 h/night for 57.5 ± 36.7% of nights during the antepartum period. While using MAS, nightly snoring time decreased from 25.9 ± 24.5% at baseline to 6.4 ± 7.8% when treated during pregnancy (p = .003). AHI decreased from 17.6 ± 5.1 to 12.9 ± 6.3 (p = .02) and fell by ≥ 30% and below 15/h in 60% of participants. During the postpartum period, MAS was used for ≥ 4 h/night on 24.8 ± 27.9% of nights. Moreover, the mean AHI off MAS was 17.9 ± 13.1; 88% of women had persistent SDB (AHI ≥ 10). CONCLUSIONS: In this cohort, treatment efficacy and objective adherence were variable. Device use was less frequent in the postpartum period even though a substantial number of women had persistent SDB after delivery. Clinical trial registered with  www. CLINICALTRIALS: gov number: NCT03138291.

Correction: Phase II Study Evaluating 2 Dosing Schedules of Oral Foretinib (GSK1363089), cMET/VEGFR2 Inhibitor, in Patients with Metastatic Gastric Cancer.

[This corrects the article DOI: 10.1371/journal.pone.0054014.].

Are different station formats assessing different dimensions in multiple mini-interviews? Findings from the Canadian integrated French multiple mini-interviews.

BACKGROUND: Multiple mini-interviews (MMI) are used to assess non-academic attributes for selection in medicine and other healthcare professions. It remains unclear if different MMI station formats (discussions, role-plays, collaboration) assess different dimensions. METHODS: Based on station formats of the 2018 and 2019 Integrated French MMI (IFMMI), which comprised five discussions, three role-plays and two collaboration stations, the authors performed confirmatory factor analysis (CFA) using the lavaan 0.6-5 R package and compared a one-factor solution to a three-factor solution for scores of the 2018 (n = 1438) and 2019 (n = 1440) cohorts of the IFMMI across three medical schools in Quebec, Canada. RESULTS: The three-factor solution was retained, with discussions, role-plays and collaboration stations all loading adequately with their scores. Furthermore, all three factors had moderate-to-high covariance (range 0.44 to 0.64). The model fit was also excellent with a Comparative fit index (CFI) of 0.983 (good if > 0.9), a Tucker Lewis index of 0.976 (good if > 0.95), a Standardized Root Mean Square Residual of 0.021 (good if < .08) and a Root Mean Square Error of 0.023 (good if < 0.08) for 2018 and similar results for 2019. In comparison, the single factor solution presented a lower fit (CFI = 0.819, TLI = 0.767, SRMR = 0.049 and RMSEA = 0.070). CONCLUSIONS: The IFMMI assessed three dimensions that were related to stations formats, a finding that was consistent across two cohorts. This suggests that different station formats may be assessing different skills, and has implications for the choice of appropriate reliability metrics and the interpretation of scores. Further studies should try to characterize the underlying constructs associated with each station format and look for differential predictive validity according to these formats.

Biological impact of iberdomide in patients with active systemic lupus erythematosus.

OBJECTIVES: Iberdomide is a high-affinity cereblon ligand that promotes proteasomal degradation of transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). Pharmacodynamics and pharmacokinetics of oral iberdomide were evaluated in a phase 2b study of patients with active systemic lupus erythematosus (SLE). METHODS: Adults with autoantibody-positive SLE were randomised to placebo (n=83) or once daily iberdomide 0.15 mg (n=42), 0.3 mg (n=82) or 0.45 mg (n=81). Pharmacodynamic changes in whole blood leucocytes were measured by flow cytometry, regulatory T cells (Tregs) by epigenetic assay, plasma cytokines by ultrasensitive cytokine assay and gene expression by Modular Immune Profiling. RESULTS: Iberdomide exhibited linear pharmacokinetics and dose-dependently modulated leucocytes and cytokines. Compared with placebo at week 24, iberdomide 0.45 mg significantly (p<0.001) reduced B cells, including those expressing CD268 (TNFRSF13C) (-58.3%), and plasmacytoid dendritic cells (-73.9%), and increased Tregs (+104.9%) and interleukin 2 (IL-2) (+144.1%). Clinical efficacy was previously reported in patients with high IKZF3 expression and high type I interferon (IFN) signature at baseline and confirmed here in those with an especially high IFN signature. Iberdomide decreased the type I IFN gene signature only in patients with high expression at baseline (-81.5%; p<0.001) but decreased other gene signatures in all patients. CONCLUSION: Iberdomide significantly reduced activity of type I IFN and B cell pathways, and increased IL-2 and Tregs, suggesting a selective rebalancing of immune abnormalities in SLE. Clinical efficacy corresponded to reduction of the type I IFN gene signature. TRIAL REGISTRATION NUMBER: NCT03161483.

