Assessment of extremely premature lambs supported by the Extrauterine Environment for Neonatal Development (EXTEND).

BACKGROUND: Our team has previously reported physiologic support by the EXTra-uterine Environment for Neonatal Development (EXTEND) of 105 to 117 days gestational age (GA) lambs for up to 28 days with normal organ maturation. However, the fetal lamb brain matures more rapidly, requiring the study of 90-105 day GA fetal lambs to assess more neurodevelopmentally equivalent lambs to the 23-25 week GA extreme premature infant. METHODS: Extremely preterm lambs (90-95 days of GA) were delivered by C-section and supported by EXTEND. Estimated circuit flows were maintained at around 325 ml/kg/min. After support on EXTEND, MRI and histopathologic analysis were performed and compared to 105-112 days GA control lambs. RESULTS: The extremely preterm group includes 10 animals with a mean GA of 91.6 days, a mean weight at cannulation of 0.98 kg and a mean length of stay on EXTEND of 13.5 days (10-21 days). Hemodynamics and oxygenation showed stable parameters. Animals showed growth and physiologic cardiac function. MRI volumetric and diffusion analysis was comparable to controls. Histologic brain analysis revealed no difference between study groups. CONCLUSION: EXTEND appears to support brain and cardiac development in an earlier gestation, less mature, lamb model. IMPACT: Prolonged (up to 21 days) physiological support of extremely preterm lambs of closer neurodevelopmental equivalence to the 24-28 gestational week human was achieved using the EXTEND system. EXTEND treatment supported brain growth and development in extremely preterm fetal lambs and was not associated with intraventricular hemorrhage or white matter injury. Daily echocardiography demonstrated physiologic heart function, absence of cardiac afterload, and normal developmental increase in cardiac chamber dimensions. This study demonstrates hemodynamic and metabolic support by the EXTEND system in the extremely preterm ovine model.

The avoiding late diagnosis of ovarian cancer (ALDO) project; a pilot national surveillance programme for women with pathogenic germline variants in BRCA1 and BRCA2.

BACKGROUND: Our study aimed to establish 'real-world' performance and cost-effectiveness of ovarian cancer (OC) surveillance in women with pathogenic germline BRCA1/2 variants who defer risk-reducing bilateral salpingo-oophorectomy (RRSO). METHODS: Our study recruited 875 female BRCA1/2-heterozygotes at 13 UK centres and via an online media campaign, with 767 undergoing at least one 4-monthly surveillance test with the Risk of Ovarian Cancer Algorithm (ROCA) test. Surveillance performance was calculated with modelling of occult cancers detected at RRSO. The incremental cost-effectiveness ratio (ICER) was calculated using Markov population cohort simulation. RESULTS: Our study identified 8 OCs during 1277 women screen years: 2 occult OCs at RRSO (both stage 1a), and 6 screen-detected; 3 of 6 (50%) were ≤stage 3a and 5 of 6 (83%) were completely surgically cytoreduced. Modelled sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) for OC were 87.5% (95% CI, 47.3 to 99.7), 99.9% (99.9-100), 75% (34.9-96.8) and 99.9% (99.9-100), respectively. The predicted number of quality-adjusted life years (QALY) gained by surveillance was 0.179 with an ICER cost-saving of -£102,496/QALY. CONCLUSION: OC surveillance for women deferring RRSO in a 'real-world' setting is feasible and demonstrates similar performance to research trials; it down-stages OC, leading to a high complete cytoreduction rate and is cost-saving in the UK National Health Service (NHS) setting. While RRSO remains recommended management, ROCA-based surveillance may be considered for female BRCA-heterozygotes who are deferring such surgery.

A case for revisiting Nodal signaling in human pluripotent stem cells.

Nodal is a transforming growth factor-ß (TGF-ß) superfamily member that plays a number of critical roles in mammalian embryonic development. Nodal is essential for the support of the peri-implantation epiblast in the mouse embryo and subsequently acts to specify mesendodermal fate at the time of gastrulation and, later, left-right asymmetry. Maintenance of human pluripotent stem cells (hPSCs) in vitro is dependent on Nodal signaling. Because it has proven difficult to prepare a biologically active form of recombinant Nodal protein, Activin or TGFB1 are widely used as surrogates for NODAL in hPSC culture. Nonetheless, the expression of the components of an endogenous Nodal signaling pathway in hPSC provides a potential autocrine pathway for the regulation of self-renewal in this system. Here we review recent studies that have clarified the role of Nodal signaling in pluripotent stem cell populations, highlighted spatial restrictions on Nodal signaling, and shown that Nodal functions in vivo as a heterodimer with GDF3, another TGF-ß superfamily member expressed by hPSC. We discuss the role of this pathway in the maintenance of the epiblast and hPSC in light of these new advances.

