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Context. The number of super-Earth and Earth-mass planet discoveries has increased significantly in the last two decades thanks to the Doppler radial velocity and planetary transit observing techniques. Either technique can detect planet candidates on its own, but the power of a combined photometric and spectroscopic analysis is unique for an insightful characterization of the planets, which in turn has repercussions for our understanding of the architecture of planetary systems and, therefore, their formation and evolution. Aims. Two transiting planet candidates with super-Earth radii around the nearby (d = 70.64 ± 0.06 pc) K7–M0 dwarf star TOI-1238 were announced by NASA’s Transiting Exoplanet Survey Satellite (TESS), which observed the field of TOI-1238 in four different sectors. We aim to validate their planetary nature using precise radial velocities taken with the CARMENES spectrograph. Methods. We obtained 55 CARMENES radial velocity measurements that span the 11 months between 9 May 2020 and 5 April 2021. For a better characterization of the parent star’s activity, we also collected contemporaneous optical photometric observations at the Joan Oró and Sierra Nevada observatories and retrieved archival photometry from the literature. We performed a combined TESS+CARMENES photometric and spectroscopic analysis by including Gaussian processes and Keplerian orbits to account for the stellar activity and planetary signals simultaneously. Results. We estimate that TOI-1238 has a rotation period of 40 ± 5 d based on photometric and spectroscopic data. The combined analysis confirms the discovery of two transiting planets, TOI-1238 b and c, with orbital periods of 0.764597−0.000011+0.000013 d and 3.294736−0.000036+0.000034 d, masses of 3.76−1.07+1.15 M⊕ and 8.32−1.88+1.90 M⊕, and radii of 1.21−0.10+0.11 R⊕ and 2.11−0.14+0.14 R⊕. They orbit their parent star at semimajor axes of 0.0137 ± 0.0004 au and 0.036 ± 0.001 au, respectively.The two planets are placed on opposite sides of the radius valley for M dwarfs and lie between the star and the inner border of TOI-1238’s habitable zone. The inner super-Earth TOI-1238 b is one of the densest ultra-short-period planets ever discovered (ρ = 11.7−3.4+4.2 g cm−3). The CARMENES data also reveal the presence of an outer, non-transiting, more massive companion with an orbital period and radial velocity amplitude of ≥600 d and ≥70 m s−1, which implies a likely mass of M ≥ 2 √(1− e2) MJup and a separation ≥1.1 au from its parent star. © ESO 2022., CARMENES is an instrument for the Centro Astronómico Hispano-Alemán de Calar Alto (CAHA, Almería, Spain). CARMENES is funded by the German Max-Planck- Gesellschaft (MPG), the Spanish Consejo Superior de Investigaciones Científicas (CSIC), the European Union through FEDER/ERF funds, and the members of the CARMENES Consortium (Max-Planck-Institut für Astronomie, Instituto de Astrofísica de Andalucía, Landessternwarte Koönigstuhl, Institut de Ciències de l’Espai, Insitut für Astrophysik Göttingen, Universidad, Complutense de Madrid, Thüringer Landessternwarte Tautenburg, Instituto de Astrofísica de Canarias, Hamburger Sternwarte, Centro de Astrobiología and Centro Astronómico Hispano-Alemán), with additional contributions by the Spanish Ministry of Economy, the state of Baden-Wüttemberg, the German Science Foundation (DFG), the Klaus Tschira Foundation (KTS), and by the Junta de Andalucía. This work was based on data from the CARMENES data archive at CAB (CSIC-INTA). This research has made use of the NASA Exoplanet Archive, which is operated by the California Institute of Technology, under contract with the National Aeronautics and Space Administration under the Exoplanet Exploration Program. Funding for the TESS mission is provided by NASA’s Science Mission Directorate. This paper includes data collected by the TESS mission that are publicly available from the Mikulski Archive for Space Telescopes. We acknowledge the use of public TESS data from pipelines at the TESS Science Office and at the TESS Science Processing Operations Center. Resources supporting this work were provided by the NASA High-End Computing (HEC) Program through the NASA Advanced Supercomputing (NAS) Division at Ames Research Center for the production of the SPOC data products. Some of the observations in the paper made use of the High-Resolution Imaging instrument ‘Alopeke obtained under Gemini LLP Proposal Number: GN/S-2021A-LP-105. ‘Alopeke was funded by the NASA Exoplanet Exploration Program and built at the NASA Ames Research Center by Steve B. Howell, Nic Scott, Elliott P. Horch, and Emmett Quigley. ‘Alopeke was mounted on the Gemini North (and/or South) telescope of the international Gemini Observatory, a program of NSF’s OIR Lab, which is managed bythe Association of Universities for Research in Astronomy (AURA) under a cooperative agreement with the National Science Foundation. on behalf of the Gemini partnership: the National Science Foundation (United States), National Research Council (Canada), Agencia Nacional de Investigación y Desarrollo (Chile), Ministerio de Ciencia, Tecnología e Innovación (Argentina), Ministério da Ciência, Tecnologia, Inovações e Comunicações (Brazil), and Korea Astronomy and Space Science Institute (Republic of Korea). Data were partly collected with the 90 cm telescope at the Sierra Nevada Observatory (SNO) operated by the Instituto de Astrofí fica de Andalucí a (IAA-CSIC). We acknowledge the telescope operators from Observatori Astronómic del Montsec, Sierra Nevada Observatory, and Centro Astronómico Hispano-Alemán de Calar Alto (CAHA). E.G.A., M.R.Z.O., J.A.C., J.S.F, and D.M. acknowledge financial support from the Spanish Ministry of Science and Innovation through project PID2019-109522GBC5[1:4]. E.G.A also acknowledges support from AEI Project No. MDM-2017-0737 Unidad de Excelencia “María de Maeztu” – Centro de Astrobiología (CSIC-INTA). V.M.P. acknowledges financial support from NASA through grant NNX17AG24G. S.V.J. acknowledges the support of the DFG priority program SPP 1992 “Exploring the Diversity of Extrasolar Planets (JE 701/5-1)”. M.J.L.-G., E.R., C.R.-L., and P.J.A. acknowledge financial support from the Agencia Estatal de Investigación of the Ministerio de Ciencia e Innovación through projects PID2019-109522GB-C52, PID2019-107061GB-C64, PID2019-110689RB-100 and the Centre of Excellence Severo Ochoa Instituto de Astrofísica de Andalucía (SEV-2017-0709). G.M. received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 895525. S.S. and S.R. acknowledgesupport by the DFG Research Unit FOR 2544 Blue Planets around Red Stars, project no. RE 2694/4-1.

