To evaluate the safety of an aerosolised surfactant, SF-RI 1, administered via nasal continuous positive airway pressure (nCPAP) and a prototype breath synchronisation device (AeroFact), to preterm infants with respiratory distress syndrome (RDS).

Multicentre, open-label, dose-escalation study with historical controls.

Newborn intensive care units at Mater Mothers’ Hospital, Brisbane, and Royal Hospital for Women, Sydney, Australia.

Infants 26 weeks through 30 weeks gestation who required nCPAP 6-8 cmH

O and fraction of inspired oxygen (FiO

) <0.30 at <2 hours of age.

In part 1, infants received a single dose of 216 mg/kg of aerosolised surfactant. In part 2, infants could receive up to four doses of aerosolised surfactant. Three historical control infants were matched for each enrolled infant.

Treatment failure was defined as Respiratory Severity Score (FiO

×cmH

O nCPAP) >2.4, nCPAP >8 cmH

O, arterial carbon dioxide >65 mm Hg, pH <7.20 or three severe apnoeas within 6 hours during the first 72 hours of life. Other outcomes included tolerance of the AeroFact treatment and complications of prematurity.

10 infants were enrolled in part 1 and 21 in part 2 and were compared with 93 historical controls. No safety issues were identified. In part 2, 6 of 21 (29%) AeroFact-treated infants compared with 30 of 63 (48%) control infants met failure criteria. Kaplan-Meier analysis of patients in part 2 showed a trend towards decreased rate of study failure in the AeroFact-treated infants compared with historical controls (p=0.10).

The AeroFact system can safely deliver aerosolised surfactant to preterm infants with RDS who are on nCPAP.

ACTRN12617001458325.

ACTRN12617001458325.

To compare the effect of two different automated oxygen control devices on target range (TR) time and occurrence of hypoxaemic and hyperoxaemic episodes.

Randomised cross-over study.

Tertiary level neonatal unit in the Netherlands.

Preterm infants (n=15) born between 24+0 and 29+6 days of gestation, receiving invasive or non-invasive respiratory support with oxygen saturation (SpO

) TR of 91%-95%. Median gestational age 26 weeks and 4 days (IQR 25 weeks 3 days-27 weeks 6 days) and postnatal age 19 (IQR 17-24) days.

Inspired oxygen concentration was titrated by the OxyGenie controller (SLE6000 ventilator) and the CLiO

controller (AVEA ventilator) for 24 hours each, in a random sequence, with the respiratory support mode kept constant.

Time spent within set SpO

TR (91%-95% with supplemental oxygen and 91%-100% without supplemental oxygen).

Time spent within the SpO

TR was higher during OxyGenie control (80.2 (72.6-82.4)% vs 68.5 (56.7-79.3)%, p<0.005). Less time was spent above TR while in supplemental oxygen (6.3 (5.1-9.9)% vs 15.9 (11.5-30.7)%, p<0.005) but more time spent below TR during OxyGenie control (14.7 (11.8%-17.2%) vs 9.3 (8.2-12.6)%, p<0.05). There was no significant difference in time with SpO

<80% (0.5 (0.1-1.0)% vs 0.2 (0.1-0.4)%, p=0.061). Long-lasting SpO

deviations occurred less frequently during OxyGenie control.

The OxyGenie control algorithm was more effective in keeping the oxygen saturation within TR and preventing hyperoxaemia and equally effective in preventing hypoxaemia (SpO

<80%), although at the cost of a small increase in mild hypoxaemia.

NCT03877198.

NCT03877198.

Children with congenital gastrointestinal malformations may be at risk of neurodevelopmental impairment due to challenges to the developing brain, including perioperative haemodynamic changes, exposure to anaesthetics and postoperative inflammatory influences. This study aggregates existing evidence on neurodevelopmental outcome in these patients using meta-analysis.

PubMed, Embase and Web of Science were searched for peer-reviewed articles published until October 2019. Out of the 5316 unique articles that were identified, 47 studies met the inclusion criteria and were included. Standardised mean differences (Cohen’s d) between cognitive, motor and language outcome of patients with congenital gastrointestinal malformations and normative data (39 studies) or the studies’ control group (8 studies) were aggregated across studies using random-effects meta-analysis. The value of (clinical) moderators was studied using meta-regression and diagnostic subgroups were compared.

The 47 included studies encompassed 62 cohorts, representing 2312 patients. Children with congenital gastrointestinal malformations had small-sized cognitive impairment (d=-0.435, p<0.001; 95% CI -0.567 to -0.302), medium-sized motor impairment (d=-0.610, p<0.001; 95% CI -0.769 to -0.451) and medium-sized language impairment (d=-0.670, p<0.001; 95% CI -0.914 to -0.425). Patients with short bowel syndrome had worse motor outcome. Neurodevelopmental outcome was related to the number of surgeries and length of total hospital stay, while no relations were observed with gestational age, birth weight, age and sex.

This study shows that children with congenital gastrointestinal malformations exhibit impairments in neurodevelopmental outcome, highlighting the need for routine screening of neurodevelopment during follow-up.

This study shows that children with congenital gastrointestinal malformations exhibit impairments in neurodevelopmental outcome, highlighting the need for routine screening of neurodevelopment during follow-up.

To evaluate the accuracy of neonatal MRI and general movements assessment (GMA) in predicting neurodevelopmental outcomes in infants with hypoxic-ischaemic encephalopathy (HIE).

Secondary analyses of a randomised controlled trial (RCT).

Tertiary neonatal intensive care unit in India.

