A new mouse model of ATR-X syndrome carrying a common patient mutation exhibits neurological and morphological defects.

ATRX is a chromatin remodelling ATPase that is involved in transcriptional regulation, DNA damage repair and heterochromatin maintenance. It has been widely studied for its role in ALT-positive cancers, but its role in neurological function remains elusive. Hypomorphic mutations in the X-linked ATRX gene cause a rare form of intellectual disability combined with alpha-thalassemia called ATR-X syndrome in hemizygous males. Clinical features also include facial dysmorphism, microcephaly, short stature, musculoskeletal defects and genital abnormalities. As complete deletion of ATRX in mice results in early embryonic lethality, the field has largely relied on conditional knockout models to assess the role of ATRX in multiple tissues. Given that null alleles are not found in patients, a more patient-relevant model was needed. Here, we have produced and characterized the first patient mutation knock-in model of ATR-X syndrome, carrying the most common causative mutation, R246C. This is one of a cluster of missense mutations located in the chromatin-binding domain and disrupts its function. The knock-in mice recapitulate several aspects of the patient disorder, including craniofacial defects, microcephaly, reduced body size and impaired neurological function. They provide a powerful model for understanding the molecular mechanisms underlying ATR-X syndrome and testing potential therapeutic strategies.

Indian immigrants' constructions of mental health and mental illness in the perinatal period: A qualitative study.

AIM: The aim of this study is to explore how immigrant women and men from India construct mental health and mental illness in the perinatal period. DESIGN: Qualitative interpretive design. METHODS: Data were collected by conducting in-depth interviews with 19 participants. Photo elicitation, free listing and pile sorting were used during the interviews. Purposive sampling was used, and data were collected in 2018 and 2019. Data were analysed using thematic analysis. FINDING/RESULTS: One major theme and three subthemes were identified. 'We do not talk about it' was the major theme and the subthemes: (1) 'living peacefully and feeling happy' described the views on mental health; (2) 'that's the elephant in the room still' captures how participants felt when talking about mental illness; and (3) 'why don't we talk about it' offers reasons why the Indian community does not talk about mental health and illness. CONCLUSION: The findings of this study have highlighted the importance of understanding the impact of immigration and being culturally sensitive when assessing mental health in the perinatal period. IMPACT: The findings of this study identify some of the reasons for non-disclosure of mental health issues by immigrants. Incorporating these findings during psychosocial assessment by health professionals in the perinatal period will help translate the cultural aspects into more effective communication. PATIENT OR PUBLIC CONTRIBUTION: Patient and public contribution to the study was provided by the Community Stakeholders Group; these were members of the immigrant community from India who had expertise in mental health. They contributed to the study design and the key terms and phrases for the free list used in interviews.

Suppressor mutations in Mecp2-null mice implicate the DNA damage response in Rett syndrome pathology.

Mutations in X-linked methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome (RTT). To identify functional pathways that could inform therapeutic entry points, we carried out a genetic screen for secondary mutations that improved phenotypes in Mecp2/Y mice after mutagenesis with N-ethyl-N-nitrosourea (ENU). Here, we report the isolation of 106 founder animals that show suppression of Mecp2-null traits from screening 3177 Mecp2/Y genomes. Whole-exome sequencing, genetic crosses, and association analysis identified 22 candidate genes. Additional lesions in these candidate genes or pathway components associate variant alleles with phenotypic improvement in 30 lines. A network analysis shows that 63% of the genes cluster into the functional categories of transcriptional repression, chromatin modification, or DNA repair, delineating a pathway relationship with MECP2. Many mutations lie in genes that modulate synaptic signaling or lipid homeostasis. Mutations in genes that function in the DNA damage response (DDR) also improve phenotypes in Mecp2/Y mice. Association analysis was successful in resolving combinatorial effects of multiple loci. One line, which carries a suppressor mutation in a gene required for cholesterol synthesis, Sqle, carries a second mutation in retinoblastoma binding protein 8, endonuclease (Rbbp8, also known as CtIP), which regulates a DDR choice in double-stranded break (DSB) repair. Cells from Mecp2/Y mice have increased DSBs, so this finding suggests that the balance between homology-directed repair and nonhomologous end joining is important for neuronal cells. In this and other lines, two suppressor mutations confer greater improvement than one alone, suggesting that combination therapies could be effective in RTT.

