CFTR Function Restoration upon Elexacaftor/Tezacaftor/Ivacaftor Treatment in Patient-Derived Intestinal Organoids with Rare CFTR Genotypes

Cystic fibrosis (CF) is caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. The combination of the CFTR modulators elexacaftor, tezacaftor, and ivacaftor (ETI) enables the effective rescue of CFTR function in people with the most prevalent F508del mutation. However, the functional restoration of rare CFTR variants remains unclear. Here, we use patient-derived intestinal organoids (PDIOs) to identify rare CFTR variants and potentially individuals with CF that might benefit from ETI. First, steady-state lumen area (SLA) measurements were taken to assess CFTR function and compare it to the level observed in healthy controls. Secondly, the forskolin-induced swelling (FIS) assay was performed to measure CFTR rescue within a lower function range, and to further compare it to ETI-mediated CFTR rescue in CFTR genotypes that have received market approval. ETI responses in 30 PDIOs harboring the F508del mutation served as reference for ETI responses of 22 PDIOs with genotypes that are not currently eligible for CFTR modulator treatment, following European Medicine Agency (EMA) and/or U.S. Food and Drug Administration (FDA) regulations. Our data expand previous datasets showing a correlation between in vitro CFTR rescue in organoids and corresponding in vivo ppFEV1 improvement upon a CFTR modulator treatment in published clinical trials, and suggests that the majority of individuals with rare CFTR variants could benefit from ETI. CFTR restoration was further confirmed on protein levels using Western blot. Our data support that CFTR function measurements in PDIOs with rare CFTR genotypes can help to select potential responders to ETI, and suggest that regulatory authorities need to consider providing access to treatment based on the principle of equality for people with CF who do not have access to treatment.</p

Effectiveness of routine third trimester ultrasonography to reduce adverse perinatal outcomes in low risk pregnancy (the IRIS study): nationwide, pragmatic, multicentre, stepped wedge cluster randomised trial

Objectives To investigate the effectiveness of routine ultrasonography in the third trimester in reducing adverse perinatal outcomes in low risk pregnancies compared with usual care and the effect of this policy on maternal outcomes and obstetric interventions. Design Pragmatic, multicentre, stepped wedge cluster randomised trial. Setting 60 midwifery practices in the Netherlands. Participants 13 046 women aged 16 years or older with a low risk singleton pregnancy. Interventions 60 midwifery practices offered usual care (serial fundal height measurements with clinically indicated ultrasonography). After 3, 7, and 10 months, a third of the practices were randomised to the intervention strategy. As well as receiving usual care, women in the intervention strategy were offered two routine biometry scans at 28-30 and 34-36 weeks’ gestation. The same multidisciplinary protocol for detecting and managing fetal growth restriction was used in both strategies. Main outcome measures The primary outcome measure was a composite of severe adverse perinatal outcomes: perinatal death, Apgar score <4, impaired consciousness, asphyxia, seizures, assisted ventilation, septicaemia, meningitis, bronchopulmonary dysplasia, intraventricular haemorrhage, periventricular leucomalacia, or necrotising enterocolitis. Secondary outcomes were two composite measures of severe maternal morbidity, and spontaneous labour and birth. Results Between 1 February 2015 and 29 February 2016, 60 midwifery practices enrolled 13 520 women in mid-pregnancy (mean 22.8 (SD 2.4) weeks’ gestation). 13 046 women (intervention n=7067, usual care n=5979) with data based on the national Dutch perinatal registry or hospital records were included in the analyses. Small for gestational age at birth was significantly more often detected in the intervention group than in the usual care group (179 of 556 (32%) v 78 of 407 (19%), P<0.001). The incidence of severe adverse perinatal outcomes was 1.7% (n=118) for the intervention strategy and 1.8% (n=106) for usual care. After adjustment for confounders, the difference between the groups was not significant (odds ratio 0.88, 95% confidence interval 0.70 to 1.20). The intervention strategy showed a higher incidence of induction of labour (1.16, 1.04 to 1.30) and a lower incidence of augmentation of labour (0.78, 0.71 to 0.85). Maternal outcomes and other obstetric interventions did not differ between the strategies. Conclusion In low risk pregnancies, routine ultrasonography in the third trimester along with clinically indicated ultrasonography was associated with higher antenatal detection of small for gestational age fetuses but not with a reduced incidence of severe adverse perinatal outcomes compared with usual care alone. The findings do not support routine ultrasonography in the third trimester for low risk pregnancies. Trial registration Netherlands Trial Register NTR4367