Inter and intra-reliability of ultrasonography for the measurement of abdominal subcutaneous & visceral adipose tissue thickness at 12 weeks gestation.

BACKGROUND: Excess abdominal adiposity cause metabolic disturbances, particularly in pregnancy. Methods of accurate measurement are limited in pregnancy due to risks associated with these procedures. This study outlines a non-invasive methodology for the measurement of adipose tissue in pregnancy and determines the intra- and inter-observer reliability of ultrasound (US) measurements of the two components of adipose tissue (subcutaneous (SAT) and visceral adipose tissue (VAT)) within a pregnant population. METHODS: Thirty pregnant women were recruited at the end of their first trimester, from routine antenatal clinic at the University Maternity Hospital Limerick, Ireland. Measurements of adipose tissue thickness were obtained using a GE Voluson E8 employing a 1-5 MHz curvilinear array transducer. Two observers, employing methodological rigour in US technique, measured thickness of adipose tissue three times, and segmented the US image systematically in order to define measurements of SAT and VAT using specifically pre-defined anatomical landmarks. RESULTS: Intra-observer and inter-observer precision was assessed using Coefficient of Variation (CV). Measurements of SAT and total adipose for both observers were < 5% CV and < 10% CV for VAT in measures by both observers. Inter-observer reliability was assessed by Limits of Agreement (LoA). LoA were determined to be - 0.45 to 0.46 cm for SAT and - 0.34 to 0.53 cm for VAT values. Systematic bias of SAT measurement was 0.01 cm and 0.10 cm for VAT. Inter-observer precision was also assessed by coefficient of variation (CV: SAT, 3.1%; VAT, 7.2%; Total adipose, 3.0%). CONCLUSION: Intra-observer precision was found to be acceptable for measures of SAT, VAT and total adipose according to anthropometric criterion, with higher precision reported in SAT values than in VAT. Inter-observer reliability assessed by Limits-Of-Agreement (LoA) confirm anthropometrically reliable to 0.5 cm. Systematic bias was minimal for both measures, falling within 95% confidence intervals. These results suggest that US can produce reliable, repeatable and accurate measures of SAT and VAT during pregnancy.

Effects of false-start disqualification rules on response-times of elite-standard sprinters.

The 100 ms ruling for false start disqualification at athletic competitions governed by the International Association of Athletics Federations has been in force since the early 1990s. Throughout this period, there have been marked changes to the rules that govern the disqualification of athletes from sprint events incorporating starts from blocks. This study analysed all available World and European Championship response-time (RT) data from 1999 to 2014 to examine effects of rule changes on competition RT at major championships. The exponentially modified Gaussian distribution was used to model RT and make comparisons relative to athletes' sex, ruling periods and competition rounds. Revised RT thresholds of 115 ms and 119 ms were identified for men and women, respectively, indicating that the current 100 ms rule could result in some false starts not being detected in competitive athletics. The study proposes that when using existing International Association of Athletics Federations approved systems, the false start detection threshold should be increased and that men and women athletes should have different thresholds because of substantial evidence of a sex-based difference in RT in elite-standard athletes.

The value of multidisciplinary team meetings within an early pregnancy assessment unit.

This is the first study to ascertain the value of multidisciplinary team (MDT) meetings within an early pregnancy assessment unit (EPAU). Our national telephone survey identified that in the United Kingdom, overall 37% of EPAU utilise regular MDT meetings. Secondary and tertiary hospitals are just as likely to hold regular MDT meetings. The participants in our interview study expressed the principal benefits of regular MDT meetings as communication, education and effective stress management. The perceived additional benefits included improved care quality, better patient experience and enhanced team cohesion. During the meetings, at least, one representative from every tier of staffing was present. The caseload of the MDT meeting comprised ectopic pregnancies and pregnancies of unknown location. We propose a number of research studies, which would build on this study. Such efforts will help enhance the effectiveness of the MDT-based EPAU service.

Propofol-related infusion syndrome: rare and fatal.

Propofol is one of the most commonly used sedating agents in critical care units worldwide. It is generally well tolerated and preferred for its pharmacokinetic profile. Here, we describe a rare and devastating adverse effect of propofol, the propofol-related infusion syndrome.

Spatial gradients in cell wall composition and transcriptional profiles along elongating maize internodes.