Evaluation of the Patient with Nasal Obstruction.

Patients often present with a complaint of nasal blockage, either primarily, or in conjunction with aesthetic concerns. The evaluation of the patient with nasal obstruction involves a comprehensive history and a detailed physical examination. The nose is an organ in which form and function are inseparable, and as such, examination of the patient with nasal obstruction must focus not only the internal structures that may cause obstruction of the nasal airway, but also the external structure of the nose as it impacts nasal breathing. Detailed facial analysis and a systematic nasal examination will reveal details regarding nasal obstruction due to internal sources such as septal deviation, turbinate hypertrophy, or nasal lining abnormalities, and structural abnormalities such as nasal valve collapse or external nasal deformity. This approach, in categorizing each component of the nasal exam and its findings, allows the surgeon to formulate an appropriate treatment plan that emerges from the details of the examination.

The experiences of new graduate nurses working in a pediatric setting: A qualitative systematic review.

OBJECTIVE: To synthesize the literature regarding the experiences of new graduate nurses working in a pediatric setting. BACKGROUND: The transition experiences of new graduate nurses can be stressful and challenging. Pediatric settings may cause additional stress due to the unique nature of children's nursing and its' environment. INCLUSION CRITERIA: Qualitative studies of any design and qualitative components of mixed method studies that explored the experiences of new graduate nurses in a pediatric setting were included in this review: neonatal intensive care units and special care nurseries were excluded. METHODS: The JBI meta-aggregation approach for synthesizing qualitative data was followed. Databases searched were CINAHL, MEDLINE (Ovid), APA PsycInfo, Scopus, PubMed Central, ERIC, and ProQuest Dissertations and Theses. Studies published between January 2000 and January 2022 inclusive were considered. RESULTS: 2229 records were screened, and nine studies selected. From the nine studies 203 findings were included, resulting in 19 categories and five synthesized findings. The synthesized findings related to support, developing identity and role transition, working conditions and environment, fear and uncertainty, and career and goal planning. CONCLUSIONS: New graduates in a pediatric setting required support that took account of their development needs with consistent preceptorship. Being considered part of a team and the support of other team members were important in developing identity as a new graduate nurse in a pediatric setting. Working conditions for the new graduate needed to be safe, and new graduates also felt fearful and uncertain when it came to their new accountability and responsibilities.

A Cross-sectional Survey of Enteral Feeding Tube Placement and Gastric Residual Aspiration Practices: Need for an Evidence-Based Clinical Practice Guideline.

BACKGROUND: Preterm infants routinely require enteral feeding via nasogastric or orogastric tubes as an alternative to oral feeding to meet their nutritional needs. Anecdotal evidence suggests variations in practice related to correct tube placement and assessment of feed intolerance. PURPOSE: To determine the current practices of enteral feeding tube placement confirmation and gastric residual (GR) aspiration of neonatal clinicians in Australia. METHODS: A cross-sectional online survey comprising 24 questions was distributed to nursing and medical health professionals working in Australian neonatal care units through 2 e-mail listservs made available by professional organizations. FINDINGS: The survey was completed by 129 clinicians. A single method was practiced by 50% of the clinicians in confirming tube placement, and most common practice was assessing the pH of GR aspirate. The majority of respondents (96%) reported that they relied on GR aspiration and clinical signs to determine feeding tolerance and subsequent decisions such as ceasing or decreasing feeds. However, the frequency of aspiration, the amount and color of aspirate considered to be normal/abnormal, and decisions on whether to replace gastric aspirate or whether aspiration should be performed during continuous tube feeding varied. IMPLICATION FOR PRACTICE: This study demonstrated considerable variability in clinical practice for enteral feeding tube placement confirmation and GR aspiration despite most respondents reporting using a unit-based clinical practice guideline. Our study findings highlight the need for not only developing evidence-based practice guidelines for safe and consistent clinical practice but also ensuring that these guidelines are followed by all clinicians. IMPLICATION FOR RESEARCH: Further research is needed to establish evidence-based methods both for enteral feeding tube placement confirmation and for the assessment of feeding intolerance during tube feeding. In addition, the reasons why evidence-based methods are not followed must be investigated.

