The Programming Power of the Placenta.

Size at birth is a critical determinant of life expectancy, and is dependent primarily on the placental supply of nutrients. However, the placenta is not just a passive organ for the materno-fetal transfer of nutrients and oxygen. Studies show that the placenta can adapt morphologically and functionally to optimize substrate supply, and thus fetal growth, under adverse intrauterine conditions. These adaptations help meet the fetal drive for growth, and their effectiveness will determine the amount and relative proportions of specific metabolic substrates supplied to the fetus at different stages of development. This flow of nutrients will ultimately program physiological systems at the gene, cell, tissue, organ, and system levels, and inadequacies can cause permanent structural and functional changes that lead to overt disease, particularly with increasing age. This review examines the environmental regulation of the placental phenotype with particular emphasis on the impact of maternal nutritional challenges and oxygen scarcity in mice, rats and guinea pigs. It also focuses on the effects of such conditions on fetal growth and the developmental programming of disease postnatally. A challenge for future research is to link placental structure and function with clinical phenotypes in the offspring.This is the final version of the article. It first appeared from Frontiers via https://doi.org/10.3389/fphys.2016.0003

Near to One's Heart: The Intimate Relationship Between the Placenta and Fetal Heart.

The development of the fetal heart is exquisitely controlled by a multitude of factors, ranging from humoral to mechanical forces. The gatekeeper regulating many of these factors is the placenta, an external fetal organ. As such, resistance within the placental vascular bed has a direct influence on the fetal circulation and therefore, the developing heart. In addition, the placenta serves as the interface between the mother and fetus, controlling substrate exchange and release of hormones into both circulations. The intricate relationship between the placenta and fetal heart is appreciated in instances of clinical placental pathology. Abnormal umbilical cord insertion is associated with congenital heart defects. Likewise, twin-to-twin transfusion syndrome, where monochorionic twins have unequal sharing of their placenta due to inter-twin vascular anastomoses, can result in cardiac remodeling and dysfunction in both fetuses. Moreover, epidemiological studies have suggested a link between placental phenotypic traits and increased risk of cardiovascular disease in adult life. To date, the mechanistic basis of the relationships between the placenta, fetal heart development and later risk of cardiac dysfunction have not been fully elucidated. However, studies using environmental exposures and gene manipulations in experimental animals are providing insights into the pathways involved. Likewise, surgical instrumentation of the maternal and fetal circulations in large animal species has enabled the manipulation of specific humoral and mechanical factors to investigate their roles in fetal cardiac development. This review will focus on such studies and what is known to date about the link between the placenta and heart development

Voltage Stability Analysis of Grid-Connected Wind Farms with FACTS: Static and Dynamic Analysis

Recently, analysis of some major blackouts and failures of power system shows that voltage instability problem has been one of the main reasons of these disturbances and networks collapse. In this paper, a systematic approach to voltage stability analysis using various techniques for the IEEE 14-bus case study, is presented. Static analysis is used to analyze the voltage stability of the system under study, whilst the dynamic analysis is used to evaluate the performance of compensators. The static techniques used are Power Flow, V–P curve analysis, and Q–V modal analysis. In this study, Flexible Alternating Current Transmission system (FACTS) devices- namely, Static Synchronous Compensators (STATCOMs) and Static Var Compensators (SVCs) - are used as reactive power compensators, taking into account maintaining the violated voltage magnitudes of the weak buses within the acceptable limits defined in ANSI C84.1. Simulation results validate that both the STATCOMs and the SVCs can be effectively used to enhance the static voltage stability and increasing network loadability margin. Additionally, based on the dynamic analysis results, it has been shown that STATCOMs have superior performance, in dynamic voltage stability enhancement, compared to SVCs

Tourmaline-quartz-cassiterite mineralization of the Land's End Granite at Nanjizal, west Cornwall

