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Permanent residence at high-altitude and chronic mountain sickness (CMS) may alter the cerebrovascular homeostasis and orthostatic responses. Healthy male participants living at sea-level (LL; n = 15), 3800 m (HL3800m; n = 13) and 5100 m (HL5100m; n = 17), respectively, and CMS highlanders living at 5100 m (n = 31) were recruited. Middle cerebral artery mean blood flow velocity (MCAv), cerebral oxygen delivery (CDO2), mean blood pressure (MAP), heart rate variability and spontaneuous cardiac baroreflex sensitivity (cBRS) were assessed while sitting, initial 30 s and after 3 min of standing. Cerebral autoregulation index (ARI) was estimated (ΔMCAv%baseline)/ΔMAP%baseline) in response to the orthostatic challenge. Altitude and CMS were associated with hypoxemia and elevated hemoglobin concentration. While sitting, MCAv and LFpower negatively correlated with altitude but were not affected by CMS. CDO2 remained preserved. BRS was comparable across all altitudes, but lower with CMS. Within initial 30 s of standing, altitude and CMS correlated with a lesser ΔMAP while ARI remained unaffected. After 3 min standing, MCAv, CDO2 and cBRS remained preserved across altitudes. The LF/HF ratio increased in HL5100m compared to LL and HL3800m from sitting to standing. In contrary, CMS showed blunted autonomic nervous activation in responses to standing. Despite altitude- and CMS-associated hypoxemia, erythrocytosis and impaired blood pressure regulation (CMS only), cerebral homeostasis remained overall preserved.

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The International Monitoring System (IMS) has been established as part of the Comprehensive Nuclear-Test-Ban Treaty to monitor nuclear testing and is comprised of infrasound, hydroacoustic, seismic, and radionuclide stations; it is also used more widely by the scientific community for scientific and civilian applications. For the infrasound stations, on-site calibration provides an accurate measure of the sensor (microbarometer + wind-noise reduction system) frequency response, used to monitor that the sensor response remains within tolerance of the baseline established when the station is certified. However, this on-site calibration can also be used when there are issues/defects with the sensors. As a result, the on-site calibration can be used to correct wave parameter estimations and increase the detection capability of the station. Examples using an experimental sensor at the IMS station IS26 (Germany) and IS47 (South Africa) demonstrate that errors of several degrees and tens of m/s can be introduced, under certain conditions, for the back azimuth and trace velocity, respectively. By using the on-site calibration, these errors are removed, and the correct back azimuth, trace velocity and amplitude are retrieved. This can be especially useful for the identification of infrasound signals, and the localization of their sources.

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Grange syndrome (GRNG-MIM#135580) is a rare recessive disorder associating variable features including diffuse vascular stenosis, brachysyndactyly, osteopenia with increased bone fragility, cardiac malformations, and variable developmental delay. Since its first description in 1998, only 15 individuals from 10 families have been reported, carrying homozygous or compound heterozygous frameshift or nonsense variants in YY1AP1. In a patient with cutaneous and bone syndactyly and a hemorrhagic stroke at the age of 16 months, consistent with a clinical diagnosis of GRNG, we performed exome sequencing after negative array-CGH and congenital limb malformation panel results. Copy number variant analysis from exome data identified a homozygous intragenic out-of-frame deletion of 1.84 kb encompassing exons seven and eight of YY1AP1, confirming a molecular diagnosis of GRNG. Genetic counseling led to the identification of additional family members compatible with GRNG. Here, we provide new insights into the phenotypic variability associated with GRNG and highlight the utility of the detection of small copy number variants to identify the molecular causes of heterogeneous malformative genetic disorders.