Additional file 13. Mounting an embryo for live imaging with the light sheet microscope The MuVi SPIM light sheet microscope stage holds a glass capillary; a piece of transparent FEP tube (that does not optically interfere with imaging) slides over top of the glass tube and provides a watertight seal: the sample must be held within this. For live imaging of embryos, we developed a new mounting protocol. Embryos were held by their extra-embryonic cones in a single coil of 0.1 mm titanium wire (to minimise toxicity). (A) A large coil was made at one end of a piece of 0.1 mm titanium wire, by winding the wire around the shank of a 0.7 mm drill bit, clamped in a vice. This large coil is designed to anchor the wire into agarose, and to centre the smaller embryo-holding coil. (B, C) To make the embryo-holding coil, the large coil is pulled over the shank of another drill bit, with a diameter suited to the size of the embryo that needs to be mounted (usually between 0.15 and 0.45 mm) and a single coil is made by winding the wire (trimming the excess). (D) Glass capillary with diameter 1.6 mm, and insulated wire (blue) that fits into the glass tube. (E) The blue wire is inserted into the glass capillary. (F) By pulling the end of the blue wire out of the glass capillary, while holding the other end of the glass capillary in 2% molten LMP agarose in CMERL-1066 medium (PANBiotech Cat# P04–84600), agarose is sucked into the glass capillary.

We begin by describing our observations of the ways in which the conduct of research has changed during the COVID-19 pandemic and go on to comment on the quality of the scientific advice that is provided to UK citizens, and especially to schools. Researchers, like many, have suffered from the effects of the pandemic. Those hardships notwithstanding, we suggest that research into COVID-19 has benefitted from a ‘seed corn’ of discovery science that has provided the basis for routine diagnostic PCR and antibody tests; for structural analyses of the way in which the SARS-CoV-2 virus interacts with cells; for the development of new treatments (and the debunking of ineffective ones); for studies of the genetics of susceptibility to SARS-CoV-2; and for the development of vaccines. The speed of dissemination of research has benefitted from the widespread use of pre-prints, and researchers and funders have become more nimble in their approaches to research and more willing to change their priorities in the face of the pandemic. In our experience, the advice provided to schools on the basis of this research was, however, often published at the last minute and was frequently flawed or inconsistent. This has led to a widening of the attainment gap between children from disadvantaged backgrounds and their peers and it has exacerbated the digital divide and holiday hunger. The consequences will be felt for many years to come and will jeopardize diversity in research and other careers.

