Autophagy and autophagy-related genes (Atg) have been attributed prominent roles in tumorigenesis, tumor growth, and metastasis. Extracellular vesicles called exosomes are also implicated in cancer metastasis. Here, we demonstrate that exosome production is strongly reduced in cells lacking Atg5 and Atg16L1, but this is independent of Atg7 and canonical autophagy. Atg5 specifically decreases acidification of late endosomes where exosomes are produced, disrupting the acidifying VV-ATPase by removing a regulatory component, ATP6V1E1, into exosomes. The effect of Atg5 on exosome production promotes the migration and in vivo metastasis of orthotopic breast cancer cells. These findings uncover mechanisms controlling exosome release and identify means by which autophagy-related genes can contribute to metastasis in autophagy-independent pathways.

Many cytoplasmic substrates degraded by autophagy have been identified; however, the impact of RNA degradation by autophagy remains uncertain. Retrotransposons comprise 40% of the human genome and are a major source of genetic variation among species, individuals and cells. Retrotransposons replicate via a copy-paste mechanism involving a cytoplasmic RNA intermediate. Here we report that autophagy degrades retrotransposon RNA from both long and short interspersed elements, preventing new retrotransposon insertions into the genome. Retrotransposon RNA localizes to RNA granules, whose selective degradation is facilitated by the autophagy receptors NDP52 and p62. Accordingly, NDP52 and p62 control retrotransposon insertion in the genome. Mice lacking a copy of Atg6/Beclin1, a gene critical for autophagy, also accumulate both retrotransposon RNA and genomic insertions. Thus, autophagy physiologically buffers genetic variegation by degrading retrotransposon RNA. This may contribute to the increased tumorigenesis occuring when autophagy is inhibited and suggest a role for autophagy in tempering evolutionary change.

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Objective: To study the effect of increasing endometrial thickness on live birth rates in fresh and frozen-thaw embryo transfer (FET) cycles. Design: Retrospective cohort study. Setting: National data from Autologous in vitro fertilization (IVF) embryo transfer and FET cycles in Canada from the Canadian Assisted Reproductive Technology Registry Plus (CARTR Plus) database for records between January 2013 and December 2019. Patients: Thirty-three Canadians clinics participated in voluntary reporting of IVF and pregnancy outcomes to the Canadian Assisted Reproductive Technology Registry Plus database, and a total of 43,383 fresh and 53,377 frozen transfers were included. Intervention(s): None. Main Outcome Measure(s): Clinical pregnancy, pregnancy loss, and live birth rates. Results: In fresh IVF-embryo transfer cycles, increasing endometrial thickness is associated with significant increases in the mean number of oocytes retrieved, peak estradiol levels, number of usable embryos, clinical pregnancy rates, live birth rates, and mean term singleton birth weights, and a decrease in pregnancy loss rates. However, live birth rates plateau after 10-12 mm. In contrast, in FET cycles live birth rates plateau after the endometrium measures 7-10 mm. The improvement in live birth rates with increasing endometrial thickness was independent of patient age, timing of embryo transfer (e.g., cleavage stage vs. blastocyst stage), or the number of oocytes at retrieval. Conclusions: In cycles with a fresh embryo transfer, live birth rates increase significantly until an endometrial thickness of 10-12 mm, while in FET cycles live birth rates plateau after 7-10 mm. However, an endometrial thickness <6 mm was associated clearly with a dramatic reduction in live birth rates in fresh and frozen embryo transfer cycles.

Objective Ontario offers a publicly funded modified contingent model of prenatal screening for aneuploidy in which cell‐free DNA (cfDNA) screening is covered for pregnancies at higher risk of fetal aneuploidy. The objective of this study was to review utilization of provincially funded cfDNA screening and adherence to the criteria laid out in Ontario prenatal screening guidelines. Methods This was a descriptive cohort study using data collected by Ontario's prescribed maternal and child registry. The study population included all pregnant individuals who received cfDNA screening from January 2016 to December 2017. Results The most common criteria for provincially funded cfDNA screening were advanced maternal age ≥40 years (37.7%), positive multiple marker screen (34.1%), modifying risk factors such as ultrasound soft markers (7.1%), and previous aneuploidy (5.5%). The audit demonstrated that 2.9% of funded cfDNA screens tests did not meet funding criteria, and that 11.4% of self‐paid cfDNA screens could have been publicly funded. Conclusion Reviewing and auditing the application of criteria for funded cfDNA screening using prescribed registry data allows an opportunity to identify areas where targeted education may improve adherence to standardized screening protocols, and provides a basis for reassessment of the funding model.