Nanjizal is one of the few locations in the southern segment of the Land's End Granite (Early Permian) where magmatic-hydrothermal tin mineralization has been worked. Three principal mineralization episodes are recognized. The first episode comprises steeply dipping ENE-WSW striking tourmaline quartz veins precipitated from magmatic-hydrothermal fluids during regional NNW-SSE extension; they are not associated with metalliferous mineralization. The second episode is represented by two sets of vertical/subvertical tourmaline veins striking, respectively, 280degrees and 340degrees. The NNW striking set hosts tourmaline-quartz-cassiterite ( alkali feldspar, apatite, zircon) mineralization and was worked for tin during the 19(th) Century. The first generation of tourmaline in these veins is dominated by the Mg-rich end-member, dravite. The subsequent two generations of tourmaline are dominated by the Ferich end-member, schorl, together with zoned cassiterite with Fe-rich cores and Fe-poor rims. The NNW striking tourmaline-quartz-cassiterite veins at Nanjizal have a similar orientation to cassiterite-bearing veins within the St. just Mining District further north. It is possible that the mineralization at Nanjizal was contemporaneous with mineralization in the St. Just Mining District and hence related to a later magmatic episode and the renewed release of magmatic-hydrothermal fluids during ENE-WSW extension. The third mineralization episode is dominated by steeply dipping WNW-NNW striking quartz-limonite-chalcedonyveins that are associated with wall rock hematisation and kaolinisation. Schorl-quartz-cassiterite mineralisation is relatively uncommon in S.W. England but there are remarkable similarities between the vein parageneses at Nanjizal and the Birch Tor-Vitifer area of Dartmoor; both are likely to have been sourced from predominantly magmatic-hydrothermal fluids

Sepsis recognition tools in acute ambulatory care::associations with process of care and clinical outcomes in a service evaluation of an Emergency Multidisciplinary Unit in Oxfordshire

To assess the performance of currently available sepsis recognition tools in patients referred to a community-based acute ambulatory care unit.Service evaluation of consecutive patients over a 4-month period.Community-based acute ambulatory care unit.Observations, blood results and outcome data were analysed from patients with a suspected infection. Clinical features at first assessment were used to populate sepsis recognition tools including: systemic inflammatory response syndrome (SIRS) criteria, National Early Warning Score (NEWS), quick Sequential Organ Failure Assessment (qSOFA) and National Institute for Health and Care Excellence (NICE) criteria. Scores were assessed against the clinical need for escalated care (use of intravenous antibiotics, fluids, ongoing ambulatory care or hospital treatment) and poor clinical outcome (all-cause mortality and readmission at 30 days after index assessment).Of 533 patients (median age 81 years), 316 had suspected infection with 120 patients requiring care escalated beyond simple community care. SIRS had the highest positive predictive value (50.9%, 95% CI 41.6% to 60.3%) and negative predictive value (68.9%, 95% CI 62.6% to 75.3%) for the need for escalated care. Both NEWS and SIRS were better at predicting the need for escalated care than qSOFA and NICE criteria in patients with suspected infection (all P<0.001). While new-onset confusion predicted the need for escalated care for infection in patients ≥85 years old (n=114), 23.7% of patients ≥85 years had new-onset confusion without evidence for infection.Acute ambulatory care clinicians should use caution in applying the new NICE endorsed criteria for determining the need for intravenous therapy and hospital-based location of care. NICE criteria have poorer performance when compared against NEWS and SIRS and new-onset confusion was prevalent in patients aged ≥85 years without infection

Clinical cardiac electrophysiologic evaluation of the positive inotropic agent, DPI 201-106

DPI 201-106 is a new positive inotropic agent. The cardiac electrophysiology of 16 patients was studied before and during DPI 201-106 administration (loading dose of intravenous DPI 201-106, 1·8 mg kg−1 h−1 administered over 10 min, followed by a maintenance dose of 0·2 mg kg−1 h−1). DPI 201-106 had no effect on the sinus node. The AH interval during fixed-rate atrial pacing became prolonged during DPI 201-106 infusion. There was a significant prolongation of the QT interval [QT (corrected), 417 ± 22 to 502 ± 35 ms, P<0·05; QT (atrial pacing at 600 ms), 374 ±17 to 419 ± 23 ms, P<0·05; QT (ventricular pacing at 600 ms), 409 ± 37 to 449 ± 30 ms, P<0·05]. The ventricular effective refractory period significantly prolonged during DPI 201-106 administration (242 ± 21 to 287 ± 56 ms, P < 0·05), but the supernormal-period duration decreased. The atrial effective refractory period was shortened in four patients and prolonged in one (261 ± 67 to 240 ± 53 ms, NS). The corrected atrial repolarization time (PTac) shortened significantly during DPI 210-106 infusion (479 ± 26 to 445 ± 22 ms at 20 min of the maintenance dose, P<0·05). Atrial fibrillation was initiated in five patients during DPI infusion, but no ventricular arrhythmia was provoked. These findings suggest that DPI 201-106 has novel differential electrophysiological effects on atria and ventricle

Robust diagnostic genetic testing using solution capture enrichment and a novel variant-filtering interface.