BACKGROUND: The elongating maize internode represents a useful system for following development of cell walls in vegetative cells in the Poaceae family. Elongating internodes can be divided into four developmental zones, namely the basal intercalary meristem, above which are found the elongation, transition and maturation zones. Cells in the basal meristem and elongation zones contain mainly primary walls, while secondary cell wall deposition accelerates in the transition zone and predominates in the maturation zone. RESULTS: The major wall components cellulose, lignin and glucuronoarabinoxylan (GAX) increased without any abrupt changes across the elongation, transition and maturation zones, although GAX appeared to increase more between the elongation and transition zones. Microarray analyses show that transcript abundance of key glycosyl transferase genes known to be involved in wall synthesis or re-modelling did not match the increases in cellulose, GAX and lignin. Rather, transcript levels of many of these genes were low in the meristematic and elongation zones, quickly increased to maximal levels in the transition zone and lower sections of the maturation zone, and generally decreased in the upper maturation zone sections. Genes with transcript profiles showing this pattern included secondary cell wall CesA genes, GT43 genes, some ß-expansins, UDP-Xylose synthase and UDP-Glucose pyrophosphorylase, some xyloglucan endotransglycosylases/hydrolases, genes involved in monolignol biosynthesis, and NAM and MYB transcription factor genes. CONCLUSIONS: The data indicated that the enzymic products of genes involved in cell wall synthesis and modification remain active right along the maturation zone of elongating maize internodes, despite the fact that corresponding transcript levels peak earlier, near or in the transition zone.

The Road To Value Can't Be Paved With A Broken Medicare Physician Fee Schedule.

Value-based payment has been promoted for increasing quality, controlling spending, and improving patient and practitioner experience. Meanwhile, needed reforms to fee-for-service payment (the Medicare Physician Fee Schedule) have been ignored as policy makers seek to move payment toward alternatives, even though the fee schedule is an intrinsic part of Alternative Payment Models. In this article, we show how value-based payment and the fee schedule should be viewed as complementary, rather than as separate silos. We trace the origins of embedded flaws in the fee schedule that must be fixed if value-based payment is to succeed. These include payment distortions that directly compromise value by overpaying for certain procedures and imaging services while underpaying for services that add value for beneficiaries. We also show how the fee schedule can accommodate bundled payments and population-based payments that are central to Alternative Payment Models. We draw two conclusions. First, the Centers for Medicare and Medicaid Services should correct misvalued services and establish a hybrid payment for primary care that blends fee-for-service and population-based payment. Second, Congress should alter the thirty-five-year-old statutory basis for setting Medicare fees to allow CMS to explicitly consider policy priorities such as workforce shortages in refining fee levels.

Patient preference and acceptability of self-sampling for cervical screening in colposcopy clinic attenders: A cross-sectional semi-structured survey.

Low vaginal self-sampling has been pioneered as an important development to improve uptake of cervical screening globally. Limited research is available in specific patient groups in the UK exploring views around self-sampling to detect high-risk human papillomavirus (hrHPV) DNA. Therefore, we explored patient views to support development of a novel point-of-care self-sampling cervical cancer screening device, by undertaking a cross-sectional semi-structured questionnaire survey to explore preferences, acceptability, barriers and facilitators around self-sampling. Patients attending a colposcopy clinic, 25-64 years old, were invited to participate after having carried out a low vaginal self-sample using a regular flocked swab. Participants self-completed an anonymous 12-point questionnaire. Quantitative data were analysed in MS Excel and Graphpad Prism, and qualitative data with Nvivo. We recruited 274 patients with a questionnaire response rate of 76%. Acceptability of self-sampling was high (95%, n = 187/197; Cronbachs-α = 0.778). Participants were asked their choice of future screening method: a) low vaginal self-sampling, b) healthcare professional collected vaginal swab, c) cervical brush sample with healthcare professional speculum examination, or d) no preference. Preferences were: a) 37% (n = 74/198), b) 19% (n = 37/198); c) 9% (n = 17/198), and d) 35% (n = 70/198), showing no single option as a strong preference. Key motivators were: Test simplicity (90%, n = 170/190), speed (81%, n = 153/190) and less pain (65%, n = 123/190). Barriers included lack of confidence taking the sample (53%, n = 10/19), resulting in preference for a healthcare professional sample (47%, n = 9/19). Whilst self-sampling showed high acceptability, lack of strong preference for screening method may reflect that respondents attending colposcopy are already engaged with screening and have differing perception of cervical cancer risk. This group appear less likely to 'switch' to self-sampling, and it may be better targeted within primary and community care, focusing on under-screened populations. Any shift in this paradigm in the UK requires comprehensive education and support for patients and providers.

