Outcomes in pediatric studies of medium-chain acyl-coA dehydrogenase (MCAD) deficiency and phenylketonuria (PKU): a review.

BACKGROUND: Inherited metabolic diseases (IMDs) are a group of individually rare single-gene diseases. For many IMDs, there is a paucity of high-quality evidence that evaluates the effectiveness of clinical interventions. Clinical effectiveness trials of IMD interventions could be supported through the development of core outcome sets (COSs), a recommended minimum set of standardized, high-quality outcomes and associated outcome measurement instruments to be incorporated by all trials in an area of study. We began the process of establishing pediatric COSs for two IMDs, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency and phenylketonuria (PKU), by reviewing published literature to describe outcomes reported by authors, identify heterogeneity in outcomes across studies, and assemble a candidate list of outcomes. METHODS: We used a comprehensive search strategy to identify primary studies and guidelines relevant to children with MCAD deficiency and PKU, extracting study characteristics and outcome information from eligible studies including outcome measurement instruments for select outcomes. Informed by an established framework and a previously published pediatric COS, outcomes were grouped into five, mutually-exclusive, a priori core areas: growth and development, life impact, pathophysiological manifestations, resource use, and death. RESULTS: For MCAD deficiency, we identified 83 outcomes from 52 articles. The most frequently represented core area was pathophysiological manifestations, with 33 outcomes reported in 29/52 articles (56%). Death was the most frequently reported outcome. One-third of outcomes were reported by a single study. The most diversely measured outcome was cognition and intelligence/IQ for which eight unique measurement instruments were reported among 14 articles. For PKU, we identified 97 outcomes from 343 articles. The most frequently represented core area was pathophysiological manifestations with 31 outcomes reported in 281/343 articles (82%). Phenylalanine concentration was the most frequently reported outcome. Sixteen percent of outcomes were reported by a single study. Similar to MCAD deficiency, the most diversely measured PKU outcome was cognition and intelligence/IQ with 39 different instruments reported among 82 articles. CONCLUSIONS: Heterogeneity of reported outcomes and outcome measurement instruments across published studies for both MCAD deficiency and PKU highlights the need for COSs for these diseases, to promote the use of meaningful outcomes and facilitate comparisons across studies

Abstracts from the NIHR INVOLVE Conference 2017

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The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Minimal information for studies of extracellular vesicles 2018 (MISEV2018):a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The Effects of Temperature on Electrical Resistivity Measurements of Concrete

Measuring resistivity as a method to calculate formation factor is becoming a popular way to evaluate transport properties of concrete. Resistivity measurements are dependent on multiple factors including the resistivity of the pore solution, leaching effects, the degree of saturation of the specimen, the age of the specimen (degree of reaction), the microstructural properties of the pore network (porosity and pore connectivity), and temperature. Temperature affects the bulk resistivity measurements of concrete specimens by changing the mobility of the ions in the pore solution. In addition to multiple fitting equations and temperature corrections, numerous values for temperature correction parameters have been proposed for a wide range of materials (i.e., solutions, pastes, mortars, and concretes at different degrees of saturation). In this study, a linear approach (using an α temperature coefficient) and an activation energy type approach (using an Ea-cond temperature coefficient) are examined. These approaches were compared with each other numerically and their predictive capabilities were studied using measured resistivity data from several concrete mixtures. An equation is developed to convert a linear correction (α) to an activation energy type correction, (Ea-cond), given the testing temperature. Using a linear approach might be suitable for solutions and for saturated concrete, which have low values of α and Ea-cond. However, the use of Ea-cond provides better predictive capabilities in sealed concretes, which have higher values of α and Ea-cond, especially at low temperatures. An analysis of literature reveals that Ea-cond values vary from 9 to 39 kJ/mol, for pore solutions, pastes, mortars and concretes with a variety of saturation states. In order to select an appropriate Ea-cond for a specific specimen type, it is important to understand the factors affecting Ea-cond of cementitious materials. Ea-cond increases as degree of saturation of the specimen is reduced with a minimum Ea-cond when the specimen is saturated. This is not due to the dilution of the pore solution, as pore solutions with different ionic strengths have similar Ea-cond. Rather, the increase of Ea-cond upon drying is because of a change in the connectivity of the fluid filled pores. Under certain circumstances, changes in ionic mobility caused by changes in viscosity, may also affect Ea-cond. While it is better to directly measure the Ea-cond of every concrete mixture, this is not always feasible. In such cases, for pore solutions a value of 13.9 kJ/mol can be used, for saturated concretes a value of 15.8 kJ/mol can be used and for sealed concretes a value of 29.8 kJ/mol can be used. For concretes with a varying degree of saturation, the Ea-cond can be estimated if the degree of saturation (DOS) is known using the equation: Ea-cond = 33.3 – 16.3∙DOS

Activation Energy of Conduction for Use in Temperature Corrections on Electrical Measurements of Concrete

The formation factor obtained through electrical resistivity measurements is becoming a popular method to determine transport properties of concrete. Resistivity measurements are dependent on multiple factors, including degree of saturation, pore solution conductivity, and temperature. The Arrhenius equation is used to correct electrical resistivity for temperature effects using an activation energy of conduction (Ea-cond). This parameter has been measured on a wide variety of materials, including pore solutions, pastes, mortars, and concretes (with a variety of saturation states). The reported values of Ea-cond typically range from 9 to 39 kJ/mol. This article examines the factors affecting Ea-cond in order to select an appropriate temperature correction. In this study, Ea-cond was determined from data measured on various concrete mixtures used in transportation infrastructure applications as well as extracted and simulated pore solutions. The Ea-cond of pore solutions remains relatively constant (an average value of 13.9 ± 1.5 kJ/mol) for typical pore solutions and was slightly lower than the Ea-cond of saturated specimens (an average value of 15.8 kJ/mol). It was found that Ea-cond increases as the degree of saturation of the specimen is reduced. Drying increases the ionic concentration of the fluid in the pores; however, this does not explain the changes in Ea-cond. The effects of drying were determined to be primarily due to a change in the volume of the conductive fluid film in the concrete and in the connectivity of the fluid-filled pores. While it is better to directly measure the Ea-cond of a concrete mixture, this is not always feasible or practical. In such cases, for pore solutions, a value of 13.9 kJ/mol can be used, and for saturated concretes, a value of 15.8 kJ/mol can be used. For concretes with a varying degree of saturation, the Ea-cond can be estimated using the developed equation

Engineered Tissue Folding by Mechanical Compaction of the Mesenchyme.

Many tissues fold into complex shapes during development. Controlling this process in vitro would represent an important advance for tissue engineering. We use embryonic tissue explants, finite element modeling, and 3D cell-patterning techniques to show that mechanical compaction of the extracellular matrix during mesenchymal condensation is sufficient to drive tissue folding along programmed trajectories. The process requires cell contractility, generates strains at tissue interfaces, and causes patterns of collagen alignment around and between condensates. Aligned collagen fibers support elevated tensions that promote the folding of interfaces along paths that can be predicted by modeling. We demonstrate the robustness and versatility of this strategy for sculpting tissue interfaces by directing the morphogenesis of a variety of folded tissue forms from patterns of mesenchymal condensates. These studies provide insight into the active mechanical properties of the embryonic mesenchyme and establish engineering strategies for more robustly directing tissue morphogenesis ex vivo