Targeted hybridization enrichment prior to next-generation sequencing is a widespread method for characterizing sequence variation in a research setting, and is being adopted by diagnostic laboratories. However, the number of variants identified can overwhelm clinical laboratories with strict time constraints, the final interpretation of likely pathogenicity being a particular bottleneck. To address this, we have developed an approach in which, after automatic variant calling on a standard unix pipeline, subsequent variant filtering is performed interactively, using AgileExomeFilter and AgilePindelFilter (http://dna.leeds.ac.uk/agile), tools designed for clinical scientists with standard desktop computers. To demonstrate the method's diagnostic efficacy, we tested 128 patients using (1) a targeted capture of 36 cancer-predisposing genes or (2) whole-exome capture for diagnosis of the genetically heterogeneous disorder primary ciliary dyskinesia (PCD). In the cancer cohort, complete concordance with previous diagnostic data was achieved across 793 variant genotypes. A high yield (42%) was also achieved for exome-based PCD diagnosis, underscoring the scalability of our method. Simple adjustments to the variant filtering parameters further allowed the identification of a homozygous truncating mutation in a presumptive new PCD gene, DNAH8. These tools should allow diagnostic laboratories to expand their testing portfolios flexibly, using a standard set of reagents and techniques

Assessment of OMT-28, a synthetic analog of omega-3 epoxyeicosanoids, in patients with persistent atrial fibrillation: Rationale and design of the PROMISE-AF phase II study.

We designed a placebo controlled, double-blind, randomized, dose-finding phase II study on OMT-28 in the maintenance of sinus rhythm after electrical cardioversion (DCC) in patients with persistent atrial fibrillation (PROMISE-AF). OMT-28 is a first-in-class, synthetic analog of 17,18-epoxyeicosatetetraenoic acid, a bioactive lipid mediator generated by cytochrome P450 enzymes from the omega-3 fatty acid eicosapentaenoic acid. OMT-28 improves Ca2+-handling and mitochondrial function in cardiomyocytes and reduces pro-inflammatory signaling. This unique mode of action may provide a novel approach to target key mechanism contributing to AF pathophysiology. In a recent phase I study, OMT-28 was safe and well tolerated and showed favorable pharmacokinetics. The PROMISE-AF study (NCT03906799) is designed to assess the efficacy (primary objective), safety, and population pharmacokinetics (secondary objectives) of three different doses of OMT-28, administered once daily, versus placebo until the end of the follow-up period. Recruitment started in March 2019 and the study will include a total of 120 patients. The primary efficacy endpoint is the AF burden (% time with any AF), evaluated over a 13-week treatment period after DCC. AF burden is calculated based on continuous ECG monitoring using an insertable cardiac monitor (ICM). The primary efficacy analysis will be conducted on the modified intention-to-treat (mITT) population, whereas the safety analysis will be done on the safety population. Although ICMs have been used in other interventional studies to assess arrhythmia, PROMISE-AF will be the first study to assess antiarrhythmic efficacy and safety of a novel rhythm-stabilizing drug after DCC by using ICMs

Long‐read nanopore sequencing resolves a TMEM231 gene conversion event causing Meckel–Gruber syndrome

The diagnostic deployment of massively parallel short‐read next‐generation sequencing (NGS) has greatly improved genetic test availability, speed, and diagnostic yield, particularly for rare inherited disorders. Nonetheless, diagnostic approaches based on short‐read sequencing have a poor ability to accurately detect gene conversion events. We report on the genetic analysis of a family in which 3 fetuses had clinical features consistent with the autosomal recessive disorder Meckel–Gruber syndrome (MKS). Targeted NGS of 29 known MKS‐associated genes revealed a heterozygous TMEM231 splice donor variant c.929+1A>G. Comparative read‐depth analysis, performed to identify a second pathogenic allele, revealed an apparent heterozygous deletion of TMEM231 exon 4. To verify this result we performed single‐molecule long‐read sequencing of a long‐range polymerase chain reaction product spanning this locus. We identified four missense variants that were absent from the short‐read dataset due to the preferential mapping of variant‐containing reads to a downstream TMEM231 pseudogene. Consistent with the parental segregation analysis, we demonstrate that the single‐molecule long reads could be used to show that the variants are arranged in trans. Our experience shows that robust validation of apparent dosage variants remains essential to avoid the pitfalls of short‐read sequencing and that new third‐generation long‐read sequencing technologies can already aid routine clinical care