"The safety of sodium reduction in the food supply: A cross-discipline balancing act"-Workshop proceedings.

This workshop, jointly presented by the ILSI North America Technical Committees on Food Microbiology and Sodium, aimed to provide greater knowledge and appreciation of the opportunities and challenges facing the food industry in answering the public health community's call to reduce sodium levels in the food supply. One major challenge is finding effective substitutes for the various antimicrobial and functional roles that sodium plays across different food categories. Sodium plays a critical role in retarding the growth of pathogens and food spoilage bacteria. Moreover, taste is an important factor for consumers when they choose food products, and the flavor changes that occur when salt is reduced or replaced must be considered and ingredients and processes adjusted accordingly. The workshop provided a platform for a multidisciplinary discussion among the microbiology, food science, nutrition, and public health communities to share progress and propose solutions, including the formation of public-private partnerships, to develop coordinated and comprehensive strategies. This paper provides an overview of the issues raised, rather than a specific summary of workshop discussions. The Food and Drug Administration's Draft Guidance for Industry on voluntary sodium reduction and the 2015 US Dietary Guidelines for Americans were released subsequent to the workshop and are also discussed.

Topical anaesthesia for needle-related pain in newborn infants.

BACKGROUND: Hospitalised newborn neonates frequently undergo painful invasive procedures that involve penetration of the skin and other tissues by a needle. One intervention that can be used prior to a needle insertion procedure is application of a topical local anaesthetic. OBJECTIVES: To evaluate the efficacy and safety of topical anaesthetics such as amethocaine and EMLA in newborn term or preterm infants requiring an invasive procedure involving puncture of skin and other tissues with a needle. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase and CINAHL up to 15 May 2016; previous reviews including cross-references, abstracts, and conference proceedings. We contacted expert informants. We contacted authors directly to obtain additional data. We imposed no language restrictions. SELECTION CRITERIA: Randomised, quasi-randomised controlled trials, and cluster and cross-over randomised trials that compared the topical anaesthetics amethocaine and eutectic mixture of local anaesthetics (EMLA) in terms of anaesthetic efficacy and safety in newborn term or preterm infants requiring an invasive procedure involving puncture of skin and other tissues with a needle DATA COLLECTION AND ANALYSIS: From the reports of the clinical trials we extracted data regarding clinical outcomes including pain, number of infants with methaemoglobin level 5% and above, number of needle prick attempts prior to successful needle-related procedure, crying, time taken to complete the procedure, episodes of apnoea, episodes of bradycardia, episodes of oxygen desaturation, neurodevelopmental disability and other adverse events. MAIN RESULTS: Eight small randomised controlled trials met the inclusion criteria (n = 506). These studies compared either EMLA and placebo or amethocaine and placebo. No studies compared EMLA and amethocaine. We were unable to meta-analyse the outcome of pain due to differing outcome measures and methods of reporting. For EMLA, two individual studies reported a statistically significant reduction in pain compared to placebo during lumbar puncture and venepuncture. Three studies found no statistical difference between the groups during heel lancing. For amethocaine, three studies reported a statistically significant reduction in pain compared to placebo during venepuncture and one study reported a statistically significant reduction in pain compared to placebo during cannulation. One study reported no statistical difference between the two groups during intramuscular injection.One study reported no statistical difference between EMLA and the placebo group for successful venepuncture at first attempt. One study similarly reported no statistically significant difference between Amethocaine and the placebo group for successful cannulation at first attempt.Risk for local redness, swelling or blanching was significantly higher with EMLA (typical risk ratio (RR) 1.65, 95% confidence interval (CI) 1.24 to 2.19; typical risk difference (RD) 0.17, 95% CI 0.09 to 0.26; n = 272; number needed to treat for an additional harmful outcome (NNTH) 6, 95% CI 4 to 11; I2 = 92% indicating considerable heterogeneity) although not for amethocaine (typical RR 2.11, 95% CI 0.72 to 6.16; typical RD 0.05, 95% CI -0.02 to 0.11, n = 221). These local skin reactions for EMLA and amethocaine were reported as short-lasting. Two studies reported no methaemoglobinaemia with single application of EMLA. The quality of the evidence on outcomes assessed according to GRADE was low to moderate. AUTHORS' CONCLUSIONS: Overall, all the trials were small, and the effects of uncertain clinical significance. The evidence regarding the effectiveness or safety of the interventions studied is inadequate to support clinical recommendations. There has been no evaluation regarding any long-term effects of topical anaesthetics in newborn infants.High quality studies evaluating the efficacy and safety of topical anaesthetics such as amethocaine and EMLA for needle-related pain in newborn term or preterm infants are required. These studies should aim to determine efficacy of these topical anaesthetics and on homogenous groups of infants for gestational age. While there was no methaemoglobinaemia in the studies that reported methaemoglobin, the efficacy and safety of EMLA, especially in very preterm infants, and for repeated application, need to be further evaluated in future studies.