YAP/TAZ signaling in allantois-derived cells is required for placental vascularization.

Normal placental development and angiogenesis are crucial for fetal growth and maternal health during pregnancy. However, molecular regulation of placental angiogenesis has been difficult to study due to a lack of specific genetic tools that isolate the placenta from the embryo and yolk sac. To address this gap in knowledge we recently developed Hoxa13 Cre mice in which Cre is expressed in allantois-derived cells, including placental endothelial and stromal cells. Mice lacking the transcriptional regulators Yes-associated protein (YAP) and PDZ-binding motif (TAZ) in allantois-derived cells exhibit embryonic lethality at midgestation with compromised placental vasculature. snRNA-seq analysis revealed transcriptional changes in placental stromal cells and endothelial cells. YAP/TAZ mutants exhibited significantly reduced placental stromal cells prior to the endothelial architectural change, highlighting the role of these cells in placental vascular growth. These results reveal a central role for YAP/TAZ signaling during placental vascular growth and implicate Hoxa13 -derived placental stromal cells as a critical component of placental vascularization.

Movement variability and skills monitoring in sports.

The aim of this paper was to present a review on the role that movement variability (MV) plays in the analysis of sports movement and in the monitoring of the athlete's skills. MV has been traditionally considered an unwanted noise to be reduced, but recent studies have re-evaluated its role and have tried to understand whether it may contain important information about the neuro-musculo-skeletal organisation. Issues concerning both views of MV, different approaches for analysing it and future perspectives are discussed. Information regarding the nature of the MV is vital in the analysis of sports movements/motor skills, and the way in which these movements are analysed and the MV subsequently quantified is dependent on the movement in question and the issues the researcher is trying to address. In dealing with a number of issues regarding MV, this paper has also raised a number of questions which are still to be addressed.

Flecainide associated torsade de pointes: A potential case of reverse use dependence.

Flecainide has been known to cause torsades de pointes (TdP) in patients with structural heart disease and its mechanism has been attributed to use-dependency. We present a patient with flecainide-induced TdP in the absence of any other precipitating factors. This case highlights potential reverse use dependence associated with flecainide resulting in TdP.

Cell wall modifications in maize pulvini in response to gravitational stress.

Changes in cell wall polysaccharides, transcript abundance, metabolite profiles, and hormone concentrations were monitored in the upper and lower regions of maize (Zea mays) pulvini in response to gravistimulation, during which maize plants placed in a horizontal position returned to the vertical orientation. Heteroxylan levels increased in the lower regions of the pulvini, together with lignin, but xyloglucans and heteromannan contents decreased. The degree of substitution of heteroxylan with arabinofuranosyl residues decreased in the lower pulvini, which exhibited increased mechanical strength as the plants returned to the vertical position. Few or no changes in noncellulosic wall polysaccharides could be detected on the upper side of the pulvinus, and crystalline cellulose content remained essentially constant in both the upper and lower pulvinus. Microarray analyses showed that spatial and temporal changes in transcript profiles were consistent with the changes in wall composition that were observed in the lower regions of the pulvinus. In addition, the microarray analyses indicated that metabolic pathways leading to the biosynthesis of phytohormones were differentially activated in the upper and lower regions of the pulvinus in response to gravistimulation. Metabolite profiles and measured hormone concentrations were consistent with the microarray data, insofar as auxin, physiologically active gibberellic acid, and metabolites potentially involved in lignin biosynthesis increased in the elongating cells of the lower pulvinus.

Harmonics of circadian gene transcription in mammals.

The circadian clock is a molecular and cellular oscillator found in most mammalian tissues that regulates rhythmic physiology and behavior. Numerous investigations have addressed the contribution of circadian rhythmicity to cellular, organ, and organismal physiology. We recently developed a method to look at transcriptional oscillations with unprecedented precision and accuracy using high-density time sampling. Here, we report a comparison of oscillating transcription from mouse liver, NIH3T3, and U2OS cells. Several surprising observations resulted from this study, including a 100-fold difference in the number of cycling transcripts in autonomous cellular models of the oscillator versus tissues harvested from intact mice. Strikingly, we found two clusters of genes that cycle at the second and third harmonic of circadian rhythmicity in liver, but not cultured cells. Validation experiments show that 12-hour oscillatory transcripts occur in several other peripheral tissues as well including heart, kidney, and lungs. These harmonics are lost ex vivo, as well as under restricted feeding conditions. Taken in sum, these studies illustrate the importance of time sampling with respect to multiple testing, suggest caution in use of autonomous cellular models to study clock output, and demonstrate the existence of harmonics of circadian gene expression in the mouse.

