Early cow's milk introduction is associated with failed personal-social milestones after 1 year of age

Both the American Academy of Pediatrics (AAP) and the Institute of Medicine (IOM) recommend delaying the introduction of cow's milk until after 1 year of age due to its low absorbable iron content. We used a novel computerized decision support system to gather data from multiple general pediatrics offices. We asked families whether their child received cow's milk before 1 year of age, had a low-iron diet, or used low-iron formula. Then, at subsequent visits, we performed a modified developmental assessment using the Denver II. We assessed the effect of early cow's milk or a low-iron diet on the later failure of achieving developmental milestones. We controlled for covariates using logistic regression. Early cow's milk introduction (odds ratio (OR) 1.30, p = 0.012), as well as a low-iron diet or low-iron formula (OR 1.42, p < 0.001), was associated with increased rates of milestone failure. Only personal-social milestones (OR 1.44, p = 0.002) showed a significantly higher rate of milestone failure. Both personal-social (OR 1.42, p < 0.001) and language (OR 1.22, p = 0.009) showed higher rates of failure in children with a low-iron diet. CONCLUSIONS: There is an association between the introduction of cow's milk before 1 year of age and the rate of delayed developmental milestones after 1 year of age. This adds strength to the recommendations from the AAP and IOM to delay cow's milk introduction until after 1 year of age

Mena/VASP and αII-Spectrin complexes regulate cytoplasmic actin networks in cardiomyocytes and protect from conduction abnormalities and dilated cardiomyopathy

BACKGROUND: In the heart, cytoplasmic actin networks are thought to have important roles in mechanical support, myofibrillogenesis, and ion channel function. However, subcellular localization of cytoplasmic actin isoforms and proteins involved in the modulation of the cytoplasmic actin networks are elusive. Mena and VASP are important regulators of actin dynamics. Due to the lethal phenotype of mice with combined deficiency in Mena and VASP, however, distinct cardiac roles of the proteins remain speculative. In the present study, we analyzed the physiological functions of Mena and VASP in the heart and also investigated the role of the proteins in the organization of cytoplasmic actin networks. RESULTS: We generated a mouse model, which simultaneously lacks Mena and VASP in the heart. Mena/VASP double-deficiency induced dilated cardiomyopathy and conduction abnormalities. In wild-type mice, Mena and VASP specifically interacted with a distinct αII-Spectrin splice variant (SH3i), which is in cardiomyocytes exclusively localized at Z- and intercalated discs. At Z- and intercalated discs, Mena and β-actin localized to the edges of the sarcomeres, where the thin filaments are anchored. In Mena/VASP double-deficient mice, β-actin networks were disrupted and the integrity of Z- and intercalated discs was markedly impaired. CONCLUSIONS: Together, our data suggest that Mena, VASP, and αII-Spectrin assemble cardiac multi-protein complexes, which regulate cytoplasmic actin networks. Conversely, Mena/VASP deficiency results in disrupted β-actin assembly, Z- and intercalated disc malformation, and induces dilated cardiomyopathy and conduction abnormalities

Transcriptional and Cellular Diversity of the Human Heart

Background: The human heart requires a complex ensemble of specialized cell types to perform its essential function. A greater knowledge of the intricate cellular milieu of the heart is critical to increase our understanding of cardiac homeostasis and pathology. As recent advances in low-input RNA sequencing have allowed definitions of cellular transcriptomes at single-cell resolution at scale, we have applied these approaches to assess the cellular and transcriptional diversity of the nonfailing human heart. Methods: Microfluidic encapsulation and barcoding was used to perform single nuclear RNA sequencing with samples from 7 human donors, selected for their absence of overt cardiac disease. Individual nuclear transcriptomes were then clustered based on transcriptional profiles of highly variable genes. These clusters were used as the basis for between-chamber and between-sex differential gene expression analyses and intersection with genetic and pharmacologic data. Results: We sequenced the transcriptomes of 287 269 single cardiac nuclei, revealing 9 major cell types and 20 subclusters of cell types within the human heart. Cellular subclasses include 2 distinct groups of resident macrophages, 4 endothelial subtypes, and 2 fibroblast subsets. Comparisons of cellular transcriptomes by cardiac chamber or sex reveal diversity not only in cardiomyocyte transcriptional programs but also in subtypes involved in extracellular matrix remodeling and vascularization. Using genetic association data, we identified strong enrichment for the role of cell subtypes in cardiac traits and diseases. Intersection of our data set with genes on cardiac clinical testing panels and the druggable genome reveals striking patterns of cellular specificity. Conclusions: Using large-scale single nuclei RNA sequencing, we defined the transcriptional and cellular diversity in the normal human heart. Our identification of discrete cell subtypes and differentially expressed genes within the heart will ultimately facilitate the development of new therapeutics for cardiovascular diseases

