Assessment of perinatal outcome after sustained tocolysis in early labour (APOSTEL-II trial)

Contains fulltext : 80242.pdf (publisher's version ) (Open Access)BACKGROUND: Preterm labour is the main cause of perinatal morbidity and mortality in the Western world. At present, there is evidence that tocolysis for 48 hours is useful in women with threatened preterm labour at least before 32 weeks. This allows transfer of the patient to a perinatal centre, and maximizes the effect of corticosteroids for improved neonatal survival. It is questionable whether treatment with tocolytics should be maintained after 48 hours. METHODS/DESIGN: The APOSTEL II trial is a multicentre placebo-controlled study. Pregnant women admitted for threatened preterm labour who have been treated with 48 hours corticosteroids and tocolysis will be eligible to participate in the trial between 26+0 and 32+2 weeks gestational age. They will be randomly allocated to nifedipine (intervention) or placebo (control) for twelve days or until delivery, whatever comes first.Primary outcome is a composite of perinatal death, and severe neonatal morbidity up to evaluation at 6 months after birth. Secondary outcomes are gestational age at delivery, number of days in neonatal intensive care and total days of the first 6 months out of hospital. In addition a cost-effectiveness analysis will be performed. Analysis will be by intention to treat. The power calculation is based on an expected 11% difference in adverse neonatal outcome. This implies that 406 women have to be randomised (two sided test, beta 0.2 at alpha 0.05). DISCUSSION: This trial will provide evidence as to whether maintenance tocolysis reduces severe perinatal morbidity and mortality in women with threatened preterm labour before 32 weeks. TRIAL REGISTRATION: Clinical trial registration: http://www.trialregister.nl, NTR 1336, date of registration: June 3rd 2008

Cost-effectiveness of fibronectin testing in a triage in women with threatened preterm labor: alleviation of pregnancy outcome by suspending tocolysis in early labor (APOSTEL-I trial)

BACKGROUND: At present, women with threatened preterm labor before 32 weeks of gestation are, after transfer to a perinatal center, treated with tocolytics and corticosteroids. Many of these women are treated unnecessarily. Fibronectin is an accurate predictor for the occurrence of preterm birth among women with threatened preterm labor. We will assess whether triage of these women with fibronectin testing, cervical length or their combination is cost-effective. METHODS/DESIGN: We will investigate a prospective cohort of women referred to a perinatal centre for spontaneous threatened preterm labor between 24 and 34 weeks with intact membranes. All women will be tested for fibronectin and cervical length. Women with a cervical length <10 mm and women with a cervical length between 10-30 mm in combination with a positive fibronectin test will be treated with tocolytics according to local protocol. Women with a cervical length between 10-30 mm in combination with a negative fibronectin test will be randomised between treatment with nifedipine (intervention) and placebo (control) for 48 hours. Women with a cervical length > 30 mm will be managed according to local protocol. Corticosteroids may be given to all women at the discretion of the attending physician. Primary outcome measure will be delivery within 7 days. Secondary outcome measures will be neonatal morbidity and mortality, complications of tocolytics, costs and health related quality of life. The analysis will be according to the intention to treat principle. We anticipate the probability on preterm birth within 7 days in the group of women with a negative fibronectine test to be 5%. Two groups of 110 women will be needed to assure that in case of non-inferiority the difference in the proportion of preterm deliveries < 7 days will be within a prespecified boundary of 7.5% (one sided test, beta 0.2, alpha 0.05). Data obtained from women with a positive and negative fibronectin tests in both the cohort study and the trial will be integrated in a cost-effectiveness analysis that will assess economic consequences of the use of fibronectin. DISCUSSION: This study will provide evidence for the use of fibronectin testing as safe and cost-effective method in a triage for threatened preterm labor. TRIAL REGISTRATION: Nederlands Trial Register (NTR) number 1857, http://www.trialregister.nl

Validity of the Patient Experiences and Satisfaction with Medications (PESaM) Questionnaire