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INTRODUCTION AND OBJECTIVES: Chronic Mountain Sickness (CMS) syndrome, combining excessive erythrocytosis and clinical symptoms in highlanders, remains a public health concern in high-altitude areas, especially in the Andes, with limited therapeutic approaches. The objectives of this study were to assess in CMS-highlanders permanently living in La Rinconada (5100-5300 m, Peru, the highest city in the world), the early efficacy of acetazolamide (ACZ) and atorvastatin to reduce hematocrit (Hct), as well as the underlying mechanisms focusing on intravascular volumes. MATERIALS AND METHODS: Forty-one males (46±8 years of age) permanently living in La Rinconada for 15 [10-20] years and suffering from CMS were randomized between ACZ (250 mg once-daily; N = 13), atorvastatin (20 mg once-daily; N = 14) or placebo (N = 14) uptake in a double-blinded parallel study. Hematocrit (primary endpoint) as well as arterial blood gasses, total hemoglobin mass (Hbmass) and intravascular volumes were assessed at baseline and after a mean (±SD) treatment duration of 19±2 days. RESULTS: ACZ increased PaO2 by +13.4% (95% CI: 4.3 to 22.5%) and decreased Hct by -5.2% (95% CI: -8.3 to -2.2%), whereas Hct remained unchanged with placebo or atorvastatin. ACZ tended to decrease Hbmass (-2.6%, 95% CI: -5.7 to 0.5%), decreased total red blood cell volume (RBCV, -5.3%, 95% CI: -10.3 to -0.3%) and increased plasma volume (PV, +17.6%, 95% CI: 4.9 to 30.3%). Atorvastatin had no effect on intravascular volumes, while Hbmass and RBCV increased in the placebo group (+6.1%, 95% CI: 4.2 to 7.9% and +7.0%, 95%CI: 2.7 to 11.4%, respectively). CONCLUSIONS: Short-term ACZ uptake was effective to reduce Hct in CMS-highlanders living at extreme altitude >5,000 m and was associated with both an increase in PV and a reduction in RBCV.

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Stromboli Volcano is well known for its persistent explosive activity. On July 3rd and August 28th 2019, two paroxysmal explosions occurred, generating an eruptive column that quickly rose up to 5 km above sea level. Both events were detected by advanced local monitoring networks operated by Istituto Nazionale di Geofisica e Vulcanologia (INGV) and Laboratorio di Geofisica Sperimentale of the University of Firenze (LGS-UNIFI). Signals were also recorded by the Italian national seismic network at a range of hundreds of kilometres and by infrasonic arrays up to distances of 3700 km. Using state-of-the-art propagation modeling, we identify the various seismic and infrasound phases that are used for precise timing of the eruptions. We highlight the advantage of dense regional seismo-acoustic networks to enhance volcanic signal detection in poorly monitored regions, to provide timely warning of eruptions and reliable source amplitude estimate to Volcanic Ash Advisory Centres (VAAC).

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This paper presents an inversion methodology where acoustic observations of infrasound waves are used to update an atmospheric model. This paper sought a flexible parameterization that permits to incorporate physical and numerical constraints without the need to reformulate the inversion. On the other hand, the optimization conveys an explicit search over the solution space, making the solver computationally expensive. Nevertheless, through a parallel implementation and the use of tight constraints, this study demonstrates that the methodology is computationally tractable. Constraints to the solution space are derived from the spread (variance) of ERA5 ensemble reanalysis members, which summarize the best current knowledge of the atmosphere from assimilated measurements and physical models. Similarly, the initial model temperature and winds for the inversion are chosen to be the average of these parameters in the ensemble members. The performance of the inversion is demonstrated with the application to infrasound observations from an explosion generated by the destruction of ammunition at Hukkakero, Finland. The acoustic signals are recorded at an array station located at 178 km range, which is within the classical shadow zone distance. The observed returns are assumed to come from stratospheric reflections. Thus, the reflection altitude is also an inverted parameter.

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Among ground-based volcano monitoring techniques, infrasound is the only one capable of detecting explosive eruptions from distances of thousands of kilometers. We show how infrasound array analysis, using acoustic amplitude and detection persistency, allows automatic, near-real-time identification of eruptions of Etna volcano (Italy), for stations at distances greater than 500 km. A semi-empirical attenuation relation is applied to recover the pressure time history at the source using infrasound recorded at global scale (>500 km). An infrasound parameter (IP), defined as the product between the number of detections, filtered for the expected back-azimuth of Etna volcano, and range corrected amplitude, is compared with the explosive activity at Etna volcano that was associated with aviation color code RED warnings. This shows that, during favourable propagation conditions, global arrays are capable of identifying explosive activity of Etna 87% of the period of analysis without negative false alerts. Events are typically not detected during unfavourable propagation conditions, thus resulting in a time variable efficiency of the system. We suggest that infrasound monitoring on a global scale can provide timely input for Volcanic Ash Advisory Centres (VAAC) even when a latency of ~1 hour, due to propagation time, is considered. The results highlight the capability of infrasound for near-real-time volcano monitoring at a regional and global scale.