Evaluating knowledge to support climate action: A framework for sustained assessment. report of an independent advisory committee on applied climate assessment.

Author Posting. © American Meteorological Society, 2019. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Weather Climate and Society 11(3), (2019):465-487, doi: 10.1175/WCAS-D-18-0134.1.As states, cities, tribes, and private interests cope with climate damages and seek to increase preparedness and resilience, they will need to navigate myriad choices and options available to them. Making these choices in ways that identify pathways for climate action that support their development objectives will require constructive public dialogue, community participation, and flexible and ongoing access to science- and experience-based knowledge. In 2016, a Federal Advisory Committee (FAC) was convened to recommend how to conduct a sustained National Climate Assessment (NCA) to increase the relevance and usability of assessments for informing action. The FAC was disbanded in 2017, but members and additional experts reconvened to complete the report that is presented here. A key recommendation is establishing a new nonfederal “climate assessment consortium” to increase the role of state/local/tribal government and civil society in assessments. The expanded process would 1) focus on applied problems faced by practitioners, 2) organize sustained partnerships for collaborative learning across similar projects and case studies to identify effective tested practices, and 3) assess and improve knowledge-based methods for project implementation. Specific recommendations include evaluating climate models and data using user-defined metrics; improving benefit–cost assessment and supporting decision-making under uncertainty; and accelerating application of tools and methods such as citizen science, artificial intelligence, indicators, and geospatial analysis. The recommendations are the result of broad consultation and present an ambitious agenda for federal agencies, state/local/tribal jurisdictions, universities and the research sector, professional associations, nongovernmental and community-based organizations, and private-sector firms.This report would not have been possible without the support and participation of numerous organizations and individuals. We thank New York State Governor Andrew M. Cuomo for announcing in his 2018 State of the State agenda that the IAC would be reconvened. The New York State Energy Research and Development Authority (Contract ID 123416), Columbia University’s Earth Institute, and the American Meteorological Society provided essential financial support and much more, including sage advice and moral support from John O’Leary, Shara Mohtadi, Steve Cohen, Alex Halliday, Peter deMenocal, Keith Seitter, Paul Higgins, and Bill Hooke. We thank the attendees of a workshop, generously funded by the Kresge Foundation in November of 2017, that laid a foundation for the idea to establish a civil-society-based assessment consortium. During the course of preparing the report, IAC members consulted with individuals too numerous to list here—state, local, and tribal officials; researchers; experts in nongovernmental and community-based organizations; and professionals in engineering, architecture, public health, adaptation, and other areas. We are so grateful for their time and expertise. We thank the members and staff of the National Academy of Sciences, Engineering, and Medicine’s Committee to Advise the U.S. Global Change Research Program for providing individual comments on preliminary recommendations during several discussions in open sessions of their meetings. The following individuals provided detailed comments on an earlier version of this report, which greatly sharpened our thinking and recommendations: John Balbus, Tom Dietz, Phil Duffy, Baruch Fischhoff, Brenda Hoppe, Melissa Kenney, Linda Mearns, Claudia Nierenberg, Kathleen Segerson, Soroosh Sorooshian, Chris Weaver, and Brian Zuckerman. Mary Black provided insightful copy editing of several versions of the report. We also thank four anonymous reviewers for their effort and care in critiquing and improving the report. It is the dedication, thoughtful feedback, expertise, care, and commitment of all these people and more that not only made this report possible, but allow us all to continue to support smart and insightful actions in a changing climate. We are grateful as authors and as global citizens. Author contributions: RM, SA, KB, MB, AC, JD, PF, KJ, AJ, KK, JK, ML, JM, RP, TR, LS, JS, JW, and DZ were members of the IAC and shared in researching, discussing, drafting, and approving the report. BA, JF, AG, LJ, SJ, PK, RK, AM, RM, JN, WS, JS, PT, GY, and RZ contributed to specific sections of the report.2020-05-2