Background: This study assessed the validity and reliability of the generic module of the recently developed Patient Experiences and Satisfaction with Medications (PESaM) questionnaire in a sample of patients in the Netherlands. Methods: The generic module of the PESaM questionnaire consists of 18 items related to the domains effectiveness, side effects and ease of use of medications. It assesses patients’ experiences regarding the impact of the medication on daily life, health and satisfaction. In 2017, the PESaM questionnaire was sent out to idiopathic pulmonary fibrosis patients using pirfenidone or nintedanib, atypical haemolytic uraemic syndrome patients receiving eculizumab and patients using tacrolimus after kidney transplantation. Mean scores for each domain were calculated applying a scoring algorithm. Construct validity and reliability were assessed using recommended methods. Results: 188 participants completed the generic module, of whom 48% used pirfenidone, 36% nintedanib, 11% tacrolimus and 5% eculizumab. The generic module has good structural properties. Internal consistency values of the domains were satisfactory (i.e. Cronbach’s coefficient alpha above 0.7). Confirmatory factor analysis provided further evidence for construct validity, with good convergent and discriminant validity. The PESaM questionnaire also showed different scores for patients using different medications, in line with expectations, and was therefore able to differentiate between patient groups. Test–retest reliability of the items and domains were rated as moderate to fair (i.e. intraclass coefficients ranged between 0.18 and 0.76). Conclusions: The PESaM questionnaire is a unique patient-reported outcome measure evaluating patient experiences and satisfaction with medications. It has been developed in conjunction with patients, ensuring coverage of domains and issues relevant from the patient’s perspective. This study has shown promising validity of the generic module of the PESaM questionnaire. Further research is recommended to assess reliability in greater detail as well as the responsiveness of the measure. Trial registration: The study

Gender differences in respiratory symptoms in 19-year-old adults born preterm

Objective: To study the prevalence of respiratory and atopic symptoms in (young) adults born prematurely, differences between those who did and did not develop Bronchopulmonary Disease (BPD) at neonatal age and differences in respiratory health between males and females. Methods: Design: Prospective cohort study. Setting: Nation wide follow-up study, the Netherlands. Participants: 690 adults (19 year old) born with a gestational age below 32 completed weeks and/or with a birth weight less than 1500g. Controls were Dutch participants of the European Community Respiratory Health Survey (ECRHS). Main outcome measures: Presence of wheeze, shortness of breath, asthma, hay fever and eczema using the ECRHS-questionnaire

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition)

The third edition of Flow Cytometry Guidelines provides the key aspects to consider when performing flow cytometry experiments and includes comprehensive sections describing phenotypes and functional assays of all major human and murine immune cell subsets. Notably, the Guidelines contain helpful tables highlighting phenotypes and key differences between human and murine cells. Another useful feature of this edition is the flow cytometry analysis of clinical samples with examples of flow cytometry applications in the context of autoimmune diseases, cancers as well as acute and chronic infectious diseases. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid. All sections are written and peer‐reviewed by leading flow cytometry experts and immunologists, making this edition an essential and state‐of‐the‐art handbook for basic and clinical researchers.DFG, 389687267, Kompartimentalisierung, Aufrechterhaltung und Reaktivierung humaner Gedächtnis-T-Lymphozyten aus Knochenmark und peripherem BlutDFG, 80750187, SFB 841: Leberentzündungen: Infektion, Immunregulation und KonsequenzenEC/H2020/800924/EU/International Cancer Research Fellowships - 2/iCARE-2DFG, 252623821, Die Rolle von follikulären T-Helferzellen in T-Helferzell-Differenzierung, Funktion und PlastizitätDFG, 390873048, EXC 2151: ImmunoSensation2 - the immune sensory syste

Limited impact of multiple 5' single-nucleotide polymorphisms on the transcriptional control of the human beta 2-adrenoceptor gene