Additional file 29. Clusters of top and bottom samples (A, B) t-distributed stochastic neighbour embedding (t-SNE) plots, showing clusters of cells of the ‘top’ part (as shown in Fig. 4a) of twenty-five (E7.25-E7.5) embryos, and the localisation of those clusters in the aggregate (B). The Tal1 expressing cells are those of cluster 5, and the Sox17 expressing cells are those of clusters 1 and 6. (C, D) t-SNE plots, showing clusters of cells of the ‘bottom’ part of twenty-five (E7.25-E7.5) embryos, and the localisation of those clusters in the aggregate (D). The Tal1 expressing cells are those of cluster 8 and the Sox17 expressing cells are those of cluster 6. Highly expressed genes in the different clusters can be found in Table S.1 and Table S.2.

International audience

Saplings of 19 valuable rain forest timber species representative of three successional status groups (early secondary, late secondary and climax) were grown in a polyhouse to examine their respons...

We present observations of five stellar occultations for (11351) Leucus and reports from two efforts on (21900) Orus. Both objects are prime mission candidate targets for the Lucy Discovery mission. Combined results for Leucus indicate a very dark surface with p V = 0.037 ± 0.001, which is derived from the average of the multichord occultations. Our estimate of the triaxial ellipsoidal shape is for axial diameters of 63.8 × 36.6 × 29.6 km assuming that the spin pole is normal to the line of sight. The actual shape of the object is only roughly elliptical in profile at each epoch. Significant topography is seen with horizontal scales up to 30 km and vertical scales up to 5 km. The most significant feature is a large depression on the southern end of the object as seen from a terrestrial viewpoint. For this work we developed a method to correct for differential refraction, accounting for the difference in color between the target object and the reference stars for astrometry derived from ground-based images.

The Red Ensign Group (REG) has recently completed the development of an updated regulatory framework for Yachts, entitled the ‘REG Yacht Code’, which entered into force on the 1st of January 2019. The Code’s aim is to further develop the well-established industry standards of the Large Commercial Yacht Code (LY3), combining the lessons learned from almost 20 years of regulating the Large Yacht sector since the first version of the Code was published in 1997 & Passenger Yacht Code (PYC) since the 1st edition was published in 2010. The revised text makes larger use of industry best practice, international standards and the IMO’s overarching remit for the provision of increased ‘Goal Based Standards’ with the intention of allowing room for more flexibility and innovation in the design and construction of Large Yachts. Here, the principle changes to the Code are presented in addition to the benefits and challenges that are associated with achieving compliance. Finally, the key technical considerations during the design and construction process when building to Parts A and B are discussed.

International audience; In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.

A family of push–pull quinoidal porphyrin monomers has been prepared from a meso-formyl porphyrin by bromination, thioacetal formation, palladium-catalyzed coupling with malononitrile and oxidation with DDQ. Attempts at extending this synthesis to a push–pull quinoidal/cumulenic porphyrin dimer were not successful. The crystal structures of the quinoidal porphyrins indicate that there is no significant contribution from singlet biradical or zwitterionic resonance forms. The crystal structure of an ethyne-linked porphyrin dimer shows that the torsion angle between the porphyrin units is only about 3°, in keeping with crystallographic results on related compounds, but contrasting with the torsion angle of about 35° predicted by computational studies. The free-base quinoidal porphyrin monomers form tightly π-stacked layer structures, despite their curved geometries and bulky aryl substituents.

A wild-type vertebrate embryo first generates its head and then extends its main body axis by successively appending trunk and tail. This rostro-caudal (head-to-tail) development is initiated by a set of morphogenetic movements known as gastrulation that recruits multipotent cells into one of the three morphologically distinct germ layers: ectoderm, endoderm, and mesoderm. These primordial tissues go on to form complementary sets of connective tissues and organs to build the head and at least some of the trunk. In contrast, the tail appears to be formed without clear germ layer segregation from a terminally located growth zone (the tailbud). Recent research shows that the tailbud retains some pregastrulation multipotency to generate derivatives of different germ layers such as spinal cord (ectoderm) and skeletal muscle (mesoderm). This review discusses the emerging role of T-box transcription factors in this process and their intricate relationship with other genetic components to regulate multipotency and germ layer segregation during axial elongation-from gastrulation to the termination of tail growth.