Framework for sustained climate assessment in the United States

Author Posting. © American Meteorological Society, 2019. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Bulletin of the American Meteorological Society, 100(5), (2019): 897-908, doi:10.1175/BAMS-D-19-0130.1.As states, cities, tribes, and private interests cope with climate damages and seek to increase preparedness and resilience, they will need to navigate myriad choices and options available to them. Making these choices in ways that identify pathways for climate action that support their development objectives will require constructive public dialogue, community participation, and flexible and ongoing access to science- and experience-based knowledge. In 2016, a Federal Advisory Committee (FAC) was convened to recommend how to conduct a sustained National Climate Assessment (NCA) to increase the relevance and usability of assessments for informing action. The FAC was disbanded in 2017, but members and additional experts reconvened to complete the report that is presented here. A key recommendation is establishing a new nonfederal “climate assessment consortium” to increase the role of state/local/tribal government and civil society in assessments. The expanded process would 1) focus on applied problems faced by practitioners, 2) organize sustained partnerships for collaborative learning across similar projects and case studies to identify effective tested practices, and 3) assess and improve knowledge-based methods for project implementation. Specific recommendations include evaluating climate models and data using user-defined metrics; improving benefit–cost assessment and supporting decision-making under uncertainty; and accelerating application of tools and methods such as citizen science, artificial intelligence, indicators, and geospatial analysis. The recommendations are the result of broad consultation and present an ambitious agenda for federal agencies, state/local/tribal jurisdictions, universities and the research sector, professional associations, nongovernmental and community-based organizations, and private-sector firms.This report would not have been possible without the support and participation of numerous organizations and individuals. We thank New York State Governor Andrew M. Cuomo for announcing in his 2018 State of the State agenda that the IAC would be reconvened. The New York State Energy Research and Development Authority (Contract ID 123416), Columbia University’s Earth Institute, and the American Meteorological Society provided essential financial support and much more, including sage advice and moral support from John O’Leary, Shara Mohtadi, Steve Cohen, Alex Halliday, Peter deMenocal, Keith Seitter, Paul Higgins, and Bill Hooke. We thank the attendees of a workshop, generously funded by the Kresge Foundation in November of 2017, that laid a foundation for the idea to establish a civil-society-based assessment consortium. During the course of preparing the report, IAC members consulted with individuals too numerous to list here—state, local, and tribal officials; researchers; experts in nongovernmental and community-based organizations; and professionals in engineering, architecture, public health, adaptation, and other areas. We are so grateful for their time and expertise. We thank the members and staff of the National Academy of Sciences, Engineering, and Medicine’s Committee to Advise the U.S. Global Change Research Program for providing individual comments on preliminary recommendations during several discussions in open sessions of their meetings. The following individuals provided detailed comments on an earlier version of this report, which greatly sharpened our thinking and recommendations: John Balbus, Tom Dietz, Phil Duffy, Baruch Fischhoff, Brenda Hoppe, Melissa Kenney, Linda Mearns, Claudia Nierenberg, Kathleen Segerson, Soroosh Sorooshian, Chris Weaver, and Brian Zuckerman. Mary Black provided insightful copy editing of several versions of the report. We also thank four anonymous reviewers for their effort and care in critiquing and improving the report. It is the dedication, thoughtful feedback, expertise, care, and commitment of all these people and more that not only made this report possible, but allow us all to continue to support smart and insightful actions in a changing climate. We are grateful as authors and as global citizens. Author contributions: RM, SA, KB, MB, AC, JD, PF, KJ, AJ, KK, JK, ML, JM, RP, TR, LS, JS, JW, and DZ were members of the IAC and shared in researching, discussing, drafting, and approving the report. BA, JF, AG, LJ, SJ, PK, RK, AM, RM, JN, WS, JS, PT, GY, and RZ contributed to specific sections of the report

