MicroRNA signatures in plasma and plasma exosome during window of implantation for implantation failure following in-vitro fertilization and embryo transfer

Background MicroRNAs (miRNAs) are small, non-coding RNAs that are dysregulated in many diseases and can act as biomarkers. Although well-studied in cancer, the role of miRNAs in embryo implantation is poorly understood. Approximately 70% of embryos fail to implant following in-vitro fertilization and embryo transfer, 10% of patients experienced recurrent implantation failure. However, there are no well-established biomarkers that can predict implantation failure. Our purpose is to investigate distinct miRNA profiles in plasma and plasma exosomes during the window of implantation between patients with failed implantation and successful implantation. Methods We select a nested case-control population of 12 patients with implantation failure or successfully clinical pregnancy using propensity score matching. RNA was extracted from plasma and plasma exosomes collected during the window of implantation (WOI). MicroRNA expression in all samples was quantified using microRNA sequencing. The intersection of differently expressed miRNAs in plasma and exosomes were further validated in the GEO dataset. Significantly altered microRNAs in both plasma and plasma exosomes were then subjected to target prediction and KEGG pathway enrichment analyses to search for key signaling pathways. WGCNA analysis was performed to identify hub miRNAs associated with implantation. Results 13 miRNAs were differentially expressed in both plasma and plasma exosomes in patients with implantation failure. Among them, miR-150-5p, miR-150-3p, miR-149-5p, and miR-146b-3p had consistent direction changes in endometrium of patients with recurrent implantation failure (RIF), miR-342-3p had consistent direction changes in blood samples of patients with RIF. Pathway enrichment analysis showed that the target genes of differentially expressed miRNAs are enriched in pathways related to embryo implantation. WGCNA analysis indicated that miR-150-5p, miR-150-3p, miR-146b-3p, and miR-342-3p are hub miRNAs. Conclusions Implantation failure is associated with distinct miRNA profiles in plasma and plasma exosomes during WOI.

Genome-Wide Association Study of Non-Alcoholic Fatty Liver Disease Identifies Association with Apolipoprotein E

Background & Aims Genome-wide association studies (GWAS) have identified several risk loci for non-alcoholic fatty liver disease (NAFLD). Previous studies have largely relied on small sample sizes and have assessed quantitative traits. We performed a case-control GWAS in the UK Biobank using recorded diagnosis of NAFLD based on diagnostic codes recommended in recent consensus guidelines. Approach & Results We performed a GWAS of 4,761 cases of NAFLD and 373,227 healthy controls without evidence of NAFLD. Sensitivity analyses were performed excluding other co-existing hepatic pathology, adjusting for BMI and adjusting for alcohol intake. 9,723,654 variants were assessed by logistic regression adjusted for age, sex, genetic principal components and genotyping batch. We performed a GWA meta-analysis using available summary association statistics from two previously published case-control GWAS of NAFLD. Six risk loci were identified (P<5*10-8) of which one is novel in GWAS (rs429358 in APOE) and five are known (PNPLA3, TM6SF2, GCKR, MARC1 and TRIB1). Rs429358 (P=2.17*10-11) is a missense variant within the APOE gene determining ϵ4 vs ϵ2/ϵ3 alleles. All loci retained significance in sensitivity analyses without co-existent hepatic pathology and after adjustment for BMI. PNPLA3 and TM6SF2 remained significant after adjustment for alcohol (alcohol intake was known in only 158,388 individuals) with others demonstrating consistent direction and magnitude of effect. All 6 loci were significant on meta-analysis including APOE P=3.42*10-13 with consistent direction and magnitude of effect in all 6 loci in all three studies. The ϵ4 allele of APOE offered protection against NAFLD (odds ratio for heterozygotes 0.84 [95%CI 0.78-0.90] and homozygotes 0.64 [0.50-0.79]). Conclusions This GWAS demonstrates that the ϵ4 allele of APOE is strongly associated with protection against NAFLD.

Byzantine-robust federated learning via credibility assessment on non-IID data

<abstract> <p>Federated learning is a novel framework that enables resource-constrained edge devices to jointly learn a model, which solves the problem of data protection and data islands. However, standard federated learning is vulnerable to Byzantine attacks, which will cause the global model to be manipulated by the attacker or fail to converge. On non-iid data, the current methods are not effective in defensing against Byzantine attacks. In this paper, we propose a Byzantine-robust framework for federated learning via credibility assessment on non-iid data (BRCA). Credibility assessment is designed to detect Byzantine attacks by combing adaptive anomaly detection model and data verification. Specially, an adaptive mechanism is incorporated into the anomaly detection model for the training and prediction of the model. Simultaneously, a unified update algorithm is given to guarantee that the global model has a consistent direction. On non-iid data, our experiments demonstrate that the BRCA is more robust to Byzantine attacks compared with conventional methods.</p> </abstract>

PLANCK UNITS AND EXTENDED SPECIAL RELATIVITY

The Planck length is an object of the relativistic quantum-gravitational theory, therefore, a more general and consistent direction of the special relativity extension, seems to be the use of the postulate of the relativistically invariant and limiting nature of all Planck units, that was introduced by V.V. Korukhov at the end of the 90s. One of the examples of the implementation of this postulate in its methodological meaning is the model of a vacuum-like medium, the physical properties of which are characterized by relativistically invariant values, which qualita-tively distinguishes it from the known types of matter –matter and field.