Sleep-disordered breathing in high-risk pregnancies is associated with elevated arterial stiffness and increased risk for preeclampsia.

BACKGROUND: Impaired vascular function is a central feature of pathologic processes preceding the onset of preeclampsia. Arterial stiffness, a composite indicator of vascular health and an important vascular biomarker, has been found to be increased throughout pregnancy in those who develop preeclampsia and at the time of preeclampsia diagnosis. Although sleep-disordered breathing in pregnancy has been associated with increased risk for preeclampsia, it is unknown if sleep-disordered breathing is associated with elevated arterial stiffness in pregnancy. OBJECTIVE: This prospective observational cohort study aimed to evaluate arterial stiffness in pregnant women, with and without sleep-disordered breathing and assess the interaction between arterial stiffness, sleep-disordered breathing, and preeclampsia risk. STUDY DESIGN: Women with high-risk singleton pregnancies were enrolled at 10 to 13 weeks' gestation and completed the Epworth Sleepiness Score, Pittsburgh Sleep Quality Index, and Restless Legs Syndrome questionnaires at each trimester. Sleep-disordered breathing was defined as loud snoring or witnessed apneas (≥3 times per week). Central arterial stiffness (carotid-femoral pulse wave velocity, the gold standard measure of arterial stiffness), peripheral arterial stiffness (carotid-radial pulse wave velocity), wave reflection (augmentation index, time to wave reflection), and hemodynamics (central blood pressures, pulse pressure amplification) were assessed noninvasively using applanation tonometry at recruitment and every 4 weeks from recruitment until delivery. RESULTS: High-risk pregnant women (n=181) were included in the study. Women with sleep-disordered breathing (n=41; 23%) had increased carotid-femoral pulse wave velocity throughout gestation independent of blood pressure and body mass index (P=.042). Differences observed in other vascular measures were not maintained after adjustment for confounders. Excessive daytime sleepiness, defined by Epworth Sleepiness Score >10, was associated with increased carotid-femoral pulse wave velocity only in women with sleep-disordered breathing (Pinteraction=.001). Midgestation (first or second trimester) sleep-disordered breathing was associated with an odds ratio of 3.4 (0.9-12.9) for preeclampsia, which increased to 5.7 (1.1-26.0) in women with sleep-disordered breathing and hypersomnolence, whereas late (third-trimester) sleep-disordered breathing was associated with an odds ratio of 8.2 (1.5-39.5) for preeclampsia. CONCLUSION: High-risk pregnant women with midgestational sleep-disordered breathing had greater arterial stiffness throughout gestation than those without. Sleep-disordered breathing at any time during pregnancy was also associated with increased preeclampsia risk, and this effect was amplified by hypersomnolence.

Correction: Phase II Study Evaluating 2 Dosing Schedules of Oral Foretinib (GSK1363089), cMET/VEGFR2 Inhibitor, in Patients with Metastatic Gastric Cancer.

[This corrects the article DOI: 10.1371/journal.pone.0054014.].

Effect of Maternal Obstructive Sleep Apnea-Hypopnea on 24-Hour Blood Pressure, Nocturnal Blood Pressure Dipping and Arterial Stiffness in Hypertensive Disorders of Pregnancy.