We propose an algorithm for maximizing the lifetime of a wireless sensor network when there is a mobile sink and the underlying application can tolerate some amount of delay in delivering the data to the sink. The algorithm is distributed, and in addition, mostly uses local information. Such an algorithm can be implemented by parallel and/or distributed execution and the overhead of message passing is low. It is also possible to embed the algorithm into a network protocol so that the sensor nodes and the sink can run it directly as part of the network operation. We give a proof of the algorithm's optimality and the boundedness of the queue sizes, both in the long-run average sense. The proof is based on analyzing a Lyapunov drift.

Codification of the Criminal Law

Mercury (Hg) is a naturally occurring element that is released into the biosphere both by natural processes and anthropogenic activities. Although its reduced, elemental form Hg(0) is relatively nontoxic, other forms such as Hg(2+) and, in particular, its methylated form, methylmercury, are toxic, with deleterious effects on both ecosystems and humans. Microorganisms play important roles in the transformation of mercury in the environment. Inorganic Hg(2+) can be methylated by certain bacteria and archaea to form methylmercury. Conversely, bacteria also demethylate methylmercury and reduce Hg(2+) to relatively inert Hg(0). Transformations and toxicity occur as a result of mercury interacting with various proteins. Clearly, then, understanding the toxic effects of mercury and its cycling in the environment requires characterization of these interactions. Computational approaches are ideally suited to studies of mercury in proteins because they can provide a detailed molecular picture and circumvent issues associated with toxicity. Here, we describe computational methods for investigating and characterizing how mercury binds to proteins, how inter- and intraprotein transfer of mercury is orchestrated in biological systems, and how chemical reactions in proteins transform the metal. We describe quantum chemical analyses of aqueous Hg(II), which reveal critical factors that determine ligand-binding propensities. We then provide a perspective on how we used chemical reasoning to discover how microorganisms methylate mercury. We also highlight our combined computational and experimental studies of the proteins and enzymes of the mer operon, a suite of genes that confer mercury resistance in many bacteria. Lastly, we place work on mercury in proteins in the context of what is needed for a comprehensive multiscale model of environmental mercury cycling.

We report the discovery and initial characterisation of Qatar-1b, a hot Jupiter orbiting a metal-rich K dwarf star, the first planet discovered by the Alsubai Project exoplanet transit survey. We describe the strategy used to select candidate transiting planets from photometry generated by the Alsubai Project instrument. We examine the rate of astrophysical and other false positives found during the spectroscopic reconnaissance of the initial batch of candidates. A simultaneous fit to the follow-up radial velocities and photometry of Qatar-1b yield a planetary mass of 1.09+/-0.08 Mjup and a radius of 1.16+/-0.05 Rjup. The orbital period and separation are 1.420033 days and 0.0234 AU for an orbit assumed to be circular. The stellar density, effective temperature and rotation rate indicate an age greater than 4 Gyr for the system.

Sandhoff disease, a GM2 gangliosidosis caused by a deficiency in β-hexosaminidase, is characterized by progressive neurodegeneration. Although loss of neurons in association with lysosomal storage of glycosphingolipids occurs in patients with this disease, the molecular pathways that lead to the accompanying neurological defects are unclear. Using an authentic murine model of GM2 gangliosidosis, we examined the pattern of neuronal loss in the central nervous system and investigated the effects of gene transfer using recombinant adeno-associated viral vectors expressing β-hexosaminidase subunits (rAAV2/1-Hex). In 4-month-old Sandhoff mice with neurological deficits, cells staining positively for the apoptotic signature in the TUNEL reaction were found in the ventroposterior medial and ventroposterior lateral (VPM/VPL) nuclei of the thalamus. There was progressive loss of neuronal density in this region with age. Comparable loss of neuronal density was identified in the lateral vestibular nucleus of the brainstem and a small but statistically significant loss was present in the ventral spinal cord. Loss of neurons was not detected in other regions that were analysed. Administration of rAAV2/1-Hex into the brain of Sandhoff mice prevented the decline in neuronal density in the VPM/VPL. Preservation of neurons in the VPM/VPL was variable at the humane endpoint in treated animals, but correlated directly with increased lifespan. Loss of neurons was localized to only a few regions in the Sandhoff brain and was prevented by rAAV-mediated transfer of β-hexosaminidase gene function at considerable distances from the site of vector administration.