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STUDY QUESTION: Does imprinted DNA methylation or imprinted gene expression differ between human blastocysts from conventional ovarian stimulation (COS) and an optimized two-step IVM method (CAPA-IVM) in age-matched polycystic ovary syndrome (PCOS) patients? SUMMARY ANSWER: No significant differences in imprinted DNA methylation and gene expression were detected between COS and CAPA-IVM blastocysts. WHAT IS KNOWN ALREADY: Animal models have revealed alterations in DNA methylation maintenance at imprinted germline differentially methylated regions (gDMRs) after use of ARTs. This effect increases as more ART interventions are applied to oocytes or embryos. IVM is a minimal-stimulation ART with reduced hormone-related side effects and risks for patients. CAPA-IVM is an improved IVM system that includes a pre-maturation step (CAPA), followed by an IVM step, both in the presence of physiological compounds that promote oocyte developmental capacity. STUDY DESIGN, SIZE, DURATION: For DNA methylation analysis 20 CAPA-IVM blastocysts were compared to 12 COS blastocysts. For RNA-Seq analysis a separate set of 15 CAPA-IVM blastocysts were compared to 5 COS blastocysts. PARTICIPANTS/MATERIALS, SETTING, METHODS: COS embryos originated from 12 patients with PCOS (according to Rotterdam criteria) who underwent conventional ovarian stimulation. For CAPA-IVM 23 women were treated for 3-5 days with highly purified hMG (HP-hMG) and no hCG trigger was given before oocyte retrieval. Oocytes were first cultured in pre-maturation medium (CAPA for 24 h containing C-type natriuretic peptide), followed by an IVM step (30 h) in medium containing FSH and Amphiregulin. After ICSI, Day 5 or 6 embryos in both groups were vitrified and used for post-bisulphite adaptor tagging (PBAT) DNA methylation analysis or RNA-seq gene expression analysis of individual embryos. Data from specific genes and gDMRs were extracted from the PABT and RNA-seq datasets. MAIN RESULTS AND THE ROLE OF CHANCE: CAPA-IVM blastocysts showed similar rates of methylation and gene expression at gDMRs compared to COS embryos. In addition, expression of major epigenetic regulators was similar between the groups. LIMITATIONS, REASONS FOR CAUTION: The embryos from the COS group were generated in a range of culture media. The CAPA-IVM embryos were all generated using the same sperm donor. The DNA methylation level of gDMRs in purely in vivo-derived human blastocysts is not known. WIDER IMPLICATIONS OF THE FINDINGS: A follow-up of children born after CAPA-IVM is important as it is for other new ARTs, which are generally introduced into clinical practice without prior epigenetic safety studies on human blastocysts. CAPA-IVM opens new perspectives for patient-friendly ART in PCOS. STUDY FUNDING/COMPETING INTEREST(S): IVM research at the Vrije Universiteit Brussel has been supported by grants from the Institute for the Promotion of Innovation by Science and Technology in Flanders (Agentschap voor Innovatie door Wetenschap en Technologie-IWT, project 110680), the Fund for Research Flanders (Fonds voor Wetenschappelijk Onderzoek-Vlaanderen-FWO-AL 679 project, project G.0343.13), the Belgian Foundation Against Cancer (HOPE project, Dossier C69Ref Nr 2016-119) and the Vrije Universiteit Brussel (IOF Project 4R-ART Nr 2042). Work in G.K.'s laboratory is supported by the UK Biotechnology and Biological Sciences Research Council and Medical Research Council. The authors have no conflicts of interest.

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Live high-train low (LHTL) using hypobaric hypoxia was previously found to improve sea-level endurance performance in well-trained individuals; however, confirmatory controlled data in athletes are lacking. Here, we test the hypothesis that natural-altitude LHTL improves aerobic performance in cross-country skiers, in conjunction with expansion of total hemoglobin mass (Hbmass , carbon monoxide rebreathing technique) promoted by accelerated erythropoiesis. Following duplicate baseline measurements at sea level over the course of 2 weeks, nineteen Norwegian cross-country skiers (three women, sixteen men, age 20 ± 2 year, maximal oxygen uptake (VO2 max) 69 ± 5 mL/min/kg) were assigned to 26 consecutive nights spent at either low (1035 m, control, n = 8) or moderate altitude (2207 m, daily exposure 16.7 ± 0.5 hours, LHTL, n = 11). All athletes trained together daily at a common location ranging from 550 to 1500 m (21.2% of training time at 550 m, 44.2% at 550-800 m, 16.6% at 800-1100 m, 18.0% at 1100-1500 m). Three test sessions at sea level were performed over the first 3 weeks after intervention. Despite the demonstration of nocturnal hypoxemia at moderate altitude (pulse oximetry), LHTL had no specific effect on serum erythropoietin, reticulocytes, Hbmass , VO2 max, or 3000-m running performance. Also, LHTL had no specific effect on (a) running economy (VO2 assessed during steady-state submaximal exercise), (b) respiratory capacities or efficiency of the skeletal muscle (biopsy), and (c) diffusing capacity of the lung. This study, showing similar physiological responses and performance improvements in the two groups following intervention, suggests that in young cross-country skiers, improvements in sea-level aerobic performance associated with LHTL may not be due to moderate-altitude acclimatization.