Rationale: Maternal obstructive sleep apnea-hypopnea (OSAH) is associated with hypertensive disorders of pregnancy (HDP). Attenuation of the normal nocturnal blood pressure (BP) decline (non-dipping) is associated with adverse pregnancy outcomes. OSAH is associated with nocturnal non-dipping in the general population, but this has not been studied in pregnancy. We therefore analyzed baseline data from an ongoing RCT (NCT03309826) assessing the impact of OSAH treatment on HDP outcomes, to evaluate the relationship of OSAH to 24-h BP profile, in particular nocturnal BP dipping, and measures of arterial stiffness. Methods: Women with a singleton pregnancy and HDP underwent level II polysomnography. Patients with OSAH (apnea-hypopnea index (AHI) ≥ 5 events/h) then underwent 24-h ambulatory BP monitoring and arterial stiffness measurements (applanation tonometry, SphygmoCor). Positive dipping was defined as nocturnal systolic blood pressure (SBP) dip ≥ 10%. The relationships between measures of OSAH severity, measures of BP and arterial stiffness were evaluated using linear regression analyses. Results: We studied 51 HDP participants (36.5 ± 4.9 years, BMI 36.9 ± 8.6 kg/m2) with OSAH with mean AHI 27.7 ± 26.4 events/h at 25.0 ± 4.9 weeks' gestation. We found no significant relationships between AHI or other OSA severity measures and mean 24-h BP values, although BP was generally well-controlled. Most women were SBP non-dippers (78.4%). AHI showed a significant inverse correlation with % SBP dipping following adjustment for age, BMI, parity, gestational age, and BP medications (ß = -0.11, p = 0.02). Significant inverse correlations were also observed between AHI and DBP (ß = -0.16, p = 0.01) and MAP (ß = -0.13, p = 0.02) % dipping. Oxygen desaturation index and sleep time below SaO2 90% were also inversely correlated with % dipping. Moreover, a significant positive correlation was observed between carotid-femoral pulse wave velocity (cfPWV) and REM AHI (ß = 0.02, p = 0.04) in unadjusted but not adjusted analysis. Conclusion: Blood pressure non-dipping was observed in a majority of women with HDP and OSAH. There were significant inverse relationships between OSAH severity measures and nocturnal % dipping. Increased arterial stiffness was associated with increasing severity of OSAH during REM sleep in unadjusted although not adjusted analysis. These findings suggest that OSAH may represent a therapeutic target to improve BP profile and vascular risk in HDP.

A Phase I, First-in-Human Study of GSK2849330, an Anti-HER3 Monoclonal Antibody, in HER3-Expressing Solid Tumors.

BACKGROUND: GSK2849330, an anti-HER3 monoclonal antibody that blocks HER3/Neuregulin 1 (NRG1) signaling in cancer cells, is engineered for enhanced antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. This phase I, first-in-human, open-label study assessed the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of GSK2849330 in patients with HER3-expressing advanced solid tumors. PATIENTS AND METHODS: Patients with various tumor types were prospectively selected for HER3 expression by immunohistochemistry; a subset was also screened for NRG1 mRNA expression. In the dose-escalation phase, patients received GSK2849330 1.4-30 mg/kg every 2 weeks, or 3 mg/kg or 30 mg/kg weekly, intravenously (IV). In the dose-expansion phase, patients received 30 mg/kg GSK2849330 IV weekly. RESULTS: Twenty-nine patients with HER3-expressing cancers, of whom two expressed NRG1, received GSK2849330 (dose escalation: n = 18, dose expansion: n = 11). GSK2849330 was well tolerated. No dose-limiting toxicities were observed. The highest dose, of 30 mg/kg weekly, expected to provide full target engagement, was selected for dose expansion. Treatment-emergent adverse events (AEs) were mostly grade 1 or 2. The most common AEs were diarrhea (66%), fatigue (62%), and decreased appetite (31%). Dose-proportional plasma exposures were achieved, with evidence of HER3 inhibition in paired tissue biopsies. Of 29 patients, only 1 confirmed partial response, lasting 19 months, was noted in a patient with CD74-NRG1-rearranged non-small cell lung cancer (NSCLC). CONCLUSION: GSK2849330 demonstrated a favorable safety profile, dose-proportional PK, and evidence of target engagement, but limited antitumor activity in HER3-expressing cancers. The exceptional response seen in a patient with CD74-NRG1-rearranged NSCLC suggests further exploration in NRG1-fusion-positive cancers. IMPLICATIONS FOR PRACTICE: This first-in-human study confirms that GSK2849330 is well tolerated. Importantly, across a variety of HER3-expressing advanced tumors, prospective selection by HER3/NRG1 expression alone was insufficient to identify patients who could benefit from treatment with this antibody-dependent cell-mediated cytotoxicity- and complement-dependent cytotoxicity-enhanced anti-HER3 antibody. The only confirmed durable response achieved was in a patient with CD74-NRG1-rearranged lung cancer. This highlights the potential utility of screening for NRG1 fusions prospectively across tumor types to enrich potential responders to anti-HER3 agents in ongoing trials.