By the action of N-bromosuccinimide the side-chain of an alkyl-naphthalene is brominated on the α-carbon atom (allyl system). Removal of hydrogen bromide gives an olefin which is easily oxidised to the naphthoic acid.

Background: Pregnancy outcomes following in utero exposure to antiepileptic drugs (AEDs) are uncertain, limiting an evidenced-based approach. Objective: To determine if fetal outcomes vary as a function of different in utero AED exposures. Methods: This ongoing prospective observational study across 25 epilepsy centers in the USA and UK enrolled pregnant women with epilepsy from October 1999 to February 2004 to determine if differential long-term cognitive and behavioral neurodevelopmental effects exist across the four most commonly used AEDs. This initial report focuses on the incidence of serious adverse outcomes including major congenital malformations (which could be attributable to AEDs) or fetal death. A total of 333 mother/child pairs were analyzed for monotherapy exposures: carbamazepine (n = 110), lamotrigine (n = 98), phenytoin (n = 56), and valproate (n = 69). Results: Response frequencies of pregnancies resulting in serious adverse outcomes for each AED were as follows: carbamazepine 8.2%, lamotrigine 1.0%, phenytoin 10.7%, and valproate 20.3%. Distribution of serious adverse outcomes differed significantly across AEDs and was not explained by factors other than in utero AED exposure. Valproate exhibited a dose-dependent effect. Conclusions: More adverse outcomes were observed in pregnancies with in utero valproate exposure vs the other antiepileptic drugs (AEDs). These results combined with several recent studies provide strong evidence that valproate poses the highest risk to the fetus. For women who fail other AEDs and require valproate, the dose should be limited if possible.

Helen A Lane, Jamie C Smith, J Stephen DaviesDepartment of Endocrinology, University of Wales College of Medicine, Heath Park, Cardiff, Wales, UKAbstract: Initially considered as a semipermeable barrier separating lumen from vessel wall, the endothelium is now recognised as a complex endocrine organ responsible for a variety of physiological processes vital for vascular homeostasis. These include the regulation of vascular tone, luminal diameter, and blood flow; hemostasis and thrombolysis; platelet and leucocyte vessel-wall interactions; the regulation of vascular permeability; and tissue growth and remodelling. The endothelium modulates arterial stiffness, which precedes overt atherosclerosis and is an independent predictor of cardiovascular events. Unsurprisingly, dysfunction of the endothelium may be considered as an early and potentially reversible step in the process of atherogenesis and numerous methods have been developed to assess endothelial status and large artery stiffness. Methodology includes flow-mediated dilatation of the brachial artery, assessment of coronary flow reserve, carotid intimamedia thickness, pulse wave analysis, pulse wave velocity, and plethysmography. This review outlines the various modalities, indications, and limitations of available methods to assess arterial dysfunction and vascular risk.Keywords: endothelial function, vascular risk, vascular stiffness

Researchers have reported that organic mineral complexes can have increased availability compared with inorganic sources. This work was conducted to examine the inclusion of a small amount of chelated calcium proteinate (CalKey) into turkey breeder hen diets and its effect on turkey breeder hen performance. Two studies were conducted, one each in Minnesota (A) and North Carolina (B). Typical corn and soybean meal diets without animal by-product meals were used as the control diets. Hens in the first study were photostimulated at 30 wk of age in December with 15L:9D for a 24-wk lay period, and hens in a second study were photostimulated after an induced molt in January with 15.5L:8.5D for a 24-wk lay period. In study A, hatchability of fertile eggs was improved during the last 4 wk of production for hens fed calcium proteinate. During 1 period, hens fed calcium proteinate had lower daily feed intake and increased incidence of soft-shelled eggs. In study B, hatchability of fertile eggs was improved for hens fed dietary calcium proteinate for 19 and 20 wk of lay. This result was associated with improved embryo livability for wk 3 and 4 of development. It was concluded that feeding 500 ppm calcium from chelated calcium proteinate improved hatchability of turkey eggs during the later period of egg production, which was associated with decreased late embryo mortality.

