Chemical genetic identification of CDKL5 substrates reveals its role in neuronal microtubule dynamics.

Loss-of-function mutations in CDKL5 kinase cause severe neurodevelopmental delay and early-onset seizures. Identification of CDKL5 substrates is key to understanding its function. Using chemical genetics, we found that CDKL5 phosphorylates three microtubule-associated proteins: MAP1S, EB2 and ARHGEF2, and determined the phosphorylation sites. Substrate phosphorylations are greatly reduced in CDKL5 knockout mice, verifying these as physiological substrates. In CDKL5 knockout mouse neurons, dendritic microtubules have longer EB3-labelled plus-end growth duration and these altered dynamics are rescued by reduction of MAP1S levels through shRNA expression, indicating that CDKL5 regulates microtubule dynamics via phosphorylation of MAP1S. We show that phosphorylation by CDKL5 is required for MAP1S dissociation from microtubules. Additionally, anterograde cargo trafficking is compromised in CDKL5 knockout mouse dendrites. Finally, EB2 phosphorylation is reduced in patient-derived human neurons. Our results reveal a novel activity-dependent molecular pathway in dendritic microtubule regulation and suggest a pathological mechanism which may contribute to CDKL5 deficiency disorder

Understanding Harris' understanding of CEA: is cost effective resource allocation undone?

We summarise and evaluate Harris' criticisms of cost-effectiveness analysis (CEA) and the alternative processes he commends to health care decision makers. In contrast to CEA, Harris' asserts that individuals have a right to life-saving treatment that cannot be denied on the basis of their capacity to benefit. We conclude that, whilst Harris' work has challenged the proponents of CEA and quality-adjusted life years to be explicit about the method's indirect discriminatory characteristics, his arguments ignore important questions about what ‘lives saved’ mean. Harris also attempts to avoid opportunity cost by advocating the same chance of treatment for every person desiring treatment. Using a simple example, we illustrate that an ‘equal chances’ lottery is not in the interest of any patient, as it reduces the chance of treatment for all patients by leaving some of the health budget unspent

Codesigned Shared Decision-Making Diabetes Management Plan Tool for Adolescents With Type 1 Diabetes Mellitus and Their Parents: Prototype Development and Pilot Test

Background: Adolescents with type 1 diabetes mellitus have difficulty achieving optimal glycemic control, partly due to competing priorities that interfere with diabetes self-care. Often, significant diabetes-related family conflict occurs, and adolescents’ thoughts and feelings about diabetes management may be disregarded. Patient-centered diabetes outcomes may be better when adolescents feel engaged in the decision-making process. Objective: The objective of our study was to codesign a clinic intervention using shared decision making for addressing diabetes self-care with an adolescent patient and parent advisory board. Methods: The patient and parent advisory board consisted of 6 adolescents (teens) between the ages 12 and 18 years with type 1 diabetes mellitus and their parents recruited through our institution’s Pediatric Diabetes Program. Teens and parents provided informed consent and participated in 1 or both of 2 patient and parent advisory board sessions, lasting 3 to 4 hours each. Session 1 topics were (1) patient-centered outcomes related to quality of life, parent-teen shared diabetes management, and shared family experiences; and (2) implementation and acceptability of a patient-centered diabetes care plan intervention where shared decision making was used. We analyzed audio recordings, notes, and other materials to identify and extract ideas relevant to the development of a patient-centered diabetes management plan. These data were visually coded into similar themes. We used the information to develop a prototype for a diabetes management plan tool that we pilot tested during session 2. Results: Session 1 identified 6 principal patient-centered quality-of-life measurement domains: stress, fear and worry, mealtime struggles, assumptions and judgments, feeling abnormal, and conflict. We determined 2 objectives to be principally important for a diabetes management plan intervention: (1) focusing the intervention on diabetes distress and conflict resolution strategies, and (2) working toward a verbalized common goal. In session 2, we created the diabetes management plan tool according to these findings and will use it in a clinical trial with the aim of assisting with patient-centered goal setting. Conclusions: Patients with type 1 diabetes mellitus can be effectively engaged and involved in patient-centered research design. Teens with type 1 diabetes mellitus prioritize reducing family conflict and fitting into their social milieu over health outcomes at this time in their lives. It is important to acknowledge this when designing interventions to improve health outcomes in teens with type 1 diabetes mellitus