The process and challenges of obtaining and sustaining clinical placements for nursing and allied health students.

AIMS AND OBJECTIVES: To describe the process and challenges from a project that aimed to develop processes, source new placements and place students primarily in the discipline of nursing, but also occupational therapy, physiotherapy, podiatry, social work, and speech therapy. BACKGROUND: Clinical experience in health facilities is an essential element of health professional education, yet globally, there is a lack of clinical placements to meet demands. Educational providers are seeking placements in nontraditional facilities, yet little has been reported on the challenges in the process of procuring clinical placements. DESIGN: The project used a descriptive approach within a quality implementation framework. METHODS: The project was guided by the quality implementation framework that included four critical steps: considerations of the host setting, structuring the implementation, supporting the implementation and improving future applications. RESULTS: A total of 115 new student placements were finalised across six health disciplines, including elderly care, nongovernment organisations and general practice. Sixty-two nursing students were placed in the new placements during the project. Challenges included communication, the time-consuming nature of the process and 'gatekeeping' blocks to obtaining placements. Recommendations included the importance of personal interaction in developing and maintaining relationships, and the need for clear communication processes and documentation. Potential areas for research are also given. CONCLUSIONS: There is great potential for growth in establishing new placements outside the traditional placement facilities for nursing and allied health and for expanding already existing nonhospital placements. RELEVANCE TO CLINICAL PRACTICE: Clinical professional experiences are essential to any nursing or allied health programme. There is an increasing demand for, and global lack of, clinical placements for nursing and allied health students. The results provide nursing and allied health educators and managers a framework for planning clinical placement procurement, and assisting in decision-making and developing strategies and processes for practice.

National Estimates of Serum Total 25-Hydroxyvitamin D and Metabolite Concentrations Measured by Liquid Chromatography-Tandem Mass Spectrometry in the US Population during 2007-2010.