In patients with cancer, adrenal enlargement due to either metastatic disease or diffuse non-metastatic hyperplasia is increasingly recognized with modern imaging techniques. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, characterized by non-suppressible hypercortisolism, has also been described in neoplasia in the absence of ectopic adrenocorticotrophic hormone (ACTH) production. In the majority of cases of malignancy-associated hypercortisolism, it might be expected that the presence of malignant disease would be clinically apparent, thus rendering a detailed endocrinological evaluation of the HPA axis unnecessary. However, in the present case we describe a patient with occult malignancy presenting with bilateral adrenocortical enlargement and non-suppressible hypercortisolism that was not due to the ectopic ACTH syndrome. There were no clinical Cushingoid features other than hypertension and new-onset diabetes mellitus. Detailed diagnostic investigations for the possibility of Cushing's syndrome were performed before the underlying diagnosis of gastric adenocarcinoma eventually became apparent. Characteristics and potential mechanisms of non-suppressible hypercortisolism in cancer are discussed. We believe that this scenario will occur with greater frequency in the future, given the increasing early use of sophisticated high-resolution imaging for the evaluation of suspected intra-abdominal pathology.

Local and national laws regulating poultry litter (PL) land application may require that PL be applied based on crop needs and PL nutrient content such as N and P. In addition, some may require monitoring of soil metals such as Cu and Zn. Even with efforts to decrease fecal nutrient excretion, there is also a need to extend the useful life of current bedding materials and to develop alternative uses of spent PL. Heat treatment of PL may extend bedding life and offer alternative uses of PL. The objective of this study was to determine if heat processed turkey litter (TL) can be reused as bedding for turkeys. Pine shavings (PS) which had been used as bedding to rear Large White male turkeys from hatch to 20 weeks of age was processed at 95 and 220 C in an enclosed auger system. Four litter treatments (LT) were used: 1) control - new PS (T ), o 1 2) TL processed at 95 C (T ), 3) a 70:30 (w/w) mixture of TL processed at 95 or 220 C (T ) and 4) a 95:5 o o 2 3 (w/w) mixture of TL processed at 95 or 220 C (T ). These bedding mixtures were placed in 36 floor pens in o 4 a randomized block design to provide 9 replicate pens per LT. Thirty Large White turkey hen poults were placed in each pen on day of hatch. The birds were reared to 14 wk. Mortality and feed consumption were monitored. Period and cumulative feed conversion (FC) ratios were calculated. Regression analysis of SAS, Inc. was used for data analysis. The LS Means procedure was used to separate treatment means (P

Objective Tracheostomies in children are increasingly performed for chronic medical conditions. There are no published studies reporting the experience of children with a tracheostomy in school. Such information would be valuable in planning the care and education of these children. The aims of this study were to identify those children with a tracheostomy in Nottinghamshire schools and determine the support they were receiving. Design, setting and participants Questionnaire survey to families and school carers of 11 children with a tracheostomy. Results All children of school age were in full-time education (five mainstream, five special schools). One preschool child attended a Family Centre. Four had problems finding suitable carers, delaying return to school in three. Four parents were dissatisfied with aspects of the child's experience at school: two felt the teaching staff were unsupportive, one was unhappy with the care of the tracheostomy, and one had problems funding a carer. Ten out of 11 school carers were satisfied with their training; 10 would have liked regular update sessions. The amount of care required varied. Those with complex medical problems in a special school setting needed frequent care, and one had required admission to hospital from school. One child had time off school because of lack of carer availability. Those who were severely disabled had less time off school for ill health after the tracheostomy than before the tracheostomy. Conclusion Children with tracheostomies can successfully and safely achieve full-time education in both mainstream and special schools. A dedicated multidisciplinary team, including input from the parents, is essential to achieve this goal. Regular revision of skills and information sessions for the teaching staff would be beneficial.