Fifty infants with HIE were included in an RCT of therapeutic hypothermia (25 cooled and 25 non-cooled). All infants underwent brain MRI at day 5, GMA at 10-15 weeks and outcome assessments including Bayley Scales of Infant and Toddler Development, third edition, at 18 months. Associations between patterns of brain injury, presence/absence of fidgety movements (FMs) and outcomes were assessed.

Seventeen of 47 (36%) had adverse outcome (5 (21%) cooled vs 12 (52%) non-cooled, p=0.025). Eight infants died (four before an MRI, another three before GMA). Two developed severe cerebral palsy and seven had Bayley-III motor/cognitive composite score <85. Twelve (26%) had moderately/severely abnormal MRI and nine (23%) had absent FMs. The positive predictive value (95% CI) of an adverse outcome was 89% (53% to 98%) for moderate/severe basal ganglia and thalami (BGT) injury, 83% (56% to 95%) for absent/equivocal signal in the posterior limb of the internal capsule (PLIC) and 67% (38% to 87%) for absent FMs. Negative predictive values (95% CI) were 85% (74% to 92%) for normal/mild BGT injury, 90% (78% to 96%) for normal PLIC and 86% (74% to 93%) for present FMs.

Neonatal MRI and GMA predicted outcomes with high accuracy in infants with HIE. The GMA is a feasible low-cost method which can be used alone or complementary to MRI in low-resource settings to prognosticate and direct follow-up.

CTRI/2013/05/003693.

CTRI/2013/05/003693.Plants synthesize many diverse small molecules that affect function of the mammalian central nervous system, making them crucial sources of therapeutics for neurological disorders. A notable portion of neuroactive phytochemicals are lysine-derived alkaloids, but the mechanisms by which plants produce these compounds have remained largely unexplored. To better understand how plants synthesize these metabolites, we focused on biosynthesis of the Lycopodium alkaloids that are produced by club mosses, a clade of plants used traditionally as herbal medicines. Hundreds of Lycopodium alkaloids have been described, including huperzine A (HupA), an acetylcholine esterase inhibitor that has generated interest as a treatment for the symptoms of Alzheimer’s disease. Through combined metabolomic profiling and transcriptomics, we have identified a developmentally controlled set of biosynthetic genes, or potential regulon, for the Lycopodium alkaloids. The discovery of this putative regulon facilitated the biosynthetic reconstitution and functional characterization of six enzymes that act in the initiation and conclusion of HupA biosynthesis. This includes a type III polyketide synthase that catalyzes a crucial imine-polyketide condensation, as well as three Fe(II)/2-oxoglutarate-dependent dioxygenase (2OGD) enzymes that catalyze transformations (pyridone ring-forming desaturation, piperidine ring cleavage, and redox-neutral isomerization) within downstream HupA biosynthesis. Our results expand the diversity of known chemical transformations catalyzed by 2OGDs and provide mechanistic insight into the function of noncanonical type III PKS enzymes that generate plant alkaloid scaffolds. These data offer insight into the chemical logic of Lys-derived alkaloid biosynthesis and demonstrate the tightly coordinated coexpression of secondary metabolic genes for the biosynthesis of medicinal alkaloids.The 14-day rule restricts the culturing of human embryos in vitro for the purposes of scientific research for no longer than 14 days. Since researchers recently developed the capability to exceed the 14-day limit, pressure to modify the rule has started to build. Sophia McCully argues that the limit should be extended to 28 days, listing numerous potential benefits of doing so. We contend that McCully has not engaged with the main reasons why the Warnock Committee set such a limit, and these still remain valid. As a result, her case for an extension of the 14-day rule is not persuasive.

Patients with HER2-positive (HER2

) metastatic breast cancer (MBC) have poor prognoses. Pyrotinib has shown promising antitumor activity in MBC to improve progression-free survival (PFS). However, findings based on real-world data to analyze whether pyrotinib affects overall survival (OS) remain scarce.

This real-world study is an exploratory analysis of brain metastasis (BM) and the final update of our preceding study of 168 patients with HER2

MBC. PFS, OS, tumor mutation burden (TMB), clinical benefit rate (CBR), and overall response rate (ORR) were analyzed.

Pyrotinib treatment led to a median PFS time of 8.00 months and a median OS of 19.07 months in the 168 participants. High TMB was associated with poor OS (

= 0.0072) and PFS (

= 0.0028). In the 39 patients with BM, the median PFS and OS were 8.67 and 13.93 months, respectively. The surgery/radiation (S/R) group of patients with BM had prolonged survival (PFS 9.97 vs. 7.73 months

= 0.19; OS 20.67 vs. 12.43 months

= 0.021) compared with the no surgery/no radiation group (NS/NR). The CBR was 58.6% (S/R) vs. 41.4% (NS/NR), while the ORR was 24.1% (S/R) vs. 31.0% (NS/NR).

Pyrotinib shows promise as a novel pan-HER2 tyrosine kinase inhibitor (TKI) for the treatment of BM and should be evaluated further. Surgical or radiotherapy in combination with pyrotinib was found to statistically improve OS in our cohort. TMB could be an exploratory biomarker for predicting PFS and OS, but its clinical application still needs further verification.

Pyrotinib shows promise as a novel pan-HER2 tyrosine kinase inhibitor (TKI) for the treatment of BM and should be evaluated further. Surgical or radiotherapy in combination with pyrotinib was found to statistically improve OS in our cohort. TMB could be an exploratory biomarker for predicting PFS and OS, but its clinical application still needs further verification.