Spring Snow Melt Timing and Changes over Arctic Lands

Spring snow cover over Arctic lands has, on average, melted approximately 4-7 days earlier since the late 1980s compared to the previous 20 years. The earlier disappearance of snow has been identified in non-mountainous regions at the 60 deg and 70 deg N parallels over Eurasia and North America using visible satellite observations of continental snow cover extent (SCE) mapped by the National Oceanic and Atmospheric Administration. The change was greater in the farthest north continental locations. Northern hemisphere SCE declined by almost 10% (May) to 20% (June) between the two intervals. At latitude 70 deg N, eight segments of longitude (each 10 deg in width) show significant (negative) trends. However, only two longitudinal segments at 60 deg N show significant trends, (one positive and one negative). SCE changes coincide with increasing spring warmth and the earlier diminution of sea ice in the last several decades. However, while sea ice has continued to decrease during this recent interval, snowmelt dates in the Arctic changed in a step-like fashion during the mid to late 1980s and have remained much the same since that time

Reliability of the Charcot-Marie-Tooth functional outcome measure

The CMT‐FOM is a 13‐item clinical outcome assessment (COA) that measures physical ability in adults with Charcot‐Marie‐Tooth disease (CMT). Test‐retest reliability, internal consistency and convergent validity have been established for the CMT‐FOM. This current study sought to establish inter‐rater reliability. Following an in‐person training of six international clinical evaluators we recruited 10 participants with genetically diagnosed CMT1A, (aged 18‐74 years, 6 female). Participants were evaluated using the CMT‐FOM over 2 days. Participants were given at least a 3 hour rest between evaluations, and were assessed twice each day. Following the provision of training by master trainers, all 13 items of the CMT‐FOM exhibited excellent inter‐rater reliability for raw scores (ICC1,1 0.825‐0.989) and z‐scores (ICC1,1 0.762‐0.969). Reliability of the CMT‐FOM total score was excellent (ICC1,1 0.983, 95% CI 0.958‐0.995). The CMT‐FOM is a reliable COA used by clinical evaluators internationally. The next steps are to establish further validation through psychometric evaluation of the CMT‐FOM in the Accelerate Clinical Trials in CMT (ACT‐CMT) study

Phenotypic Variability of Childhood Charcot-Marie-Tooth Disease

IMPORTANCE: Disease severity of childhood Charcot-Marie-Tooth disease (CMT) has not been extensively characterized, either within or between types of CMT to date. OBJECTIVE: To assess the variability of disease severity in a large cohort of children and adolescents with CMT. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study was conducted among 520 children and adolescents aged 3 to 20 years at 8 universities and hospitals involved in the Inherited Neuropathies Consortium between August 6, 2009, and July 31, 2014, in Australia, Italy, the United Kingdom, and the United States. Data analysis was conducted from August 1, 2014, to December 1, 2015. MAIN OUTCOMES AND MEASURES: Scores on the Charcot-Marie-Tooth Disease Pediatric Scale (CMTPedS), a well-validated unidimensional clinical outcome measure to assess disease severity. This instrument includes 11 items assessing fine and gross motor function, sensation, and balance to produce a total score ranging from 0 (unaffected) to 44 (severely affected). RESULTS: Among the 520 participants (274 males) aged 3 to 20 years, CMT type 1A (CMT1A) was the most prevalent type (252 [48.5%]), followed by CMT2A (31 [6.0%]), CMT1B (15 [2.9%]), CMT4C (13 [2.5%]), and CMTX1 (10 [1.9%]). Disease severity ranged from 1 to 44 points on the CMTPedS (mean [SD], 21.5 [8.9]), with ankle dorsiflexion strength and functional hand dexterity test being most affected. Participants with CMT1B (mean [SD] CMTPedS score, 24.0 [7.4]), CMT2A (29.7 [7.1]), and CMT4C (29.8 [8.6]) were more severely affected than those with CMT1A (18.9 [7.7]) and CMTX1 (males: 15.3 [7.7]; females: 13.0 [3.6]) (P < .05). Scores on the CMTPedS tended to worsen principally during childhood (ages, 3-10 years) for participants with CMT4C and CMTX1 and predominantly during adolescence for those with CMT1B and CMT2A (ages, 11-20 years), while CMT1A worsened consistently throughout childhood and adolescence. For individual items, participants with CMT4C recorded more affected functional dexterity test scores than did those with all other types of CMT (P < .05). Participants with CMT1A and CMTX1 performed significantly better on the 9-hole peg test and balance test than did those with all other types of CMT (P < .05). Participants with CMT2A had the weakest grip strength (P < .05), while those with CMT2A and CMT4C exhibited the weakest ankle plantarflexion and dorsiflexion strength, as well as the lowest long jump and 6-minute walk test distances (P < .05). Multiple regression modeling identified increasing age (r = 0.356, β = 0.617, P < .001) height (r = 0.251, β = 0.309, P = .002), self-reported foot pain (r = 0.162, β = .114, P = .009), and self-reported hand weakness (r = 0.243, β = 0.203, P < .001) as independent predictors of disease severity. CONCLUSIONS AND RELEVANCE: These results highlight the phenotypic variability within CMT genotypes and mutation-specific manifestations between types. This study has identified distinct functional limitations and self-reported impairments to target in future therapeutic trials