Managing structural uncertainty in health economic decision models: a discrepancy approach

Healthcare resource allocation decisions are commonly informed by computer model predictions of population mean costs and health effects. It is common to quantify the uncertainty in the prediction due to uncertain model inputs, but methods for quantifying uncertainty due to inadequacies in model structure are less well developed. We introduce an example of a model that aims to predict the costs and health effects of a physical activity promoting intervention. Our goal is to develop a framework in which we can manage our uncertainty about the costs and health effects due to deficiencies in the model structure. We describe the concept of `model discrepancy': the difference between the model evaluated at its true inputs, and the true costs and health effects. We then propose a method for quantifying discrepancy based on decomposing the cost-effectiveness model into a series of sub-functions, and considering potential error at each sub-function. We use a variance based sensitivity analysis to locate important sources of discrepancy within the model in order to guide model refinement. The resulting improved model is judged to contain less structural error, and the distribution on the model output better reflects our true uncertainty about the costs and effects of the intervention

Searching for a threshold, not setting one: The role of the National Institute for Health and Clinical Excellence

There has been much speculation about whether the National Institute for Health and Clinical Excellence (NICE) has, or ought to have, a'threshold' figure for the cost of an additional quality-adjusted life-year above which a technology will not be recommended for use. We argue that it is not constitutionally appropriate for NICE to set such a threshold, which is properly the business of parliament. Instead, the task for NICE is as a 'threshold-searcher' - to seek to identify an optimal threshold incremental cost-effectiveness ratio, at the ruling rate of expenditure, that is consistent with the aim of the health service to maximize population health. This will involve the identification of technologies currently made available by the National Health Service that have incremental cost-effectiveness ratios above the threshold, and alternative uses for those resources in the shape of technologies not currently provided that fall below the threshol

Technology teacher education requirements

What is the role of teacher education in preparing and supporting teachers of technology education? Before student teachers can even consider teaching technology education, they need an overarching, holistic view of the purpose of technology education in the curriculum, as well as what technology is and how it impacts and influences our world, people, and environment. They also need to understand the role content, pedagogical, and pedagogical content knowledge (PCK) play in developing quality technology education teachers. Teacher education occurs at two levels, one in initial teacher education (ITE) programs where students are taught the fundamentals of teaching technology at early childhood, primary, or secondary school level. The second is in-service teacher education, targeted at practicing teachers, aimed at keeping them abreast with changes and contemporary understandings of teaching and learning. This entry’s main focus is the ITE and is based on the premise that student teachers come to technology classes in ITE programs with wide-ranging understandings of technology and little knowledge about pedagogical practices. In their development of the Pre-service Technology Teacher Education Resource (PTTER) framework, Forret et al. (2013) identified four cornerstones for quality technology teacher education. These are that to teach technology successfully, teachers need to understand the philosophy of technology, have a strong rationale for teaching technology, understand the underpinning ideas of the technology curriculum, and plan and implement it using sound pedagogical practices. This entry is structured around these four cornerstones. Throughout this entry, technology education refers to the school curriculum learning area of design and technology. Teachers teach technology either in early childhood centers, primary schools, or as specialist teachers of technology in intermediate or secondary schools, including junior and senior levels

Muonium as a hydrogen analogue in silicon and germanium; quantum effects and hyperfine parameters

We report a first-principles theoretical study of hyperfine interactions, zero-point effects and defect energetics of muonium and hydrogen impurities in silicon and germanium. The spin-polarized density functional method is used, with the crystalline orbitals expanded in all-electron Gaussian basis sets. The behaviour of hydrogen and muonium impurities at both the tetrahedral and bond-centred sites is investigated within a supercell approximation. To describe the zero-point motion of the impurities, a double adiabatic approximation is employed in which the electron, muon/proton and host lattice degrees of freedom are decoupled. Within this approximation the relaxation of the atoms of the host lattice may differ for the muon and proton, although in practice the difference is found to be slight. With the inclusion of zero-point motion the tetrahedral site is energetically preferred over the bond-centred site in both silicon and germanium. The hyperfine and superhyperfine parameters, calculated as averages over the motion of the muon, agree reasonably well with the available data from muon spin resonance experiments.Comment: 20 pages, including 9 figures. To appear in Phys. Rev.