The Effect of the Mediterranean Diet on Metabolic Health: A Systematic Review and Meta-Analysis of Controlled Trials in Adults

The Mediterranean diet (MD) may provide metabolic benefits but no systematic review to date has examined its effect on a multitude of outcomes related to metabolic health. This systematic review with meta-analysis (International Prospective Register of Systematic Reviews, PROSPERO; number CRD42019141459) aimed to examine the MD’s effect on metabolic syndrome (MetSyn) incidence, components and risk factors (primary outcomes), and incidence and/or mortality from MetSyn-related comorbidities and receipt of pharmacologic treatment for MetSyn components and comorbidities (secondary outcomes). We searched Pubmed, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Web of Science for controlled trials published until June 2019, comparing the MD with no treatment, usual care, or different diets in adults. Studies not published in English and not promoting the whole MD were excluded. Two authors independently extracted data and assessed risk of bias using the Cochrane Collaboration’s and Risk of Bias in non-randomised studies (ROBINS-I) tools. Reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Random-effects meta-analyses, subgroup analyses and meta-regressions were performed, and heterogeneity was quantified using the I2 statistic. We identified 2654 reports and included 84 articles reporting 57 trials (n = 36,983). In random effects meta-analyses, the MD resulted in greater beneficial changes in 18 of 28 MetSyn components and risk factors (body weight, body mass index, waist circumference, systolic and diastolic blood pressure, glucose, insulin, homeostatic model assessment of insulin resistance (HOMA-IR) index, total-, low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol, triglycerides, alanine transaminase, hepatic fat mass, C-reactive protein, interleukin-6, tumour necrosis factor-a, and flow-mediated dilatation) and lower risk of cardiovascular disease incidence (risk ratio (RR) = 0.61, 95% confidence intervals (CI) 0.42–0.80; I2 = 0%), and stroke (RR = 0.67, 95% CI 0.35–0.98; I2 = 0%). Only six studies reported effects on pharmacotherapy use, and pooled analysis indicated no differences between diet groups. Lack of consistency in comparator groups and other study characteristics across studies resulted in high heterogeneity for some outcomes, which could not be considerably explained by meta-regressions. However, a consistent direction of beneficial effect of the MD was observed for the vast majority of outcomes examined. Findings support MD’s beneficial effect on all components and most risk factors of the MetSyn, in addition to cardiovascular disease and stroke incidence. More studies are needed to establish effects on other clinical outcomes and use of pharmacotherapy for MetSyn components and comorbidities. Despite the high levels of heterogeneity for some outcomes, this meta-analysis enabled the comparison of findings across studies and the examination of consistency of effects. The consistent direction of effect, suggesting the MD’s benefits on metabolic health, supports the need to promote this dietary pattern to adult populations.

A biphasic navigational strategy in loggerhead sea turtles

The homing journeys of nine loggerhead turtles translocated from their nesting beach to offshore release sites, were reconstructed through Argos and GPS telemetry while their water-related orientation was simultaneously recorded at high temporal resolution by multi-sensor data loggers featuring a three-axis magnetic sensor. All turtles managed to return to the nesting beach area, although with indirect routes encompassing an initial straight leg not precisely oriented towards home, and a successive homebound segment carried out along the coast. Logger data revealed that, after an initial period of disorientation, turtles were able to precisely maintain a consistent direction for several hours while moving in the open sea, even during night-time. Their water-related headings were in accordance with the orientation of the resulting route, showing little or no effect of current drift. This study reveals a biphasic homing strategy of displaced turtles involving an initial orientation weakly related to home and a successive shift to coastal navigation, which is in line with the modern conceptual framework of animal migratory navigation as deriving from sequential mechanisms acting at different spatial scales.

Genotype-Guided Hydralazine Therapy

<b><i>Background:</i></b> Despite its approval in 1953, hydralazine hydrochloride continues to be used in the management of resistant hypertension, a condition frequently managed by nephrologists and other clinicians. Hydralazine hydrochloride undergoes metabolism by the N-acetyltransferase 2 (NAT2) enzyme. NAT2 is highly polymorphic as approximately 50% of the general population are slow acetylators. In this review, we first evaluate the link between NAT2 genotype and phenotype. We then assess the evidence available for genotype-guided therapy of hydralazine, specifically addressing associations of NAT2 acetylator status with hydralazine pharmacokinetics, antihypertensive efficacy, and toxicity. <b><i>Summary:</i></b> There is a critical need to use hydralazine in some patients with resistant hypertension. Available evidence supports a significant link between genotype and NAT2 enzyme activity as 29 studies were identified with an overall concordance between genotype and phenotype of 92%. The literature also supports an association between acetylator status and hydralazine concentration, as fourteen of fifteen identified studies revealed significant relationships with a consistent direction of effect. Although fewer studies are available to directly link acetylator status with hydralazine antihypertensive efficacy, the evidence from this smaller set of studies is significant in 7 of 9 studies identified. Finally, 5 studies were identified which support the association of acetylator status with hydralazine-induced lupus. Clinicians should maintain vigilance when prescribing maximum doses of hydralazine. <b><i>Key Messages:</i></b> NAT2 slow acetylator status predicts increased hydralazine levels, which may lead to increased efficacy and adverse effects. Caution should be exercised in slow acetylators with total daily hydralazine doses of 200 mg or more. Fast acetylators are at risk for inefficacy at lower doses of hydralazine. With appropriate guidance on the usage of <i>NAT2</i> genotype, clinicians can adopt a personalized approach to hydralazine dosing and prescription, enabling more efficient and safe treatment of resistant hypertension.

