Diseño Flexible como Oportunidad de Adquisición

Navies around the world adopt different ways of acquiring ships. Using a single large prime contractor, placing individual contracts for design, build and integration, or employing a state-owned shipyard with external support are all procurement options that we see today.‘Flexibility’ in warship design is normally perceived as provision of extra empty space, weight and power, which could be filled with new equipment at some point in the future. However, this idea can be extended to describe a design that achieves true flexibility by exploiting the synergy with different acquisition strategies, adaptability allowing a choice of balanced capability and options for incremental acquisition to control cost and risk profiles. This leads to a design that will deliver a class of warships able to meet the evolving roles and threats throughout its life, whilst not introducing additional risk and cost into the programmes of any modern Navy around the world which adopts it.To achieve this flexibility BMT have created a single base design with multiple configurations; a warship with a functional arrangement that is able to be tailored to meet the specific requirements and budget of each Navy, minimising the initial cost penalty in a programme, and maximising commonality. It also allows for modular construction techniques which not only apply to single yard construction, including small and medium shipyards, but enables blocks to be built in several shipyards.This paper will describe the underlying considerations behind this flexibility, including incremental acquisition as a cost mitigation in procurement programmes, and the different potential partnership models between shipyard, designer and integrator in effective acquisition programmes which work to the strengths of each party.Las armadas nacionales alrededor del mundo adoptan diferentes maneras de adquirir barcos. El uso de un solo contratista principal de gran tamaño, la asignación de contratos individuales para el diseño, la construcción y la integración, o el empleo de un astillero de propiedad estatal con apoyo externo son todas opciones de adquisición que vemos hoy en día.La "flexibilidad" en el diseño de buques de guerra se percibe normalmente como la provisión de espacios vacíos, peso y potencia adicionales, que podrían ser utilizados con nuevo equipo en algún momento en el futuro. Sin embargo, esta idea puede ampliarse con el fin describir un diseño que logre una verdadera flexibilidad  al explotar la sinergia entre diferentes estrategias de adquisición y adaptabilidad permitiendo la posibilidad de una capacidad equilibrada y opciones para la adquisición incremental con el fin de controlar los perfiles de costos y riesgos. Esto conduce a un diseño que ofrecerá un tipo de buques de guerra capaces de cumplir con los cambiantes roles y amenazas a lo largo de su vida útil, sin generar riesgos y costos adicionales en los programas de cualquier Marina moderna alrededor del mundo que los adopte.Con el fin lograr esta flexibilidad, BMT ha creado un diseño de base única con múltiples configuraciones; un buque de guerra con un arreglo funcional que puede ser adaptado para cumplir con los requisitos específicos y el presupuesto de cada Armada, minimizando la penalización del costo inicial en un programa y maximizando la homogeneidad. También permite las técnicas de construcción modular que no sólo se aplican a la construcción de astilleros únicos, incluidos los astilleros pequeños y medianos, sino que permite la construcción de bloques en varios astilleros.Este documento describirá las consideraciones subyacentes detrás de esta flexibilidad, incluyendo la adquisición incremental como una forma de mitigar costos en los programas de adquisición y los diferentes modelos potenciales de asociación entre astillero, diseñador e integrador en programas efectivos de adquisición que trabajen enfocándose en las fortalezas de cada parte

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Flexible Design as an Acquisition Opportunity