A longitudinal analysis of arterial stiffness and wave reflection in preeclampsia: Identification of changepoints.

PURPOSE: Preeclampsia (PrE) is a leading complication of pregnancy characterized by vascular dysfunction. Characterizing the longitudinal changes in vascular function prior to PrE onset is critical to the identification of optimal timepoints for vascular assessment and the development of effective early screening strategies. METHODS: In this prospective longitudinal study of women with singleton high-risk pregnancies, arterial stiffness and wave reflection parameters were assessed using applanation tonometry at 10-13 weeks' gestation and repeated every 4 weeks throughout pregnancy. Changepoints in carotid-femoral pulse wave velocity (cfPWV), carotid-radial PWV (crPWV), augmentation index (AIx), time to wave reflection (T1R), pulse pressure amplification (PPA), and subendocardial viability ratio (SEVR) were compared between women who did and did not subsequently develop PrE. RESULTS: A changepoint in cfPWV and crPWV was detected at 14-17 weeks' gestation. cfPWV then increased in women who went on to develop PrE but decreased in women who did not; a 1.2 m/s difference in cfPWV between the groups was observed at 22-25 weeks' gestation. Conversely, crPWV converged in the two groups from a baseline difference of 1.05 m/s (95% credible interval: 0.37, 1.72). Women who subsequently developed PrE demonstrated an increase in AIx at 18-21 weeks' gestation that was not seen in women who did not develop PrE until 30-33 weeks. No differences in T1R, PPA, or SEVR were observed between the groups. CONCLUSIONS: Altered vascular adaptations were detected using measures of arterial stiffness and wave reflection in the early second trimester of pregnant women who developed PrE compared to those who did not. These findings demonstrate the potential clinical utility of arterial stiffness and wave reflection parameters as an early screening tool for PrE, which can be used to inform clinical management of high-risk pregnancies.

Accuracy of rating scale interval values used in multiple mini-interviews: a mixed methods study.

When determining the score given to candidates in multiple mini-interview (MMI) stations, raters have to translate a narrative judgment to an ordinal rating scale. When adding individual scores to calculate final ranking, it is generally presumed that the values of possible scores on the evaluation grid are separated by constant intervals, following a linear function, although this assumption is seldom validated with raters themselves. Inaccurate interval values could lead to systemic bias that could potentially distort candidates' final cumulative scores. The aim of this study was to establish rating scale values based on rater's intent, to validate these with an independent quantitative method, to explore their impact on final score, and to appraise their meaning according to experienced MMI interviewers. A 4-round consensus-group exercise was independently conducted with 42 MMI interviewers who were asked to determine relative values for the 6-point rating scale (from A to F) used in the Canadian integrated French MMI (IFMMI). In parallel, relative values were also calculated for each option of the scale by comparing the average scores concurrently given to the same individual in other stations every time that option was selected during three consecutive IFMMI years. Data from the same three cohorts was used to simulate the impact of using new score values on final rankings. Comments from the consensus group exercise were reviewed independently by two authors to explore raters' rationale for choosing specific values. Relative to the maximum (A = 100%) and minimum (F = 0%), experienced raters concluded to values of 86.7% (95% CI 86.3-87.1), 69.5% (68.9-70.1), 51.2% (50.6-51.8), and 29.3% (28.1-30.5), for scores of B, C, D and E respectively. The concurrent score approach was based on 43,412 IFMMI stations performed by 4345 medical school applicants. It provided quasi-identical values of 87.1% (82.4-91.5), 70.4% (66.1-74.7), 51.2% (47.1-55.3) and 31.8% (27.9-35.7), respectively. Qualitative analysis explained that while high scores are usually based on minor details of relatively low importance, low scores are usually attributed for more serious offenses and were assumed by the raters to carry more weight in the final score. Individual drop or increase in final MMI ranking with the use of new scale values ranged from - 21 to + 5 percentiles, with the average candidate changing by ± 1.4 percentiles. Consulting with experienced interviewers is a simple and effective approach to establish rating scale values that truly reflects raters' intent in MMI, thus improving the accuracy of the instrument and contributing to the general fairness of the process.