The human beta(2)-adrenoceptor (beta(2)-AR) is subject to agonist-induced down-regulation. The degree of down-regulation is associated with certain single-nucleotide polymorphisms (SNPs) through yet unknown mechanisms. The 5'-leader sequence of the beta(2)-AR gene contains several SNPs that are in strong linkage disequilibrium. The -367 T/C polymorphism, in particular, has been shown to affect transcriptional activity in reporter gene assays. In the present study we analysed the impact of this -367 SNP on the transcription rate of the beta(2)-AR gene in the context of the complete natural locus. Taking advantage of the additional full disequilibrium with the +79 SNP in the beta(2)-AR coding sequence, allele-specific transcript quantification was performed in PBMCs of six -367 heterozygous mild asthmatic patients. Our data are in line with the reported impact of the -367 SNP and give no indication of additional haplotype-related effects on beta(2)-AR transcription. We further show that the -367 SNP affects the binding of a yet unidentified transcription factor complex, whose binding activity is not modulated by pharmacological compounds that induce or down-regulate beta(2)-AR expression, suggesting a role in constitutive steady state expression rather than in inducible expression. As the beta(2)-AR allele with a higher transcription rate associates with stronger agonist-induced down-regulation, it is not likely that the -367 SNP is causally related to the degree of down-regulatio

The influence of the AA 16 beta 2-adrenoceptor polymorphism on systemic and airway responses in asthma

BACKGROUND: The impact of the polymorphic amino acids 16 and 27 of the beta 2-adrenoceptor (beta 2-AR) on the susceptibility to bronchodilator tolerance remains unclear since clinical studies thus far have shown discordant results. Tolerance towards the effects of inhaled beta 2-AR agonists generally is more easily shown for systemic parameters than for airway effects and can be substantial. This study evaluates whether differences exist between position 16 homozygous genotyped asthmatics, in tolerance development towards airway responses and the systemic effect hypokalemia. METHODS: Twenty patients were genotyped for amino acids 16 and 27 of the beta 2-AR gene. Time-effect curves for FEV1 and serum potassium concentration were constructed after s.c. administration of terbutaline after two-week treatment periods with either terbutaline inhalation or matching placebo in a double-blind, randomised and cross-over design. Statistical analysis was done by a repeated measures multivariate analysis on area under time-effect curve (AUC). MAIN RESULTS: Pre-treatment with inhaled terbutaline did not influence the improvement in FEV1 in response to s.c. terbutaline and there were no significant differences between Arg-16 and Gly-16 individuals in this respect. Pre-treatment with inhaled terbutaline resulted in an overall increase of baseline plasma potassium before administration of s.c. terbutaline (3.78-3.95 mmol/L, p=0.034). However, this effect appeared to be solely confined to the Arg-16 homozygous individuals, leading to a statistically highly significant difference between the Arg-16 and Gly-16 subjects (p=0.005). However, there was no genotype related difference in the decrease in plasma potassium response to s.c. terbutaline relative to baseline. CONCLUSION: In patients carrying the Arg-16 genotype the development of hypokalemia by s.c. terbutaline is attenuated after pre-treatment with inhaled terbutaline, be it on the basis of higher baseline value

Localization of DNA probes with tight linkage to the cystic fibrosis locus by in situ hybridization using fibroblasts with a 7q22 deletion

Five DNA probes known to originate from the region 7q22-q31 were sublocalized by in situ hybridization to metaphase preparations of fibroblasts having besides a normal chromosome 7, a homologue 7 with an apparent interstitial deletion of a large part of band q22. A flow cytometric chromosome analysis confirmed a loss of material from one of the homologues of chromosome 7. Four of the probes, B79a, 7C22, metH, and pJ3.11, have been shown to be closely linked to the cystic fibrosis (CF) locus. We localized probes B79a and 7C22 to the part of 7q22 involved in the deletion, whereas metH and pJ3.11 could be assigned to band 7q31. Probe pJu28, for which polymorphisms have not yet been described, also appeared to derive from the latter band. Since pJ3.11 and metH are most tightly linked to the CF locus, this disease locus is indirectly assigned to 7q31. A comparison of our findings with linkage data suggests a discrepancy between genetic and physical distances in the region 7q22-q31