Background Gastroschisis is a congenital anomaly of the abdomen in which the intestines are found outside of the body at birth. While no clear causative factors have been identified, it is strongly associated with young maternal age. Other reported associations include low maternal socioeconomic status, low maternal body mass index (BMI), and smoking. Methods This is a retrospective review of epidemiologic data relating to cases of gastroschisis in Ontario from 2012‐2018 in the Better Outcomes Registry & Network (BORN) Ontario database, which is the province's prescribed maternal‐newborn registry. We describe the epidemiology of gastroschisis in Ontario with respect to birth prevalence, maternal age, health, exposures, and geography. Results The birth prevalence of gastroschisis is 2.31 cases/10,000 births. There was no apparent change in birth prevalence over the study period and there was no difference between male and female infants. Gastroschisis was associated with younger maternal ages and was inversely correlated with maternal BMI. Gastroschisis was associated with first completed pregnancy. Maternal diabetes was associated with a lower birth prevalence of gastroschisis than average. Mothers of babies with gastroschsis were more likely to report use of tobacco, alcohol, and drugs during pregnancy than those without gastroschisis, with marijuana use showing the largest increase in birth prevalence of gastroschisis. Mothers living in rural areas were more likely to have a baby with gastroschisis than those in urban centers, even after controlling for maternal age. Conclusions This Ontario registry study reveals that mothers with babies with gastroschisis are more likely to be young and thin, live in rural areas, and report prenatal smoking, alcohol use, and drug use than women whose pregnancies do not have gastroschsis.

Poly(lactic acid) (PLA) and poly(ε-caprolactone) (PCL) blends with various components for melt-blown nonwovens were prepared by a twin-screw extruder. Tributyl citrate (TBC) was added in order to improve the miscibility between PLA and PCL. The results showed that small circular particles of PCL were dispersed in PLA matrix uniformly. The addition of PCL had the heterogeneous nucleation effect on the crystallization of PLA and decreased thermal stability of PLA. The flow of pure PLA and blends approached to Newtonian liquid at a low shear rate and expressed more obvious viscoelasticity at a high shear rate.

BACKGROUND:The emergence of cellfree fetal DNA (cfDNA) testing technology has disrupted the landscape of prenatal screening for trisomies 21 (T21) and 18 (T18). Publicly funded systems around the world are grappling with how to best integrate this more accurate but costly technology, as there is limited evidence about its incremental value in real-world conditions. The objectives of this study were to describe the population-based performance of Ontario's prenatal screening program, which incorporates publicly funded cfDNA screening for specific indications, and the effect of cfDNA testing on the screening and diagnostic choices made by pregnant people. METHODS:We conducted a retrospective, descriptive cohort study using routinely collected data from Better RESULTS:The study cohort included 373 682 pregnancies. The prenatal screening program had an uptake of 69.9%, a screen-positive rate and sensitivity of 1.6% and 89.9% for T21, and 0.2% and 80.5% for T18, respectively. The test failure rate for cfDNA screening was 2.2%. Invasive prenatal diagnostic testing decreased from 4.4% in 2012-2013 to 2.4% over the study period; 65.2% of pregnant people who received a screen-positive result from cfDNA testing went on to have invasive prenatal diagnostic testing.INTERPRETATION: This publicly funded screening program, incorporating cfDNA analysis for common aneuploidies, showed robust performance, a substantial reduction in invasive prenatal diagnostic testing and that pregnant people exercise autonomy in their choices about prenatal screening and diagnosis.