BACKGROUND: The 2007-2010 NHANES provides the first US nationally representative serum 25-hydroxyvitamin D [25(OH)D] concentrations measured by standardized liquid chromatography-tandem mass spectrometry. OBJECTIVE: We describe patterns for total 25(OH)D and individual metabolites in persons aged ≥1 y stratified by race-ethnicity and grouped by demographic, intake, physiologic, and lifestyle variables. METHODS: We measured 25-hydroxycholecalciferol [25(OH)D3], 25-hydroxyergocalciferol [25(OH)D2], and C3-epimer of 25(OH)D3 [C3-epi-25(OH)D3] in serum samples (n = 15,652) from the 2007-2010 cross-sectional NHANES [total 25(OH)D = 25(OH)D3 + 25(OH)D2]. RESULTS: Concentrations (median, detection rate) of 25(OH)D3 (63.6 nmol/L, 100%) and C3-epi-25(OH)D3 (3.40 nmol/L, 86%) were generally detectable; 25(OH)D2 was detectable in 19% of the population. Total 25(OH)D, 25(OH)D3, and C3-epi-25(OH)D3 displayed similar demographic patterns and were strongly correlated (Spearman's r > 0.70). Concentrations of 25(OH)D2 (90th percentile) were much higher in persons aged ≥60 y (17.3 nmol/L) than in younger age groups (≤4.88 nmol/L). We noted significant race-ethnicity differences in mean total 25(OH)D [non-Hispanic blacks (NHBs), Hispanics, and non-Hispanic whites (NHWs): 46.6, 57.2, and 75.2 nmol/L, respectively] and in the prevalence of total 25(OH)D <30 nmol/L overall (24% of NHBs, 6.4% of Hispanics, and 2.3% of NHWs) as well as stratified by season (winter months: 30% of NHBs, 7.5% of Hispanics, and 3.8% of NHWs; summer months: 17% of NHBs, 4.4% of Hispanics, and 1.6% of NHWs). Persons with higher vitamin D intakes (diet, supplements, or both) and those examined during May-October had significantly higher total 25(OH)D. Significant race-ethnicity interactions in a multiple linear regression model confirmed the necessity of providing race-ethnicity-specific estimates of total 25(OH)D. CONCLUSIONS: Race-ethnicity differences in the prevalence of low total 25(OH)D remained strong even after adjustment for season to account for the NHANES design imbalance between season, latitude, and race-ethnicity. The strong correlation between C3-epi-25(OH)D3 and 25(OH)D3 may be because the epimer is a metabolite of 25(OH)D3. The presence of 25(OH)D2 mainly in older persons is likely a result of high-dose prescription vitamin D2.

Differential Child Maltreatment Risk Across Deployment Periods of US Army Soldiers.

OBJECTIVES: We described the risk for maltreatment among toddlers of US Army soldiers over different deployment cycles to develop a systematic response within the US Army to provide families appropriate supports. METHODS: We conducted a person-time analysis of substantiated maltreatment reports and medical diagnoses among children of 112,325 deployed US Army soldiers between 2001 and 2007. RESULTS: Risk of maltreatment was elevated after deployment for children of soldiers deployed once but not for children of soldiers deployed twice. During the 6 months after deployment, children of soldiers deployed once had 4.43 substantiated maltreatment reports and 4.96 medical diagnoses per 10,000 child-months. The highest maltreatment rate among children of soldiers deployed twice occurred during the second deployment for substantiated maltreatment (4.83 episodes per 10,000 child-months) and before the first deployment for medical diagnoses of maltreatment (3.78 episodes per 10,000 child-months). CONCLUSIONS: We confirmed an elevated risk for child maltreatment during deployment but also found a previously unidentified high-risk period during the 6 months following deployment, indicating elevated stress within families of deployed and returning soldiers. These findings can inform efforts by the military to initiate and standardize support and preparation to families during periods of elevated risk.

Discovery of a Highly Selective Glycogen Synthase Kinase-3 Inhibitor (PF-04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging.

Glycogen synthase kinase-3 (GSK-3) regulates multiple cellular processes in diabetes, oncology, and neurology. N-(3-(1H-1,2,4-triazol-1-yl)propyl)-5-(3-chloro-4-methoxyphenyl)oxazole-4-carboxamide (PF-04802367 or PF-367) has been identified as a highly potent inhibitor, which is among the most selective antagonists of GSK-3 to date. Its efficacy was demonstrated in modulation of tau phosphorylation in vitro and in vivo. Whereas the kinetics of PF-367 binding in brain tissues are too fast for an effective therapeutic agent, the pharmacokinetic profile of PF-367 is ideal for discovery of radiopharmaceuticals for GSK-3 in the central nervous system. A (11) C-isotopologue of PF-367 was synthesized and preliminary PET imaging studies in non-human primates confirmed that we have overcome the two major obstacles for imaging GSK-3, namely, reasonable brain permeability and displaceable binding.

Use and applications of systematic reviews in public health nutrition.