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BACKGROUND: To compare histological feature of prostate cancer (PCa) according androgenic status in patients who underwent radical prostatectomy (RP). METHODS: Between March 2007 and September 2013, we prospectively analysed 937 patients who were referred to our centre for RP. Clinical, pathological and biological data have been prospectively collected. Preoperative total testosterone (TT) and bioavailable testosterone (BT) serum determinations were carried out. The threshold for low serum testosterone was set at TT<3 ng/ml. Preoperative PSA value was registered. Gleason score (GS) and predominant Gleason pattern were determined in prostate biopsies and in prostate tissue specimens, crosschecked by two uro-pathologists. RESULTS: Nine hundred and thirty-seven consecutive patients were included. In all, 14.9% patients had low TT in the population. An exact match between biopsy and prostate specimens in GS grading was observed for 50.6% patients (n=474). Also, 40.9% of all patients were upgraded (n=383): 45.3% (n=63) in low serum testosterone patients and 40.1% (n=320) in normal serum testosterone patients. For prostate specimens, the proportion of patients with predominant Gleason pattern 4 was higher in patients with low TT compared with normal TT (41.7% vs 29.1%, P=0.0029). In all, 20.1% were upgraded from predominant Gleason pattern 3 on biopsies specimen to predominant Gleason 4 pattern on the prostate specimen in patients with low TT, whereas 11.6% were upgraded for normal TT patients (P=0.002). CONCLUSIONS: Low serum testosterone is an independent risk factor for predominant Gleason pattern 4 on prostate specimen after RP and for upgrading from low- to high-grade cancer between prostate needle biopsies and RP specimen. This observation should be taken into account in localised PCa management, especially for active surveillance or when a nerve-sparing approach is considered.

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In this paper, we describe the design and the main performances of the PHARAO laser source flight model. PHARAO is a laser cooled cesium clock specially designed for operation in space and the laser source is one of the main sub-systems. The flight model presented in this work is the first remote-controlled laser system designed for spaceborne cold atom manipulation. The main challenges arise from mechanical compatibility with space constraints, which impose a high level of compactness, a low electric power consumption, a wide range of operating temperature, and a vacuum environment. We describe the main functions of the laser source and give an overview of the main technologies developed for this instrument. We present some results of the qualification process. The characteristics of the laser source flight model, and their impact on the clock performances, have been verified in operational conditions.

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Several techniques assessing cardiac output (Q) during exercise are available. The extent to which the measurements obtained from each respective technique compares to one another, however, is unclear. We quantified Q simultaneously using four methods: the Fick method with blood obtained from the right atrium (Q(Fick-M)), Innocor (inert gas rebreathing; Q(Inn)), Physioflow (impedance cardiography; Q(Phys)), and Nexfin (pulse contour analysis; Q(Pulse)) in 12 male subjects during incremental cycling exercise to exhaustion in normoxia and hypoxia (FiO2 = 12%). While all four methods reported a progressive increase in Q with exercise intensity, the slopes of the Q/oxygen uptake (VO2) relationship differed by up to 50% between methods in both normoxia [4.9 ± 0.3, 3.9 ± 0.2, 6.0 ± 0.4, 4.8 ± 0.2 L/min per L/min (mean ± SE) for Q(Fick-M), Q(Inn), QP hys and Q(Pulse), respectively; P = 0.001] and hypoxia (7.2 ± 0.7, 4.9 ± 0.5, 6.4 ± 0.8 and 5.1 ± 0.4 L/min per L/min; P = 0.04). In hypoxia, the increase in the Q/VO2 slope was not detected by Nexfin. In normoxia, Q increases by 5-6 L/min per L/min increase in VO2, which is within the 95% confidence interval of the Q/VO2 slopes determined by the modified Fick method, Physioflow, and Nexfin apparatus while Innocor provided a lower value, potentially reflecting recirculation of the test gas into the pulmonary circulation. Thus, determination of Q during exercise depends significantly on the applied method.