Natural history of Charcot-Marie-Tooth disease during childhood

OBJECTIVE: To determine the rate of disease progression in a longitudinal natural history study of children with Charcot-Marie-Tooth disease (CMT). METHODS: 206 (103 female) participants aged 3-20 years enrolled in the Inherited Neuropathies Consortium were assessed at baseline and 2-years. Demographic, anthropometric, and diagnostic information were collected. Disease progression was assessed with the CMT Pediatric Scale (CMTPedS), a reliable Rasch-built linearly weighted disability scale evaluating fine and gross motor function, strength, sensation, and balance. RESULTS: On average CMTPedS Total scores progressed at a rate of 2.4±4.9 over 2-years (14% change from baseline, p<0.001). There was no difference between males and females (mean difference 0.5, 95%CI -0.9 to 1.9, p=0.49). The most responsive CMTPedS items were dorsiflexion strength (z-score change: -0.3, 95% CI -0.6 to -0.05, p=0.02), balance (z-score change: -1.0, 95% CI -1.9 to -0.09, p=0.03), and long jump (z-score change: -0.4, 95% CI -0.7 to -0.02, p=0.04). Of the most common genetic subtypes, 111 participants with CMT1A/PMP22 duplication progressed by 1.8±4.2 (12% change from baseline, p<0.001), nine participants with CMT1B/MPZ mutation progressed by 2.2±5.1 (11% change), six participants with CMT2A/MFN2 mutation progressed by 6.2±7.9 (23% change), and seven participants with CMT4C/SH3TC2 mutations progressed by 3.0±4.5 (12% change). Participants with CMT2A progressed faster than CMT1A (mean difference -4.4, 95%CI -8.1 to -0.8, p=0.02). Children with CMT1A progressed consistently through early childhood (3-10 years) and adolescence (11-20 years) (mean difference 1.1, 95%CI -0.6 to 2.7, p=0.19) while CMT2A appeared to progress faster during early childhood than adolescence (mean difference 10.0, 95%CI -2.2 to 22.2, p=0.08). INTERPRETATION: Using the CMTPedS as an outcome measure of disease severity, children with CMT progress at a significant rate over 2-years. Understanding the rate at which children with CMT deteriorate is essential for adequately powering trials of disease-modifying interventions. This article is protected by copyright. All rights reserved

Assessing non-Mendelian inheritance in inherited axonopathies

PURPOSE: Inherited axonopathies (IA) are rare, clinically and genetically heterogeneous diseases that lead to length-dependent degeneration of the long axons in central (hereditary spastic paraplegia [HSP]) and peripheral (Charcot–Marie–Tooth type 2 [CMT2]) nervous systems. Mendelian high-penetrance alleles in over 100 different genes have been shown to cause IA; however, about 50% of IA cases do not receive a genetic diagnosis. A more comprehensive spectrum of causative genes and alleles is warranted, including causative and risk alleles, as well as oligogenic multilocus inheritance. METHODS: Through international collaboration, IA exome studies are beginning to be sufficiently powered to perform a pilot rare variant burden analysis. After extensive quality control, our cohort contained 343 CMT cases, 515 HSP cases, and 935 non-neurological controls. We assessed the cumulative mutational burden across disease genes, explored the evidence for multilocus inheritance, and performed an exome-wide rare variant burden analysis. RESULTS: We replicated the previously described mutational burden in a much larger cohort of CMT cases, and observed the same effect in HSP cases. We identified a preliminary risk allele for CMT in the EXOC4 gene (p value= 6.9 × 10-6, odds ratio [OR] = 2.1) and explored the possibility of multilocus inheritance in IA. CONCLUSION: Our results support the continuing emergence of complex inheritance mechanisms in historically Mendelian disorders