The Knight of Malta

BACKGROUND: For most women, participation in decision-making during maternity care has a positive impact on their childbirth experiences. Shared decision-making (SDM) is widely advocated as a way to support people in their healthcare choices. The aim of this study was to identify quality criteria and professional competencies for applying shared decision-making in maternity care. We focused on decision-making in everyday maternity care practice for healthy women. METHODS: An international three-round web-based Delphi study was conducted. The Delphi panel included international experts in SDM and in maternity care: mostly midwives, and additionally obstetricians, educators, researchers, policy makers and representatives of care users. Round 1 contained open-ended questions to explore relevant ingredients for SDM in maternity care and to identify the competencies needed for this. In rounds 2 and 3, experts rated statements on quality criteria and competencies on a 1 to 7 Likert-scale. A priori, positive consensus was defined as 70% or more of the experts scoring >/=6 (70% panel agreement). RESULTS: Consensus was reached on 45 quality criteria statements and 4 competency statements. SDM in maternity care is a dynamic process that starts in antenatal care and ends after birth. Experts agreed that the regular visits during pregnancy offer opportunities to build a relationship, anticipate situations and revisit complex decisions. Professionals need to prepare women antenatally for unexpected, urgent decisions in birth and revisit these decisions postnatally. Open and respectful communication between women and care professionals is essential; information needs to be accurate, evidence-based and understandable to women. Experts were divided about the contribution of professional advice in shared decision-making and about the partner's role. CONCLUSIONS: SDM in maternity care is a dynamic process that takes into consideration women's individual needs and the context of the pregnancy or birth. The identified ingredients for good quality SDM will help practitioners to apply SDM in practice and educators to prepare (future) professionals for SDM, contributing to women's positive birth experience and satisfaction with care

Phase 1b randomized, double-blind study of namilumab, an anti-granulocyte macrophage colony-stimulating factor monoclonal antibody, in mild-to-moderate rheumatoid arthritis

Change from baseline in swollen (a) and tender (b) joint counts. *Error bars show upper SE for placebo and lower SE for namilumab. SE standard error, SJC swollen joint count, TJC tender joint count. (PDF 1292 kb

Knowledge and skills used for clinical decision-making on childbirth interventions:A qualitative study among midwives in the Netherlands

INTRODUCTION: Appropriate use of interventions in maternity care is a worldwide issue. Midwifery-led models of care are associated with more efficient use of resources, fewer medical interventions, and improved outcomes. However, the use of interventions varies considerably between midwives. The aim of this study was to explore how knowledge and skills influence clinical decision-making of midwives on the appropriate use of childbirth interventions. METHODS: A qualitative study using in-depth interviews with 20 primary care midwives was performed in June 2019. Participants’ clinical experience varied in the use of interventions. The interviews combined a narrative approach with a semi-structured question route. Data were analyzed using deductive content analysis. RESULTS: ‘Knowledge’, ‘Critical thinking skills’, and ‘Communication skills’ influenced midwives’ clinical decision-making towards childbirth interventions. Midwives obtained their knowledge through the formal education program and extended their knowledge by reflecting on experiences and evidence. Midwives with a low use of interventions seem to have a higher level of reflective skills, including reflection-in-action. These midwives used a more balanced communication style with instrumental and affective communication skills in interaction with women, and have more skills to engage in discussions during collaboration with other professionals, and thus personalizing their care. CONCLUSIONS: Midwives with a low use of interventions seemed to have the knowledge and skills of a reflective practitioner, leading to more personalized care compared to standardized care as defined in protocols. Learning through reflectivity, critical thinking skills, and instrumental and affective communication skills, need to be stimulated and trained to pursue appropriate, personalized use of interventions

Knowledge and skills used for clinical decision-making on childbirth interventions: A qualitative study among midwives in the Netherlands

INTRODUCTION: Appropriate use of interventions in maternity care is a worldwide issue. Midwifery-led models of care are associated with more efficient use of resources, fewer medical interventions, and improved outcomes. However, the use of interventions varies considerably between midwives. The aim of this study was to explore how knowledge and skills influence clinical decision-making of midwives on the appropriate use of childbirth interventions. METHODS: A qualitative study using in-depth interviews with 20 primary care midwives was performed in June 2019. Participants' clinical experience varied in the use of interventions. The interviews combined a narrative approach with a semi-structured question route. Data were analyzed using deductive content analysis. RESULTS: 'Knowledge', 'Critical thinking skills', and 'Communication skills' influenced midwives' clinical decision-making towards childbirth interventions. Midwives obtained their knowledge through the formal education program and extended their knowledge by reflecting on experiences and evidence. Midwives with a low use of interventions seem to have a higher level of reflective skills, including reflection-in-action. These midwives used a more balanced communication style with instrumental and affective communication skills in interaction with women, and have more skills to engage in discussions during collaboration with other professionals, and thus personalizing their care. CONCLUSIONS: Midwives with a low use of interventions seemed to have the knowledge and skills of a reflective practitioner, leading to more personalized care compared to standardized care as defined in protocols. Learning through reflectivity, critical thinking skills, and instrumental and affective communication skills, need to be stimulated and trained to pursue appropriate, personalized use of interventions