Use of directed acyclic graphs (DAGs) in applied health research: review and recommendations

ABSTRACTBackgroundDirected acyclic graphs (DAGs) are an increasingly popular approach for identifying confounding variables that require adjustment when estimating causal effects. This review examined the use of DAGs in applied health research to inform recommendations for improving their transparency and utility in future research.MethodsOriginal health research articles published during 1999-2017 mentioning “directed acyclic graphs” or similar or citing DAGitty were identified from Scopus, Web of Science, Medline, and Embase. Data were extracted on the reporting of: estimands, DAGs, and adjustment sets, alongside the characteristics of each article’s largest DAG.ResultsA total of 234 articles were identified that reported using DAGs. A fifth (n=48, 21%) reported their target estimand(s) and half (n=115, 48%) reported the adjustment set(s) implied by their DAG(s).Two-thirds of the articles (n=144, 62%) made at least one DAG available. Diagrams varied in size but averaged 12 nodes (IQR: 9-16, range: 3-28) and 29 arcs (IQR: 19-42, range: 3-99). The median saturation (i.e. percentage of total possible arcs) was 46% (IQR: 31-67, range: 12-100). 37% (n=53) of the DAGs included unobserved variables, 17% (n=25) included super-nodes (i.e. nodes containing more than one variable, and a 34% (n=49) were arranged so the constituent arcs flowed in a consistent direction.ConclusionsThere is substantial variation in the use and reporting of DAGs in applied health research. Although this partly reflects their flexibility, it also highlight some potential areas for improvement. This review hence offers several recommendations to improve the reporting and use of DAGs in future research.

Individual variation in the development of the Western Vowel System of Utah

The BIT, BING, BET, BAT, BAN, BOOK, and BUT vowels of ten Utah English speakers (born 1883–1928) were analyzed over the course of several decades of their adult lives. Most speakers participated in the Western Vowel System by lowering BIT and BET, retracting BAT, and raising BAN, with some fronting BOOK and BUT. Speakers generally did not exhibit monotonic change across the years from expected positions for BET, BAT, and BAN, and for the most part for BOOK and BUT; however, most speakers showed change with regard to BIT, though speakers differed from each other on the direction of change. Even for those vowels with no consistent direction of intraindividual change, however, in many cases speakers were inconsistent in their production from year to year. Further, speakers’ envelopes of variation were different for various vowels, with the widest range of intraindividual variation in BET and BAT, less variation in BAN and BUT, and little in BIT and BOOK. It is suggested that the envelope of variation is at least as much as an important issue for studies of linguistic behavior across adulthood as any actual shift in linguistic behavior across real time.

The contradictory influence of velocity: representational momentum in the tactile modality

Representational momentum (RM) is the term used to describe a systematic mislocalization of dynamic stimuli, a forward shift; that is, an overestimation of the location of a stimulus along its anticipated trajectory. In the present study, we investigate the effect of velocity on tactile RM, because two distinct and contrasting predictions can be made, based on different theoretical accounts. According to classical accounts of RM, based on numerous visual and auditory RM studies, an increase of the forward shift with increasing target velocity is predicted. In contrast, theoretical accounts explaining spatiotemporal tactile illusions such as the tau or cutaneous rabbit effect predict a decrease of the forward shift with increasing target velocity. In three experiments reported here, a tactile experimental setup modeled on existing RM setups was implemented. Participants indicated the last location of a sequence of three tactile stimuli, which either did or did not imply motion in a consistent direction toward the elbow/wrist. Velocity was manipulated by changing the interstimulus interval as well as the duration of the stimuli. The results reveal that increasing target velocity led to a decrease and even a reversal of the forward shift, resulting in a backward shift. This result is consistent with predictions based on the evidence from tactile spatiotemporal illusions. The theoretical implications of these results for RM are discussed. NEW & NOTEWORTHY This study tests two distinct predictions concerning the influence of velocity on the localization of dynamic tactile stimuli. We demonstrate for tactile stimuli that with increasing velocity, a misperception in the direction of anticipated motion (termed “representational momentum”) turns into a misperception against the direction of motion. This result is in line with predictions based on tactile spatiotemporal illusions but challenges classical theoretical accounts of representational momentum based on evidence from vision and audition.