Decisions related to a spectrum of nutrition-related public health and clinical concerns must consider many factors and are best informed by evaluating the totality and quality of the evidence. Systematic review (SR) is a structured process to evaluate, compare, and synthesize relevant evidence for the SR-specific question(s). Applications of SR are exemplified here through the discussion of four case studies: research agendas, nutrient reference intakes, dietary guidance, and practice guidelines. Concerns that SR cannot be effectively applied to nutrition evidence because of the lack of an unexposed comparator and the complex homeostasis in nutrition are discussed. Central to understanding the applicability of SR is its flexibility in defining key inclusion criteria and rigorous elements as appropriate for the SR-specific question(s). Through the reduction of bias and random error by explicit, reproducible, comprehensive, and rigorous examination of all of the evidence, SR informs the scientific judgment needed for sound evidence-based public health nutrition.

Use of Folate-Based and Other Fortification Scenarios Illustrates Different Shifts for Tails of the Distribution of Serum 25-Hydroxyvitamin D Concentrations.

BACKGROUND: The purpose of food fortification is to affect those at the lower end of the distribution curve for nutrient status while avoiding unintended consequences for those at the high end of the distribution. Vitamin D presents challenges in this regard. OBJECTIVES: We used scenarios to model changes in concentrations of serum 25-hydroxyvitamin D [25(OH)D] based on increases made because of assumptions about fortification. We then examined the outcomes for balance between improving serum 25(OH)D status for those at risk of inadequacy while avoiding high concentrations for those not at risk. METHODS: Data from NHANES 2001-2006 served as baseline serum 25(OH)D concentrations and were used to model shifts in serum 25(OH)D distribution after application of 3 fortification scenarios, including conceptual scenarios and an experiential predictive scenario we developed with the use of statistical modeling of changes in NHANES serum folate concentrations between prefortification and postfortification time periods. RESULTS: All scenarios suggested the possibility of increasing serum 25(OH)D above 125 nmol/L among the proportion of the population at the high end of baseline serum 25(OH)D distribution. The scenario based on serum folate change struck a middle ground between the 2 conceptual scenarios. It predicted a prevalence of 11% <40 nmol/L serum 25(OH)D compared with 17% currently (study baseline), and 8% prevalence of serum 25(OH)D >125 nmol/L compared with <1% currently (study baseline). It also confirmed that fortification affects those at the low end of the status distribution curve differently from those at the high end. CONCLUSIONS: Nutrient inadequacy of the type demonstrated by vitamin D--in which the risk is not universal--requires a thorough exploration of the unintended consequences of the overall shift in the distribution of serum 25(OH)D if efforts are made to use fortification to increase the status of persons at risk of deficiency. Fortification is at best a blunt instrument that must be implemented with caution. Moreover, fortification must be preceded by more research to elucidate the dose-response relation between intake and changes in serum 25(OH)D.

Including food 25-hydroxyvitamin D in intake estimates may reduce the discrepancy between dietary and serum measures of vitamin D status.

The discrepancy between the commonly used vitamin D status measures-intake and serum 25-hydroxyvitamin D [25(OH)D] concentrations--has been perplexing. Sun exposure increases serum 25(OH)D concentrations and is often used as an explanation for the higher population-based serum concentrations in the face of apparently low vitamin D intake. However, sun exposure may not be the total explanation. 25(OH)D, a metabolite of vitamin D, is known to be present in animal-based foods. It has been measured and reported only sporadically and is not currently factored into U.S. estimates of vitamin D intake. Previously unavailable preliminary USDA data specifying the 25(OH)D content of a subset of foods allowed exploration of the potential change in the reported overall vitamin D content of foods when the presence of 25(OH)D was included. The issue of 25(OH)D potency was addressed, and available commodity intake estimates were used to outline trends in projected vitamin D intake when 25(OH)D in foods was taken into account. Given the data available, there were notable increases in the total vitamin D content of a number of animal-based foods when potency-adjusted 25(OH)D was included, and in turn there was a potentially meaningful increase (1.7-2.9 µg or 15-30% of average requirement) in vitamin D intake estimates. The apparent increase could reduce discrepancies between intake estimates and serum 25(OH)D concentrations. The relevance to dietary interventions is discussed, and the need for continued exploration regarding 25(OH)D measurement is highlighted.

Review of the Australian nurse teacher professional practice standards: An e-Delphi study.