Navies around the world adopt different ways of acquiring ships. Using a single large prime contractor, placing individual contracts for design, build and integration, or employing a state-owned shipyard with external support are all procurement options that we see today.‘Flexibility’ in warship design is normally perceived as provision of extra empty space, weight and power, which could be filled with new equipment at some point in the future. However, this idea can be extended to describe a design that achieves true flexibility by exploiting the synergy with different acquisition strategies, adaptability allowing a choice of balanced capability and options for incremental acquisition to control cost and risk profiles. This leads to a design that will deliver a class of warships able to meet the evolving roles and threats throughout its life, whilst not introducing additional risk and cost into the programmes of any modern Navy around the world which adopts it.To achieve this flexibility BMT have created a single base design with multiple configurations; a warship with a functional arrangement that is able to be tailored to meet the specific requirements and budget of each Navy, minimising the initial cost penalty in a programme, and maximising commonality. It also allows for modular construction techniques which not only apply to single yard construction, including small and medium shipyards, but enables blocks to be built in several shipyards.This paper will describe the underlying considerations behind this flexibility, including incremental acquisition as a cost mitigation in procurement programmes, and the different potential partnership models between shipyard, designer and integrator in effective acquisition programmes which work to the strengths of each party.Las armadas nacionales alrededor del mundo adoptan diferentes maneras de adquirir barcos. El uso de un solo contratista principal de gran tamaño, la asignación de contratos individuales para el diseño, la construcción y la integración, o el empleo de un astillero de propiedad estatal con apoyo externo son todas opciones de adquisición que vemos hoy en día.La "flexibilidad" en el diseño de buques de guerra se percibe normalmente como la provisión de espacios vacíos, peso y potencia adicionales, que podrían ser utilizados con nuevo equipo en algún momento en el futuro. Sin embargo, esta idea puede ampliarse con el fin describir un diseño que logre una verdadera flexibilidad  al explotar la sinergia entre diferentes estrategias de adquisición y adaptabilidad permitiendo la posibilidad de una capacidad equilibrada y opciones para la adquisición incremental con el fin de controlar los perfiles de costos y riesgos. Esto conduce a un diseño que ofrecerá un tipo de buques de guerra capaces de cumplir con los cambiantes roles y amenazas a lo largo de su vida útil, sin generar riesgos y costos adicionales en los programas de cualquier Marina moderna alrededor del mundo que los adopte.Con el fin lograr esta flexibilidad, BMT ha creado un diseño de base única con múltiples configuraciones; un buque de guerra con un arreglo funcional que puede ser adaptado para cumplir con los requisitos específicos y el presupuesto de cada Armada, minimizando la penalización del costo inicial en un programa y maximizando la homogeneidad. También permite las técnicas de construcción modular que no sólo se aplican a la construcción de astilleros únicos, incluidos los astilleros pequeños y medianos, sino que permite la construcción de bloques en varios astilleros.Este documento describirá las consideraciones subyacentes detrás de esta flexibilidad, incluyendo la adquisición incremental como una forma de mitigar costos en los programas de adquisición y los diferentes modelos potenciales de asociación entre astillero, diseñador e integrador en programas efectivos de adquisición que trabajen enfocándose en las fortalezas de cada parte

Preparation for commissioning of materials detritiation facility at Culham Science Centre

The Materials Detritiation Facility has been designed to thermally treat solid non-combustible radioactive waste produced during operations of the Joint European Torus (JET) that is classified as Intermediate Level Waste in the UK due to its tritium inventory (> 12 kBq/g). The waste will be thermally treated in a retort furnace at temperatures up to 1000 degrees C under a flowing air atmosphere to reduce its tritium inventory sufficiently to allow its disposal at a lower waste category via existing disposal routes. The gaseous flow from the furnace will be processed via a bubbler system, where released tritium will be trapped in water. Commissioning of the facility will be divided into two main parts: inactive and active. The main purpose of the inactive commissioning is to verify that all components and safety systems of the facility are installed, tested and operated properly and within their operational limits. Several trials of the furnace with non-radioactive materials will be performed to verify its temperature profile, and to verify operation of the gaseous process line. During the active commissioning, small amounts of tritium-contaminated material will be introduced into the facility and used for active trials. The tritium inventory in this material has been selected based on the As low as reasonably practicable (ALARP) principle, to ensure that the activity levels are sufficient to fully test the control instrumentation and pose minimal risk to operators during commissioning. Overall, four active trials will be performed with carbon-based and Inconel materials with total tritium inventories of 1MBq, 3GBq, 20GBq and 26GBq. Tritium levels in the bubblers as well as in aerial discharge from the facility will be monitored. Furthermore, all materials used in the active trials will be sampled and analyzed to verify the performance of the process and confirm that a major part of tritium inventory can be removed from materials by the process

Global COVID-19 lockdown highlights humans as both threats and custodians of the environment

The global lockdown to mitigate COVID-19 pandemic health risks has altered human interactions with nature. Here, we report immediate impacts of changes in human activities on wildlife and environmental threats during the early lockdown months of 2020, based on 877 qualitative reports and 332 quantitative assessments from 89 different studies. Hundreds of reports of unusual species observations from around the world suggest that animals quickly responded to the reductions in human presence. However, negative effects of lockdown on conservation also emerged, as confinement resulted in some park officials being unable to perform conservation, restoration and enforcement tasks, resulting in local increases in illegal activities such as hunting. Overall, there is a complex mixture of positive and negative effects of the pandemic lockdown on nature, all of which have the potential to lead to cascading responses which in turn impact wildlife and nature conservation. While the net effect of the lockdown will need to be assessed over years as data becomes available and persistent effects emerge, immediate responses were detected across the world. Thus initial qualitative and quantitative data arising from this serendipitous global quasi-experimental perturbation highlights the dual role that humans play in threatening and protecting species and ecosystems. Pathways to favorably tilt this delicate balance include reducing impacts and increasing conservation effectiveness