Changing climate both increases and decreases European river floods

Climate change has led to concerns about increasing river floods resulting from the greater water-holding capacity of a warmer atmosphere. These concerns are reinforced by evidence of increasing economic losses associated with flooding in many parts of the world, including Europe. Any changes in river floods would have lasting implications for the design of flood protection measures and flood risk zoning. However, existing studies have been unable to identify a consistent continental-scale climatic-change signal in flood discharge observations in Europe, because of the limited spatial coverage and number of hydrometric stations. Here we demonstrate clear regional patterns of both increases and decreases in observed river flood discharges in the past five decades in Europe, which are manifestations of a changing climate. Our results—arising from the most complete database of European flooding so far—suggest that: increasing autumn and winter rainfall has resulted in increasing floods in northwestern Europe; decreasing precipitation and increasing evaporation have led to decreasing floods in medium and large catchments in southern Europe; and decreasing snow cover and snowmelt, resulting from warmer temperatures, have led to decreasing floods in eastern Europe. Regional flood discharge trends in Europe range from an increase of about 11 per cent per decade to a decrease of 23 per cent. Notwithstanding the spatial and temporal heterogeneity of the observational record, the flood changes identified here are broadly consistent with climate model projections for the next century, suggesting that climate-driven changes are already happening and supporting calls for the consideration of climate change in flood risk management

A long-term Northern Hemisphere snow cover extent data record for climate studies and monitoring

This paper describes the long-term, satellite-based visible snow cover extent National Oceanic and Atmospheric Administration (NOAA) climate data record (CDR) currently available for climate studies, monitoring, and model validation. This environmental data product is developed from weekly Northern Hemisphere snow cover extent data that have been digitized from snow cover maps onto a Cartesian grid draped over a polar stereographic projection. The data have a spatial resolution of 190.6 km at 60° latitude, are updated monthly, and span the period from 4 October 1966 to the present. The data comprise the longest satellite-based CDR of any environmental variable. Access to the data is provided in Network Common Data Form (netCDF) and archived by NOAA's National Climatic Data Center (NCDC) under the satellite Climate Data Record Program (doi:10.7289/V5N014G9). The basic characteristics, history, and evolution of the data set are presented herein. In general, the CDR provides similar spatial and temporal variability to its widely used predecessor product. Key refinements included in the CDR improve the product's grid accuracy and documentation and bring metadata into compliance with current standards for climate data records

Development and Validation of the Pediatric Charcot–Marie–Tooth Disease Quality of Life Outcome Measure

OBJECTIVE: Charcot-Marie-Tooth disease (CMT) reduces health-related quality of life (QOL), especially in children. Defining QOL in pediatric CMT can help physicians monitor disease burden clinically and in trials. We identified items pertaining to QOL in children with CMT and conducted validation studies to develop a pediatric CMT-specific QOL outcome measure (pCMT-QOL). METHODS: Development and validation of the pCMT-QOL patient-reported outcome measure was iterative, involving identifying relevant domains, item pool generation, prospective pilot testing and clinical assessments, structured focus-group interviews, and psychometric testing. Testing was conducted in children with CMT seen at participating sites from the USA, United Kingdom, and Australia. RESULTS: We conducted systematic literature reviews and analysis of generic QOL measures to identify six domains relevant to QOL in children with CMT. 60 items corresponding to those domains were developed de novo, or identified from literature review and CMT-specific modification of items from the pediatric Neuro-QOL measures. The draft version underwent prospective feasibility and face content validity assessments to develop a working version of the pCMT-QOL measure. From 2010-2016, the pCMT-QOL working version was administered to 398 children ages 8-18 seen at the participating study sites of the Inherited Neuropathies Consortium. The resulting data underwent rigorous psychometric analysis, including factor analysis, test-retest reliability, internal consistency, convergent validity, IRT analysis, and longitudinal analysis, to develop the final pCMT-QOL patient-reported outcome measure. INTERPRETATION: The pCMT-QOL patient-reported outcome measure is a reliable, valid, and sensitive measure of health-related QOL for children with CMT