Although GH deficiency may underlie the increased cardiovascular risk in adult hypopituitarism, other coexisting hormonal deficiencies and/or unphysiological hormone replacement may contribute. l-Deamino-8-d-arginine (DDAVP), when administered parenterally, potentiates hemostasis by increasing plasma procoagulant factors. We investigated whether chronic intranasal DDAVP therapy influences clotting factors (plasma fibrinogen, factor VIII, and von Willebrand factor antigen) and endothelial function (flow-mediated dilation of the brachial artery) in 30 GH-treated hypopituitary subjects, including both DDAVP-treated subjects (group A) (mean age, 46 ± 11 yr) and vasopressin-sufficient subjects (group B) (mean age, 47 ± 16 yr). Fifteen healthy controls (group C) (mean age, 48 ± 12 yr) were also studied. All hypopituitary patients were receiving stable GH replacement (median duration, 19 months). Comparing the three groups, concentrations of fibrinogen (mean ± sd) (A, 3.3 ± 1.0 g/liter vs. B, 3.5 ± 0.9 vs. C, 2.6 ± 0.8, P < 0.05), factor VIII (A, 130% ± 30% vs. B, 128% ± 30% vs. C, 104% ± 35%, P < 0.05) and von Willebrand factor antigen (A, 124% ± 35% vs. B, 134% ± 45% vs. C, 93% ± 36%, P < 0.05) were higher in hypopituitary subjects, compared with controls. However, there were no differences in clotting factors between groups A and B. Flow-mediated dilation did not differ significantly between the two hypopituitary groups (A, 5.9% ± 2.0% vs. B, 4.7% ± 1.6%) and was similar to that in the control group (C, 5.7% ± 2.1%). In conclusion, although endothelium-dependent vasodilation is intact in GH-treated hypopituitary adults, elevated concentrations of hemostatic markers suggest the persistence of a prothrombotic tendency and endothelial dysfunction. Intranasal DDAVP does not appear to influence this proatherogenic profile in hypopituitary adults with vasopressin deficiency.

Summary objectives Untreated growth hormone deficiency (GHD) is implicated in the increased cardiovascular risk associated with adult hypopituitarism. Oxidative stress, predisposing to lipid peroxidation, may be an important mediator of endothelial dysfunction, a pro-atherogenic state associated with adult GHD. design and patients In a randomized, double-blind, placebo-controlled study we investigated the effects of GH replacement on low-density lipoprotein (LDL) oxidation and neutrophil superoxide (O2−) generating capacity in 32 GHD adults (19 males, 13 females; age range 19–64 years) over 3 months. Thirty age- and sex-matched healthy controls were also studied. measurements Lipid hydroperoxides (HPOs) in plasma were measured using the ferrous oxidation with xylenol orange (FOX) assay. The susceptibility of LDL to oxidation was assessed by the copper-catalysed lag phase of LDL oxidation. Neutrophil O2−generating capacity was assessed by a lucigenin-based chemiluminescent assay of NADPH oxidase activity. Body composition was assessed using bioelectrical impedance analysis. results Compared to controls, GHD subjects had higher LDL cholesterol (4·0 ± 0·8 vs. 3·5 ± 0·9 mmol/l, P

OBJECTIVES Hypopituitary adults with growth hormone deficiency (GHD) have an increased cardiovascular mortality, although the mechanisms remain unclear. Endothelial dysfunction, characterized by reduced nitric oxide (NO) bioavailability, is a key early event in atherogenesis and is associated with increased vascular smooth muscle tone and arterial stiffening. DESIGN AND PATIENTS In a randomized, double-blind, placebo-controlled study, we investigated the effects of GH replacement on endothelial function and large-artery stiffness in 32 GHD adults (19 males, 13 females) (age range 19-64 years) over a 6-month period. Thirty-two age- and sex-matched healthy controls were also studied. MEASUREMENTS Endothelial function was assessed using ultrasonic wall tracking to measure flow-mediated dilatation (FMD) of the brachial artery. Large artery stiffness was assessed by pulse wave analysis of the radial artery pressure waveform, allowing determination of the corresponding central arterial pressure waveform and derivation of the augmentation index. Fasting lipid profiles, glucose and insulin were also measured. RESULTS At baseline, FMD (mean +/- SD) was impaired in GH-deficient subjects vs. controls (3.4 +/- 2.3 vs. 5.7 +/- 2.0%, P < 0.0001), although endothelium-independent dilatation was similar. The augmentation index was higher in GH-deficient subjects vs. controls (23 +/- 12 vs. 14 +/- 14%, P < 0.01). GH-deficient subjects had higher LDL cholesterol (4.1 +/- 0.8 vs. 3.5 +/- 0.8 mmol/l, P < 0.01) and lower HDL cholesterol (1.1 +/- 0.3 vs. 1.4 +/- 0.4 mmol/l, P < 0.01). In GH-deficient subjects, there were inverse correlations between LDL cholesterol and FMD (r = -0.40, P < 0.05) and between FMD and the augmentation index (r = - 0.58, P < 0.01). Regression analysis identified FMD as an independent predictor of the augmentation index (P < 0.0001). In comparison with baseline, GH replacement resulted in an increase in FMD (5.0 +/- 2.6 vs. 2.8 +/- 1.9%, P < 0.01). There were decreases in central aortic systolic pressure (117 +/- 15 vs. 123 +/- 17 mmHg, P < 0.01), diastolic pressure (82 +/- 10 vs. 86 +/- 8 mmHg, P < 0.01) and the augmentation index (22 +/- 8% vs. 26 +/- 10%, P < 0.05) despite unchanged brachial pressure indices. LDL cholesterol also decreased (3.5 +/- 0.8 vs. 4.2 +/- 0.8 mmol/l, P < 0.01). There were no significant changes in the placebo group. CONCLUSIONS Adult GHD is associated with endothelial dysfunction and increased large-artery stiffness. An improvement in endothelial function and a reduction in arterial stiffness following GH replacement suggests an important therapeutic role for GH in reducing cardiovascular risk associated with adult GHD.