Maternal Sleep-Disordered Breathing in Pregnancy and Increased Nocturnal Glucose Levels in Women with Gestational Diabetes Mellitus.

BACKGROUND: Women with hyperglycemia during pregnancy are at high risk for adverse perinatal outcomes. Maternal sleep-disordered breathing (SDB) during pregnancy is common and is a risk factor for gestational diabetes mellitus (GDM). However, the relationship between SDB severity and glucose control is unknown. RESEARCH QUESTION: Is there an association between SDB severity and glucose levels as assessed by continuous glucose monitoring in GDM? STUDY DESIGN AND METHODS: Women with GDM underwent sleep recordings and 72-hour continuous glucose monitoring. Linear mixed models were used to estimate the association of the apnea-hypopnea index (AHI), rapid eye movement (REM)-AHI, and non-REM-AHI with mean glucose levels during nighttime (two periods: 11 pm to 3 am and 3 am to 6 am), daytime (8 am to 9 pm), and 24-hours. Models were adjusted for BMI and antihyperglycemic medications. RESULTS: In 65 participants who were 35 ± 5 (mean ± SD) years of age with BMI of 33 ± 7 kg/m2, 31% were undergoing insulin and/or metformin therapy. A ten-unit increase in AHI was associated with elevated nocturnal glucose levels (11 pm to 3 am: 0.20 mmol/L [95% CI, 0.04-0.40]) with persistent elevations into the morning (8 am: 0.26 mmol/L [95% CI, 0.08-0.4]) when adjusted for BMI and medications. REM-AHI was also associated with higher nocturnal and morning glucose levels, whereas non-REM was not. AHI was not associated with either mean daytime or 24-hour glucose levels. INTERPRETATION: Greater severity of SDB was associated with higher nocturnal and morning glucose levels in women with GDM.

Guideline No. 393-Diabetes in Pregnancy.

OBJECTIVES: This guideline reviews the evidence relating to the diagnosis and obstetrical management of diabetes in pregnancy. OUTCOMES: The outcomes evaluated were short and long-term maternal outcomes including pre-eclampsia, Caesarean section, future diabetes and other cardiovascular complications; and fetal outcomes including congenital anomalies, stillbirth, macrosomia, birth trauma, hypoglycemia and long-term effects. EVIDENCE: Published literature was retrieved through searches of PubMed and The Cochrane Library using appropriate controlled vocabulary (MeSH terms "diabetes" and "pregnancy"). Where appropriate, results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date limits but results were limited to English or French language materials. VALUES: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. SUMMARY STATEMENTS: RECOMMENDATIONS.

Directive clinique N° 393 - Le diabète pendant la grossesse.

OBJECTIF: La présente Directive passe en revue les données probantes liées au diagnostic et à la prise en charge obstétricale du diabète durant la grossesse. ISSUES: Les issues évaluées étaient les issues maternelles à court et à long terme, dont la prééclampsie, la césarienne, le diabète éventuel et d'autres complications cardiovasculaires et les issues fœtales, dont les anomalies congénitales, la mortinaissance, la macrosomie, le traumatisme de la naissance, l'hypoglycémie et les effets à long terme. RéSULTATS: La littérature publiée a été récupérée par l'intermédiaire de recherches menées dans PubMed et The Cochrane Library au moyen d'un vocabulaire contrôlé (termes MeSH « diabète ¼ et « grossesse ¼) approprié. Le cas échéant, les résultats ont été restreints aux analyses systématiques, aux essais comparatifs randomisés / essais cliniques comparatifs et aux études observationnelles. Aucune limite n'a été imposée en matière de date, mais les résultats ont été limités aux articles publiés en anglais ou en français. VALEURS: La qualité des résultats a été évaluée au moyen des critères décrits dans le rapport du Groupe d'étude canadien sur les soins de santé préventifs. DÉCLARATIONS SOMMAIRES: RECOMMANDATIONS.