Early treatment versus expectative management of patent ductus arteriosus in preterm infants

_Background:_ Much controversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants, especially in those born at a gestational age (GA) less than 28weeks. No causal relationship has been proven between a (haemodynamically significant) PDA and neonatal complications related to pulmonary hyperperfusion and/or systemic hypoperfusion. Although studies show conflicting results, a common understanding is that medical or surgical treatment of a PDA does not seem to reduce the risk of major neonatal morbidities and mortality. As the PDA might have closed spontaneously, treated children are potentially exposed to iatrogenic adverse effects. A conservative approach is gaining interest worldwide, although convincing evidence to support its use is lacking. _Methods:_ This multicentre, randomised, non-inferiority trial is conducted in neonatal intensive care units. The study population consists of preterm infants (GA1.5mm. Early treatment (between 24 and 72h postnatal age) with the cyclooxygenase inhibitor(COXi) ibuprofen (IBU) is compared with an expectative management (no intervention intended to close a PDA). The primary outcome is the composite of mortality, and/or necrotising enterocolitis (NEC) Bell stage ≥ IIa, and/or bronchopulmonary dysplasia (BPD) defined as the need for supplemental oxygen, all at a postmenstrual age (PMA) of 36weeks. Secondary outcome parameters are short term sequelae of cardiovascular failure, comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. Consequences regarding health economics are evaluated by cost effectiveness analysis and budget impact analysis. _Discussion:_ As a conservative approach is gaining interest, we investigate whether in preterm infants, born at a GA less than 28weeks, with a PDA an expectative management is non-inferior to early treatment with IBU regarding to the composite outcome of mortality and/or NEC and/or BPD at a PMA of 36weeks

FMR1 Genotype with Autoimmunity-Associated Polycystic Ovary-Like Phenotype and Decreased Pregnancy Chance

The FMR1 gene partially appears to control ovarian reserve, with a specific ovarian sub-genotype statistically associated with a polycystic ovary (PCO)- like phenotype. Some forms of PCO have been associated with autoimmunity. We, therefore, investigated in multiple regression analyses associations of ovary-specific FMR1 genotypes with autoimmunity and pregnancy chances (with in vitro fertilization, IVF) in 339 consecutive infertile women (455 IVF cycles), 75 with PCO-like phenotype, adjusted for age, race/ethnicity, medication dosage and number of oocytes retrieved. Patients included 183 (54.0%) with normal (norm) and 156 (46%) with heterozygous (het) FMR1 genotypes; 133 (39.2%) demonstrated laboratory evidence of autoimmunity: 51.1% of het-norm/low, 38.3% of norm and 24.2% het-norm/high genotype and sub-genotypes demonstrated autoimmunity (p = 0.003). Prevalence of autoimmunity increased further in PCO-like phenotype patients with het-norm/low genotype (83.3%), remained unchanged with norm (34.0%) and decreased in het-norm/high women (10.0%; P<0.0001). Pregnancy rates were significantly higher with norm (38.6%) than het-norm/low (22.2%, p = 0.001). FMR1 sub-genotype het-norm/low is strongly associated with autoimmunity and decreased pregnancy chances in IVF, reaffirming the importance of the distal long arm of the X chromosome (FMR1 maps at Xq27.3) for autoimmunity, ovarian function and, likely, pregnancy chance with IVF

Use of model systems to understand the etiology of fragile X-associated primary ovarian insufficiency (FXPOI)

Fragile X-associated primary ovarian insufficiency (FXPOI) is among the family of disorders caused by the expansion of a CGG repeat sequence in the 5' untranslated region of the X-linked gene FMR1. About 20% of women who carry the premutation allele (55 to 200 unmethylated CGG repeats) develop hypergonadotropic hypogonadism and cease menstruating before age 40. Some proportion of those who are still cycling show hormonal profiles indicative of ovarian dysfunction. FXPOI leads to subfertility and an increased risk of medical conditions associated with early estrogen deficiency. Little progress has been made in understanding the etiology of this clinically significant disorder. Understanding the molecular mechanisms of FXPOI requires a detailed knowledge of ovarian FMR1 mRNA and FMRP’s function. In humans, non-invasive methods to discriminate the mechanisms of the premutation on ovarian function are not available, thus necessitating the development of model systems. Vertebrate (mouse and rat) and invertebrate (Drosophila melanogaster) animal studies for the FMR1 premutation and ovarian function exist and have been instrumental in advancing our understanding of the disease phenotype. For example, rodent models have shown that FMRP is highly expressed in oocytes where it is important for folliculogenesis. The two premutation mouse models studied to date show evidence of ovarian dysfunction and, together, suggest that the long repeat in the transcript itself may have some pathological effect quite apart from any effect of the toxic protein. Further, ovarian morphology in young animals appears normal and the primordial follicle pool size does not differ from that of wild-type animals. However, there is a progressive premature decline in the levels of most follicle classes. Observations also include granulosa cell abnormalities and altered gene expression patterns. Further comparisons of these models are now needed to gain insight into the etiology of the ovarian dysfunction. Premutation model systems in non-human primates and those based on induced pluripotent stem cells show particular promise and will complement current models. Here, we review the characterization of the current models and describe the development and potential of the new models. Finally, we will discuss some of the molecular mechanisms that might be responsible for FXPOI