HILL, D. W., D. C. POOLE, and J. C. SMITH. The relationship between power and the time to achieve VO2max. Med. Sci. Sports Exerc., Vol. 34, No. 4, pp. 709–714, 2002.PurposeThe severe exercise intensity domain may be defined as that range of work rates over which VO2max can be elicited during const

Many wind integration studies have been performed in recent years, with evolving methodologies. Since power systems and data availability vary significantly, the results and methodologies used in these studies have varied accordingly. This paper presents the main findings from the IEA WIND Recommended Practices for Wind Integration studies. An overview of a complete wind integration study is presented as a flow chart. The main simulation steps are presented with recommendations on methodologies: an increase in reserve requirements, estimating impacts on other generation and balancing, capacity value of wind power and transmission expansion due to wind power. The study set-up and the main assumptions are outlined, as they can have a critical impact on the results. The recommendations are applicable for other variable renewable sources, including photovoltaics.

Sex hormones appear to play a pivotal role in determining cardiovascular risk. Androgen deprivation therapy for males with prostate cancer results in a hypogonadal state that may have important, but as yet undetermined, effects on the vasculature. We studied the effects of androgen deprivation therapy on large artery stiffness in 22 prostate cancer patients (mean age, 67 +/- 8 yr) over a 6-month period. Arterial stiffness was assessed using pulse-wave analysis, a technique that measures peripheral arterial pressure waveforms and generates corresponding central aortic waveforms. This allows determination of the augmentation of central pressure resulting from wave reflection and the augmentation index, a measure of large artery stiffness. Body compositional changes were assessed using bioelectrical impedance analysis. Fasting lipids, glucose, insulin, testosterone, and estradiol were measured. After a 3-month treatment period, the augmentation index increased from 24 +/- 6% (mean +/- SD) at baseline to 29 +/- 9% (P = 0.003) despite no change in peripheral blood pressure. Timing of wave reflection was reduced from 137 +/- 7 to 129 +/- 10 msec (P = 0.003). Fat mass increased from 20.2 +/- 9.4 to 21.9 +/- 9.6 kg (P = 0.008), whereas lean body mass decreased from 63.2 +/- 6.8 to 61.5 +/- 6.0 kg (P = 0.016). There were no changes in lipids or glucose during treatment. Median serum insulin rose from 11.8 (range, 5.6-49.1) to 15.1 (range, 7.3-83.2) mU/liter at 1 month (P = 0.021) and to 19.3 (range, 0-85.0 mU/liter by 3 months (P = 0.020). There was a correlation between the changes in fat mass and insulin concentration over the 3-month period (r = 0.56; P = 0.013). In a subgroup of patients whose treatment was discontinued after 3 months, the augmentation index decreased from 31 +/- 7% at 3 months to 29 +/- 5% by 6 months, in contrast to patients receiving continuing treatment in whom the augmentation index remained elevated at 6 months compared with baseline (P = 0.043). These data indicate that induced hypogonadism in males with prostate cancer results in a rise in the augmentation of central arterial pressure, suggesting large artery stiffening. Adverse body compositional changes associated with rising insulin concentrations suggest reduced insulin sensitivity. These adverse hemodynamic and metabolic effects may increase cardiovascular risk in this patient group.