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Most large (over a kilometre in diameter) near-Earth asteroids are now known, but recognition that airbursts (or fireballs resulting from nuclear-weapon-sized detonations of meteoroids in the atmosphere) have the potential to do greater damage than previously thought has shifted an increasing portion of the residual impact risk (the risk of impact from an unknown object) to smaller objects. Above the threshold size of impactor at which the atmosphere absorbs sufficient energy to prevent a ground impact, most of the damage is thought to be caused by the airburst shock wave, but owing to lack of observations this is uncertain. Here we report an analysis of the damage from the airburst of an asteroid about 19 metres (17 to 20 metres) in diameter southeast of Chelyabinsk, Russia, on 15 February 2013, estimated to have an energy equivalent of approximately 500 (±100) kilotons of trinitrotoluene (TNT, where 1 kiloton of TNT = 4.185×10(12) joules). We show that a widely referenced technique of estimating airburst damage does not reproduce the observations, and that the mathematical relations based on the effects of nuclear weapons--almost always used with this technique--overestimate blast damage. This suggests that earlier damage estimates near the threshold impactor size are too high. We performed a global survey of airbursts of a kiloton or more (including Chelyabinsk), and find that the number of impactors with diameters of tens of metres may be an order of magnitude higher than estimates based on other techniques. This suggests a non-equilibrium (if the population were in a long-term collisional steady state the size-frequency distribution would either follow a single power law or there must be a size-dependent bias in other surveys) in the near-Earth asteroid population for objects 10 to 50 metres in diameter, and shifts more of the residual impact risk to these sizes.

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Advances in sequencing technologies are giving unprecedented insights into the spectrum of somatic mutations underlying acute myeloid leukaemia with a normal karyotype (AML-NK). It is clear that the prognosis of individual patients is strongly influenced by the combination of mutations in their leukaemia and that many leukaemias are composed of multiple subclones, with differential susceptibilities to treatment. Here, we describe a method, employing targeted capture coupled with next-generation sequencing and tailored bioinformatic analysis, for the simultaneous study of 24 genes recurrently mutated in AML-NK. Mutational analysis was performed using open source software and an in-house script (Mutation Identification and Analysis Software), which identified dominant clone mutations with 100% specificity. In each of seven cases of AML-NK studied, we identified and verified mutations in 2-4 genes in the main leukaemic clone. Additionally, high sequencing depth enabled us to identify putative subclonal mutations and detect leukaemia-specific mutations in DNA from remission marrow. Finally, we used normalised read depths to detect copy number changes and identified and subsequently verified a tandem duplication of exons 2-9 of MLL and at least one deletion involving PTEN. This methodology reliably detects sequence and copy number mutations, and can thus greatly facilitate the classification, clinical research, diagnosis and management of AML-NK.

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Abnormalities of the male genitalia have increased in the last 2 decades in numerous developed countries and remain a frequent reason of consultation in pediatric surgery. The diagnostic spectrum is wide, and surgeons should pay particular attention to these abnormalities because of their potential psychological effect. Anatomically, these abnormalities can affect one of three parts of the penis. First, the foreskin may not be fully retracted. This is normal at birth and can be caused by prepuce adherents that can continue until adolescence. Today, true phimosis is treated with topical corticoids from the age of 3 years. If medical treatment fails, a surgical procedure is required. Second, the urethra can be affected by hypospadia, which is the most frequent abnormality of the urethra. It is associated with ectopic urethral meatus, hypoplastic foreskin, and penis curvature. Its pathogenic background is not clearly understood. Surgery options differ according to the type of hypospadia and according to the surgeon's experience. It is sometimes hard to deal with, especially in a perineal form, where genetic and hormonal studies are recommended. These interventions can lead to complications ranging from stenosis to fistula. Therefore, parents have to be informed of the benefits and risks of the surgical procedures. Epispadias is rare but more serious because of the increasing risk of urinary incontinence. Finally, abnormalities of the corpora cavernosa - often associated with hypospadias - can include penis curvature and micropenis, for which an endocrinological analysis is essential.

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