Behavioral responses of terrestrial mammals to COVID-19 lockdowns

COVID-19 lockdowns in early 2020 reduced human mobility, providing an opportunity to disentangle its effects on animals from those of landscape modifications. Using GPS data, we compared movements and road avoidance of 2300 terrestrial mammals (43 species) during the lockdowns to the same period in 2019. Individual responses were variable with no change in average movements or road avoidance behavior, likely due to variable lockdown conditions. However, under strict lockdowns 10-day 95th percentile displacements increased by 73%, suggesting increased landscape permeability. Animals' 1-hour 95th percentile displacements declined by 12% and animals were 36% closer to roads in areas of high human footprint, indicating reduced avoidance during lockdowns. Overall, lockdowns rapidly altered some spatial behaviors, highlighting variable but substantial impacts of human mobility on wildlife worldwide.acceptedVersio

Behavioral responses of terrestrial mammals to COVID-19 lockdowns

COVID-19 lockdowns in early 2020 reduced human mobility, providing an opportunity to disentangle its effects on animals from those of landscape modifications. Using GPS data, we compared movements and road avoidance of 2300 terrestrial mammals (43 species) during the lockdowns to the same period in 2019. Individual responses were variable with no change in average movements or road avoidance behavior, likely due to variable lockdown conditions. However, under strict lockdowns 10-day 95th percentile displacements increased by 73%, suggesting increased landscape permeability. Animals' 1-hour 95th percentile displacements declined by 12% and animals were 36% closer to roads in areas of high human footprint, indicating reduced avoidance during lockdowns. Overall, lockdowns rapidly altered some spatial behaviors, highlighting variable but substantial impacts of human mobility on wildlife worldwide.acceptedVersio

A communal catalogue reveals Earth’s multiscale microbial diversity

Our growing awareness of the microbial world’s importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth’s microbial diversity

A communal catalogue reveals Earth's multiscale microbial diversity

Our growing awareness of the microbial world's importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth's microbial diversity.Peer reviewe

Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease

BACKGROUND: Acute graft-versus-host disease (GVHD) remains a major limitation of allogeneic stem-cell transplantation; not all patients have a response to standard glucocorticoid treatment. In a phase 2 trial, ruxolitinib, a selective Janus kinase (JAK1 and JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory acute GVHD. METHODS: We conducted a multicenter, randomized, open-label, phase 3 trial comparing the efficacy and safety of oral ruxolitinib (10 mg twice daily) with the investigator's choice of therapy from a list of nine commonly used options (control) in patients 12 years of age or older who had glucocorticoid-refractory acute GVHD after allogeneic stem-cell transplantation. The primary end point was overall response (complete response or partial response) at day 28. The key secondary end point was durable overall response at day 56. RESULTS: A total of 309 patients underwent randomization; 154 patients were assigned to the ruxolitinib group and 155 to the control group. Overall response at day 28 was higher in the ruxolitinib group than in the control group (62% [96 patients] vs. 39% [61]; odds ratio, 2.64; 95% confidence interval [CI], 1.65 to 4.22; P<0.001). Durable overall response at day 56 was higher in the ruxolitinib group than in the control group (40% [61 patients] vs. 22% [34]; odds ratio, 2.38; 95% CI, 1.43 to 3.94; P<0.001). The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group and 39% in the control group. The median failure-free survival was considerably longer with ruxolitinib than with control (5.0 months vs. 1.0 month; hazard ratio for relapse or progression of hematologic disease, non-relapse-related death, or addition of new systemic therapy for acute GVHD, 0.46; 95% CI, 0.35 to 0.60). The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (hazard ratio for death, 0.83; 95% CI, 0.60 to 1.15). The most common adverse events up to day 28 were thrombocytopenia (in 50 of 152 patients [33%] in the ruxolitinib group and 27 of 150 [18%] in the control group), anemia (in 46 [30%] and 42 [28%], respectively), and cytomegalovirus infection (in 39 [26%] and 31 [21%]). CONCLUSIONS: Ruxolitinib therapy led to significant improvements in efficacy outcomes, with a higher incidence of thrombocytopenia, the most frequent toxic effect, than that observed with control therapy