Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies

Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies

Harnessing the NEON data revolution to advance open environmental science with a diverse and data-capable community

It is a critical time to reflect on the National Ecological Observatory Network (NEON) science to date as well as envision what research can be done right now with NEON (and other) data and what training is needed to enable a diverse user community. NEON became fully operational in May 2019 and has pivoted from planning and construction to operation and maintenance. In this overview, the history of and foundational thinking around NEON are discussed. A framework of open science is described with a discussion of how NEON can be situated as part of a larger data constellation—across existing networks and different suites of ecological measurements and sensors. Next, a synthesis of early NEON science, based on >100 existing publications, funded proposal efforts, and emergent science at the very first NEON Science Summit (hosted by Earth Lab at the University of Colorado Boulder in October 2019) is provided. Key questions that the ecology community will address with NEON data in the next 10 yr are outlined, from understanding drivers of biodiversity across spatial and temporal scales to defining complex feedback mechanisms in human–environmental systems. Last, the essential elements needed to engage and support a diverse and inclusive NEON user community are highlighted: training resources and tools that are openly available, funding for broad community engagement initiatives, and a mechanism to share and advertise those opportunities. NEON users require both the skills to work with NEON data and the ecological or environmental science domain knowledge to understand and interpret them. This paper synthesizes early directions in the community’s use of NEON data, and opportunities for the next 10 yr of NEON operations in emergent science themes, open science best practices, education and training, and community building

Assessment of Mortality and Smoking Rates Before and After Reduction in Community-wide Prevention Programs in Rural Maine

Importance: It is unclear whether effective population-wide interventions that reduce risk factors and improve health result in sustained benefits to a community\u27s health. If benefits do persist after a program is ended, interventions could be brief rather than maintained long term. Objective: To measure mortality and smoking rates in a rural community over decades before, during, and after prevention program reductions. Design, Setting, and Participants: This cross-sectional study compared smoking and mortality rates in a rural Maine county with other Maine counties over time by 5-year intervals. Multiple changes occurred between 2001 and 2015 in the physiological and behavioral risk factor reduction programs offered in the county. They included reductions in leadership, staff, institutional resources, data monitoring, and the programs themselves. Data were analyzed from May 2018 to March 2019. Intervention: Previous multifaceted interventions and outcome monitoring were withdrawn or diminished in the past decade. Main Outcomes and Measures: Smoking and age-adjusted mortality rates vs household income. Results: Reduced mortality rates in Franklin County in 1986 to 2005 reverted to those predicted by household incomes, relative to other Maine counties, by 2006 to 2015 (1986-1990 T score = -2.86 [P = .01] and 2001-2005 T score = -3.00 [P = .01] to 2006 to 2010 T score = -0.43 [P = .67] and 2011-2015 T score = -0.72 [P = .48]). Analysis of County Health Rankings data from 2010 to 2018 also showed that Franklin County\u27s outcomes have reverted to no better than predicted by socioeconomic status. The county\u27s T scores increased from -3.62 (P = .003) in 2010 to -0.41 (P = .69) in 2015 to 0.13 (P = .90) in 2018. Statewide association of income with mortality by analyses of variance showed that the R2 values have increased from the decades preceding 2000 (1976-1980, R2 = 0.21; P = .08; 1986-1990, R2 = 0.32; P = .02) to 2006 to 2010 (R2 = 0.73; P \u3c .001) and 2011 to 2015 (R2 = 0.70; P \u3c .001). Conclusions and Relevance: This study suggests that gains associated with population health interventions may be lost when the interventions are reduced. Adjusting outcome measures for socioeconomic status may allow quicker and more sensitive monitoring of intervention adequacy and success. The increasing trend of age-adjusted mortality in Maine and nationally to correlate inversely with incomes may warrant further community interventions, especially for poorer populations

Community-wide cardiovascular disease prevention programs and health outcomes in a rural county, 1970-2010

IMPORTANCE: Few comprehensive cardiovascular risk reduction programs, particularly those in rural, low-income communities, have sustained community-wide interventions for more than 10 years and demonstrated the effect of risk factor improvements on reductions in morbidity and mortality. OBJECTIVE: To document health outcomes associated with an integrated, comprehensive cardiovascular risk reduction program in Franklin County, Maine, a low-income rural community. DESIGN, SETTING, AND PARTICIPANTS: Forty-year observational study involving residents of Franklin County, Maine, a rural, low-income population of 22,444 in 1970, that used the preceding decade as a baseline and compared Franklin County with other Maine counties and state averages. INTERVENTIONS: Community-wide programs targeting hypertension, cholesterol, and smoking, as well as diet and physical activity, sponsored by multiple community organizations, including the local hospital and clinicians. MAIN OUTCOMES AND MEASURES: Resident participation; hypertension and hyperlipidemia detection, treatment, and control; smoking quit rates; hospitalization rates from 1994 through 2006, adjusted for median household income; and mortality rates from 1970 through 2010, adjusted for household income and age. RESULTS: More than 150,000 individual county resident contacts occurred over 40 years. Over time, as cardiovascular risk factor programs were added, relevant health indicators improved. Hypertension control had an absolute increase of 24.7% (95% CI, 21.6%-27.7%) from 18.3% to 43.0%, from 1975 to 1978; later, elevated cholesterol control had an absolute increase of 28.5% (95% CI, 25.3%-31.6%) from 0.4% to 28.9%, from 1986 to 2010. Smoking quit rates improved from 48.5% to 69.5%, better than state averages (observed - expected [O - E], 11.3%; 95% CI, 5.5%-17.7%; P \u3c .001), 1996-2000; these differences later disappeared when Maine\u27s overall quit rate increased. Franklin County hospitalizations per capita were less than expected for the measured period, 1994-2006 (O - E, -17 discharges/1000 residents; 95% CI -20.1 to -13.9; P \u3c .001). Franklin was the only Maine county with consistently lower adjusted mortality than predicted over the time periods 1970-1989 and 1990-2010 (O - E, -60.4 deaths/100,000; 95% CI, -97.9 to -22.8; P \u3c .001, and -41.6/100,000; 95% CI, -77.3 to -5.8; P = .005, respectively). CONCLUSIONS AND RELEVANCE: Sustained, community-wide programs targeting cardiovascular risk factors and behavior changes to improve a Maine county\u27s population health were associated with reductions in hospitalization and mortality rates over 40 years, compared with the rest of the state. Further studies are needed to assess the generalizability of such programs to other US county populations, especially rural ones, and to other parts of the world