Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000–3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons—Leu844, Cys845, Ala846, Leu847, and Gly848—located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844–848 exists and will be valuable in the management and genetic counseling of a significant number of individuals

The State of Remote Sensing Capabilities of Cascading Hazards Over High Mountain Asia

Cascading hazard processes refer to a primary trigger such as heavy rainfall, seismic activity, or snow melt, followed by a chain or web of consequences that can cause subsequent hazards influenced by a complex array of preconditions and vulnerabilities. These interact in multiple ways and can have tremendous impacts on populations proximate to or downstream of these initial triggers. High Mountain Asia (HMA) is extremely vulnerable to cascading hazard processes given the tectonic, geomorphologic, and climatic setting of the region, particularly as it relates to glacial lakes. Given the limitations of in situ surveys in steep and often inaccessible terrain, remote sensing data are a valuable resource for better understanding and quantifying these processes. The present work provides a survey of cascading hazard processes impacting HMA and how these can be characterized using remote sensing sources. We discuss how remote sensing products can be used to address these process chains, citing several examples of cascading hazard scenarios across HMA. This work also provides a perspective on the current gaps and challenges, community needs, and view forward toward improved characterization of evolving hazards and risk across HMA

Evidence-based Kernels: Fundamental Units of Behavioral Influence

This paper describes evidence-based kernels, fundamental units of behavioral influence that appear to underlie effective prevention and treatment for children, adults, and families. A kernel is a behavior–influence procedure shown through experimental analysis to affect a specific behavior and that is indivisible in the sense that removing any of its components would render it inert. Existing evidence shows that a variety of kernels can influence behavior in context, and some evidence suggests that frequent use or sufficient use of some kernels may produce longer lasting behavioral shifts. The analysis of kernels could contribute to an empirically based theory of behavioral influence, augment existing prevention or treatment efforts, facilitate the dissemination of effective prevention and treatment practices, clarify the active ingredients in existing interventions, and contribute to efficiently developing interventions that are more effective. Kernels involve one or more of the following mechanisms of behavior influence: reinforcement, altering antecedents, changing verbal relational responding, or changing physiological states directly. The paper describes 52 of these kernels, and details practical, theoretical, and research implications, including calling for a national database of kernels that influence human behavior

Psychological interventions for parents of children and adolescents with chronic illness

BACKGROUND: Psychological therapies have been developed for parents of children and adolescents with a chronic illness. Such therapies include parent only or parent and child/adolescent, and are designed to treat parent behaviour, parent mental health, child behaviour/disability, child mental health, child symptoms and/or family functioning. No comprehensive, meta-analytic reviews have been published in this area. OBJECTIVES: To evaluate the effectiveness of psychological therapies that include coping strategies for parents of children/adolescents with chronic illnesses (painful conditions, cancer, diabetes mellitus, asthma, traumatic brain injury, inflammatory bowel diseases, skin diseases or gynaecological disorders). The therapy will aim to improve parent behaviour, parent mental health, child behaviour/disability, child mental health, child symptoms and family functioning. SEARCH METHODS: We searched CENTRAL, MEDLINE, EMBASE and PsyclNFO for randomised controlled trials (RCTs) of psychological interventions that included parents of children and adolescents with a chronic illness. The initial search was from inception of these databases to June 2011 and we conducted a follow-up search from June 2011 to March 2012. We identified additional studies from the reference list of retrieved papers and from discussion with investigators. SELECTION CRITERIA: Included studies were RCTs of psychological interventions that delivered treatment to parents of children and adolescents (under 19 years of age) with a chronic illness compared to active control, wait list control or treatment as usual. We excluded studies if the parent component was a coaching intervention, the aim of the intervention was health prevention/promotion, the comparator was a pharmacological treatment, the child/adolescent had an illness not listed above or the study included children with more than one type of chronic illness. Further to this, we excluded studies when the sample size of either comparator group was fewer than 10 at post-treatment. DATA COLLECTION AND ANALYSIS: We included 35 RCTs involving a total of 2723 primary trial participants. Two review authors extracted data from 26 studies. We analysed data using two categories. First, we analysed data by each medical condition across all treatment classes at two time points (immediately post-treatment and the first available follow-up). Second, we analysed data by each treatment class (cognitive behavioural therapy (CBT), family therapy (FT), problem solving therapy (PST) and multisystemic therapy (MST)) across all medical conditions at two time points (immediately post-treatment and the first available follow-up). We assessed treatment effectiveness on six possible outcomes: parent behaviour, parent mental health, child behaviour/disability, child mental health, child symptoms and family functioning. MAIN RESULTS: Across all treatment types, psychological therapies that included parents significantly improved child symptoms for painful conditions immediately post-treatment. Across all medical conditions, cognitive behavioural therapy (CBT) significantly improved child symptoms and problem solving therapy significantly improved parent behaviour and parent mental health immediately post-treatment. There were no other effects at post-treatment or follow-up. The risk of bias of included studies is described. AUTHORS' CONCLUSIONS: There is no evidence on the effectiveness of psychological therapies that include parents in most outcome domains of functioning, for a large number of common chronic illnesses in children. There is good evidence for the effectiveness of including parents in psychological therapies that reduce pain in children with painful conditions. There is also good evidence for the effectiveness of CBT that includes parents for improving the primary symptom complaints when available data were included from chronic illness conditions. Finally, there is good evidence for the effectiveness of problem solving therapy delivered to parents on improving parent problem solving skills and parent mental health. All effects are immediately post-treatment. There are no significant findings for any treatment effects in any condition at follow-up

Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation

Purpose: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. Methods: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. Results: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_297

Primate responses to changing environments in the anthropocene

Most primates have slow life-histories and long generation times. Because environmental change is occurring at an unprecedented rate, gene-based adaptations are unlikely to evolve fast enough to offer successful responses to these changes. The paper reviews the most common types of habitat/landscape alterations, the extent of human-primate interactions, and the impact of climate change. It demonstrates how understanding behavioural flexibility as a response to environmental change will be crucial to optimize conservation efforts by constructing informed management plans. Comparisons across species, space, and time can be used to draw generalizations about primate responses to environmental change while considering their behavioural flexibility

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)