AIM: The aim of the study was to review the 2010 Australian nurse teacher professional practice standards ('the Standards') to see if they were still relevant to current nursing educator practice in any practice setting, such as academia or clinical settings. BACKGROUND: It has been over 10 years since 'the Standards have been reviewed. Nurse education practice has met many challenges in the past decade, so it is timely to evaluate whether the Standards are still relevant to nursing educators today. DESIGN: A modified Delphi technique was used for this study. METHODS: Delphi surveys were used to obtain consensus on the relevance of the Standards' statements to any nursing educator. Links to two electronic surveys were sent to an expert panel of nursing educator leaders. Also, two online focus groups of nursing educators from any practice setting or level of experience were held. Results from the first survey and focus groups led to word changes and additional statements, which were included in the second Delphi survey. RESULTS: Forty participants responded to the first survey and 38 to the second. Fifteen nursing educators attended the focus groups. There was ≥85 % agreement on all statements in the first survey. with similar high agreement responses in the second survey. Changes in the Standards included language used around culture, inclusion of 'sustainability of the program' and 'demonstrates knowledge and expertise in teaching and educational practice'. CONCLUSIONS: The Australian nurse teacher professional practice standards remain highly relevant to nursing educators across all practice settings. In response to feedback from nursing educators some changes to language and additional standard statements were included in the revised standards.

Applying empirical methods in clinical practice: introducing the model for assessing treatment effect.

BACKGROUND: One challenge in rehabilitation is determining whether improvement in the patient is a treatment-specific effect or due to extraneous factors (eg, the passage of time, spontaneous recovery). DESIGN: Descriptive, model building, and 2 cases illustrating the model. METHOD: The Model for Assessing Treatment Effect (MATE) incorporates the conceptual frameworks of the International Classification of Functioning, Disability, and Health (ICF), along with single-case experimental methodology. RESULTS: The MATE contains 7 levels organized in a hierarchy, representing (i) increasing specificity of evaluation procedures and (ii) control of extraneous variables during therapy. Two illustrative cases of patients with traumatic brain injury undergoing inpatient rehabilitation for, inter alia, cognitive-communication impairments are described to illustrate common clinical practice (level 2 of MATE) and a superior method using a multiple-baseline design across behaviors, enabling rigorous evaluation of treatment effect (level 6 of MATE). CONCLUSIONS: The MATE offers a systematic, evidence-based approach for implementing ICF-informed goals into clinical practice. It also provides a benchmark against which a clinical service can be evaluated in terms of the rigor of its therapy program.

Cerebrospinal fluid ß-Amyloid turnover in the mouse, dog, monkey and human evaluated by systematic quantitative analyses.

BACKGROUND: Reducing brain ß-amyloid (Aß) via inhibition of ß-secretase, or inhibition/modulation of γ-secretase, has been widely pursued as a potential disease-modifying treatment for Alzheimer's disease. Compounds that act through these mechanisms have been screened and characterized with Aß lowering in the brain and/or cerebrospinal fluid (CSF) as the primary pharmacological end point. Interpretation and translation of the pharmacokinetic (PK)/pharmacodynamic (PD) relationship for these compounds is complicated by the relatively slow Aß turnover process in these compartments. OBJECTIVE: To understand Aß turnover kinetics in preclinical species and humans. METHODS: We collected CSF Aß dynamic data after ß- or γ-secretase inhibitor treatment from in-house experiments and the public domain, and analyzed the data using PK/PD modeling to obtain CSF Aß turnover rates (kout) in the mouse, dog, monkey and human. RESULTS: The kout for CSF Aß40 follows allometry (kout = 0.395 × body weight(-0.351)). The kout for CSF Aß40 is approximately 2-fold higher than the turnover of CSF in rodents, but in higher species, the two are comparable. CONCLUSION: The turnover of CSF Aß40 was systematically examined, for the first time, in multiple species through quantitative modeling of multiple data sets. Our result suggests that the clearance mechanisms for CSF Aß in rodents may be different from those in the higher species. The understanding of Aß turnover has considerable implications for the discovery and development of Aß-lowering therapeutics, as illustrated from the perspectives of preclinical PK/PD characterization and preclinical-to-clinical translation.