[Body dysmorphic disorder in cosmetic surgery - prevalence, psychiatric comorbidity and outcome]

BACKGROUND: Patients suffering from body dysmorphic disorder (bdd) are preoccupied with a slight or imagined defect in appearance. AIM: First of all, to review the literature on the prevalence of bdd in cosmetic surgery and thereafter to review the literature on psychiatric comorbidity and the outcome of surgical interventions. METHOD: We based our search strategy on Embase, Medline and PubMed, using the search terms 'body dysmorphic disorder', 'cosmetic surgery', 'prevalence', 'comorbidity' and 'outcome'. Our search covered English and Dutch literature published after the introduction of bdd in dsm-iii-r and before 1 November, 2013. A study of the relevant articles enabled us to access additional articles mentioned in these texts. RESULTS: Our initial search strategy turned out to be too narrow. It was therefore broadened to include 'body dysmorphic disorder', 'cosmetic surgery', and 'prevalence'. Eventually we included 23 original articles. In 11 of these the prevalence of bdd varied from 3.2 to 53.6%. Twelve articles on psychiatric comorbidity revealed predominantly mood and anxiety disorders on axis I and cluster C personality disorders on axis II. Only two studies reported on the outcome of cosmetic surgery performed on bdd patients; surgical interventions, however, seemed to result in new preoccupations with the prolongation of psychiatric comorbidity. CONCLUSION: bdd is a common psychiatric disorder that can sometimes lead to cosmetic surgery. However, pre-operative screening of bdd patients is vital so that efficient psychiatric treatment can be initiated and patients are not subjected to surgical interventions which may be ineffective or even harmful

Performing newborn life support in advance of neonatal advanced life support course-back to basics?

In this retrospective analysis, the Newborn Life Support (NLS) test scenario performance of participants of the Dutch Neonatal Advanced Life Support (NALS) course was assessed. Characteristics of participants and total amount of failures were collected. Failures were subdivided in (1) errors of omission; (2) errors of commission; and (3) unspecified if data was missing. Pearson's chi-squared test was used to assess differences between participant groups. In total, 23 out of 86 participants (27%) failed their NLS test scenario. Life support course instructors in general (20/21) passed their test scenario more often compared to other participants (43/65) (p = 0.008). In total 110 fail items were recorded; the most common errors being not assessing heart rate (error of omission) (n = 47) and inadequate performance of airway management (error of commission) (n = 24).Conclusion: A substantial part of NALS participants failed their NLS test scenario. Errors of omission could be reduced by the availability of a checklist/NLS algorithm. Life support course instructors possibly make less errors of commission due to retention of skills by teaching these skills at least twice a year. Therefore, our study suggests that neonatal basic life support skills should be retained by local assurance of training programmes. What is Known: • Retention of skills after life support courses decreases after three months. • Adherence to newborn life support guidelines is suboptimal. What is New: • NLS performance is suboptimal in participants for advanced neonatal life support. • Most common failures are not assessing heart rate and inadequate airway management

Factors Associated With Benefit of Treatment of Patent Ductus Arteriosus in Preterm Infants: A Systematic Review and Meta-Analysis

Context: There is an ongoing debate on the optimal management of patent ductus arteriosus (PDA) in preterm infants. Identifying subgroup of infants who would benefit from pharmacological treatment might help. Objective: To investigate the modulating effect of the differences in methodological quality, the rate of open-label treatment, and patient characteristics on relevant outcome measures in randomized controlled trials (RCTs). Data Sources: Electronic database search between 1950 and May 2020. Study Selection: RCTs that assessed pharmacological treatment compared to placebo/no treatment. Data Extraction: Data is extracted following the PRISMA guidelines. Outcome measures were failure to ductal closure, surgical ligation, incidence of necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, periventricular leukomalacia, intraventricular hemorrhage (IVH) grade ≥3, retinopathy of prematurity and mortality. Results: Forty-seven studies were eligible. The incidence of IVH grade ≥3 was lower in the treated infants compared to the placebo/no treatment (RR 0.77, 95% CI 0.64-0.94) and in the subgroups of infants with either a gestational age <28 weeks (RR 0.77, 95% CI 0.61-0.98), a birth weight <1,000 g (RR 0.77, 95% CI 0.61-0.97), or if untargeted treatment with indomethacin was started <24 h after birth (RR 0.70, 95% CI 0.54-0.90). Limitations: Statistical heterogeneity caused by missing data and variable definitions of outcome parameters. Conclusions: Although the quality of evidence is low, this meta-analysis suggests that pharmacological treatment of PDA reduces severe IVH in extremely preterm, extremely low birth weight infants or if treatment with indomethacin was started <24 h after birth. No other beneficial effects of pharmacological treatment were found

Understanding the pathobiology in patent ductus arteriosus in prematurity-beyond prostaglandins and oxygen

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Reply to the Letters from Murray et al. and Vianna-Morgante and Costa

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