Sprint start performance: the potential influence of triceps surae electromechanical delay.

In the sprint start, a defined sequence of distinct response delays occurs before the athlete produces a movement response. Excitation of lower limb muscles occurs prior to force production against the blocks, culminating in a movement response. The time delay between muscle excitation and movement, electromechanical delay (EMD), is considered to influence sprint start response time (SSRT). This study examined the delay in sprint start performance from EMD of the triceps surae muscle and examined whether certain sprinters gain an advantage in SSRT. Nineteen experienced sprinters performed sprint starts from blocks, with SSRT measured by an International Association of Athletics Federations (IAAF)-approved starting block system. EMD times were detected during a heel-lift experiment. Using revised SSRT limits, based on concerns over the validity of the IAAF 100 ms false start limit, EMD produced a significant moderate correlation with SSRT (r = 0.572, p = 0.011). Regression analysis determined that together, EMD and signal processing time (the delay between the auditory signal and muscle excitation) accounted for 37% of the variance in SSRT. Initial results suggest EMD is part of the response time process and that certain athletes may gain a performance advantage due to reduced EMD.

Prenatal treprostinil reduces the pulmonary hypertension phenotype in the rat model of congenital diaphragmatic hernia.

BACKGROUND: Persistent pulmonary hypertension (PH) causes significant mortality and morbidity in infants with congenital diaphragmatic hernia (CDH). Since pulmonary vascular abnormalities in CDH develop early during foetal development, we hypothesized that prenatal maternal administration of treprostinil, through its anti-remodelling effect, would improve the PH-phenotype in the nitrofen rat model of CDH. METHODS: In a dose-finding study in normal, healthy pregnant rats, we demonstrated target-range foetal plasma treprostinil concentrations without signs of toxicity. Next, an efficacy study was performed assessing the effects of treprostinil administration at 900 and 1500ng/kg/min from gestational day (GD) 16 until term (GD 21) in CDH and control pups. Pulmonary vascular and airway morphometry, lung mechanics, and expression patterns of genes implicated in the prostaglandin vasoactive pathway were studied. FINDINGS: In rats maternal administration of 1500ng/kg/min treprostinil reached target foetal concentrations, with no detrimental maternal or foetal side-effects. Prenatal exposure to 900 and 1500 ng/kg/min treprostinil reduced the medial wall thickness (%MWT) (CDH·900, 38.5± 8·4%; CDH.1500, 40·2±9·7%; CDH, 46·6±8·2%; both p < 0·0001) in rat pups with CDH, however increased the %MWT in normal foetuses (C.T.900, 36·6±11·1%; C.T.1500, 36·9±9·3%; C.P., 26·9±6·2%; both p < 0·001). Pulmonary airway development, lung hypoplasia and pulmonary function were unaffected by drug exposure. INTERPRETATION: In pregnant rats maternally administered treprostinil crosses the placenta, attains foetal target concentrations, and is well tolerated by both mother and foetuses. This report shows a significant reduction of pulmonary arteriole muscularization with prenatal treprostinil in a nitrofen rat model, supporting the promise of this treatment approach for PH of CDH. FUNDING: United Therapeutics Corporation provided treprostinil and financial support (ISS-2020-10879).

Sprint Start Regulation in Athletics: A Critical Review.

The sprint start in athletics is strictly controlled to ensure the fairness of competition. World athletics (WA)-certified start information systems (SIS) record athletes' response times in competition to ensure that no athletes gain an unfair advantage by responding in < 100 ms after the start signal. This critical review examines the legitimacy of the 100 ms rule, the factors that affect response times and the technologies and rules that support the regulation of the start in competition. The review shows that several SIS use different technologies to deliver the start signal and record response time (RT). The lack of scientific evidence about the definition of the 100 ms false start threshold by the WA is criticized in the literature and the 100 ms rule is challenged. SIS technologies, expertise and sex appear to affect the RT detected in competition. A lack of standardization in event detection has led to validity and reliability problems in RT determination. The onset of the foot response on the blocks is currently used to assess RT in athletics via block-mounted sensors; however, research shows that the onset of arm force reaction is the first detectable biomechanical event in the start. Further research and development should consider whether the onset of arm force can be used to improve the false start detection in competition. Further research is also needed to develop a precise understanding of the event sequence and motor control of the start to improve the SIS technology and rigorously determine the minimum limit of RT in the sprint start.