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The rapid technological developments of the past decade and the changes in echocardiographic practice brought about by these developments have resulted in the need for updated recommendations to the previously published guidelines for cardiac chamber quantification, which was the goal of the joint writing group assembled by the American Society of Echocardiography and the European Association of Cardiovascular Imaging. This document provides updated normal values for all four cardiac chambers, including three-dimensional echocardiography and myocardial deformation, when possible, on the basis of considerably larger numbers of normal subjects, compiled from multiple databases. In addition, this document attempts to eliminate several minor discrepancies that existed between previously published guidelines.

We prospectively studied treatment and outcome in 5030 patients in intensive care units at 13 tertiary care hospitals. We stratified each hospital's patients by individual risk of death using diagnosis, indication for treatment, and Acute Physiology and Chronic Health Evaluation (APACHE) II score. We then compared actual and predicted death rates using group results as the standard. One hospital had significantly better results with 69 predicted but 41 observed deaths (p less than 0.0001). Another hospital had significantly inferior results with 58% more deaths than expected (p less than 0.0001). These differences occurred within specific diagnostic categories, for medical patients alone and for medical and surgical patients combined, and were related more to the interaction and coordination of each hospital's intensive care unit staff than to the unit's administrative structure, amount of specialized treatment used, or the hospital's teaching status. Our findings support the hypothesis that the degree of coordination of intensive care significantly influences its effectiveness.

Abstract Here the Human Pangenome Reference Consortium presents a first draft of the human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse individuals 1 . These assemblies cover more than 99% of the expected sequence in each genome and are more than 99% accurate at the structural and base pair levels. Based on alignments of the assemblies, we generate a draft pangenome that captures known variants and haplotypes and reveals new alleles at structurally complex loci. We also add 119 million base pairs of euchromatic polymorphic sequences and 1,115 gene duplications relative to the existing reference GRCh38. Roughly 90 million of the additional base pairs are derived from structural variation. Using our draft pangenome to analyse short-read data reduced small variant discovery errors by 34% and increased the number of structural variants detected per haplotype by 104% compared with GRCh38-based workflows, which enabled the typing of the vast majority of structural variant alleles per sample.

The Ecological Society of America has evaluated current U.S. national policies and practices on biological invasions in light of current scientific knowledge. Invasions by harmful nonnative species are increasing in number and area affected; the damages to ecosystems, economic activity, and human welfare are accumulating. Without improved strategies based on recent scientific advances and increased investments to counter invasions, harm from invasive species is likely to accelerate. Federal leadership, with the cooperation of state and local governments, is required to increase the effectiveness of prevention of invasions, detect and respond quickly to new potentially harmful invasions, control and slow the spread of existing invasions, and provide a national center to ensure that these efforts are coordinated and cost effective. Specifically, the Ecological Society of America recommends that the federal government take the following six actions: (1) Use new information and practices to better manage commercial and other pathways to reduce the transport and release of potentially harmful species; (2) Adopt more quantitative procedures for risk analysis and apply them to every species proposed for importation into the country; (3) Use new cost-effective diagnostic technologies to increase active surveillance and sharing of information about invasive species so that responses to new invasions can be more rapid and effective; (4) Create new legal authority and provide emergency funding to support rapid responses to emerging invasions; (5) Provide funding and incentives for cost-effective programs to slow the spread of existing invasive species in order to protect still uninvaded ecosystems, social and industrial infrastructure, and human welfare; and (6) Establish a National Center for Invasive Species Management (under the existing National Invasive Species Council) to coordinate and lead improvements in federal, state, and international policies on invasive species. Recent scientific and technical advances provide a sound basis for more cost-effective national responses to invasive species. Greater investments in improved technology and management practices would be more than repaid by reduced damages from current and future invasive species. The Ecological Society of America is committed to assist all levels of government and provide scientific advice to improve all aspects of invasive-species management.

Twenty-nine teams involving 61 analysts used the same data set to address the same research question: whether soccer referees are more likely to give red cards to dark-skin-toned players than to light-skin-toned players. Analytic approaches varied widely across the teams, and the estimated effect sizes ranged from 0.89 to 2.93 ( Mdn = 1.31) in odds-ratio units. Twenty teams (69%) found a statistically significant positive effect, and 9 teams (31%) did not observe a significant relationship. Overall, the 29 different analyses used 21 unique combinations of covariates. Neither analysts’ prior beliefs about the effect of interest nor their level of expertise readily explained the variation in the outcomes of the analyses. Peer ratings of the quality of the analyses also did not account for the variability. These findings suggest that significant variation in the results of analyses of complex data may be difficult to avoid, even by experts with honest intentions. Crowdsourcing data analysis, a strategy in which numerous research teams are recruited to simultaneously investigate the same research question, makes transparent how defensible, yet subjective, analytic choices influence research results.

Calcified coronary artery plaque, measured at cardiac computed tomography (CT), is a predictor of cardiovascular disease and may play an increasing role in cardiovascular disease risk assessment. The Multi-Ethnic Study of Atherosclerosis (MESA) and the Coronary Artery Risk Development in Young Adults (CARDIA) study of the National Heart, Lung, and Blood Institute are population-based studies in which calcified coronary artery plaque was measured with electron-beam and multi-detector row CT and a standardized protocol in 6814 (MESA) and 3044 (CARDIA study) participants. The studies were approved by the appropriate institutional review board from the study site or agency, and written informed consent was obtained from each participant. Participation in the CT examination was high, image quality was good, and agreement for the presence of calcified plaque was high (kappa = 0.92, MESA; kappa = 0.77, CARDIA study). Extremely high agreement was observed between and within CT image analysts for the presence (kappa > 0.90, all) and amount (intraclass correlation coefficients, >0.99) of calcified plaque. Measurement of calcified coronary artery plaque with cardiac CT is well accepted by participants and can be implemented with consistently high-quality results with a standardized protocol and trained personnel. If predictive value of calcified coronary artery plaque for cardiovascular events proves sufficient to justify screening a segment of the population, then a standardized cardiac CT protocol is feasible and will provide reproducible results for health care providers and the public.

T he majority of plants used in agriculture, forestry, and horticulture in North America are not native to the continent. Most of the plants that have been introduced are not invasive; they carry out their intended purpose and therefore benefit humans in multiple ways, causing no problems. A small portion of introduced plants, however, escape from cultivation and become pests of natural areas. A recent study found that invasive plants, animals, and fungi are second only to habitat loss and degradation in endangering native plant species Fifty-seven percent of the imperiled species studied were negatively affected by nonnative invasive species. The impacts on native species include competition for resources A recent estimate put the economic cost of invasive plants in natural areas, agriculture, and gardens at $35 billion per year

I. Summary and conclusions, 388. — Loss offset provisions, 391. — II. The rationale of investment behavior: yield and risk defined, 393; yield and risk of an asset combination, 398; investor's indifference map and investment equilibrium, 402. — III. Taxation without loss offset: effects of the tax on yield and risk, tax sensitiveness, 403; adjustment of asset combination held, 405. popular versions of the argument, 408. — IV. Taxation with full loss offset: effects on yield and risk, 409; total risk and private risk distinguished, 410; adjustment of asset combination held, 411; total risk increased as result of tax, 412. — V. The general case, taxation with variable loss offset: effects of varying tax rate and varying loss offset, 415; adjustment of asset combination to changes in tax rate, with given loss offset, 418; adjustment to changes in loss offset, with given tax rate, 419. — VI. Qualifications, 421.

Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.

BACKGROUND: Emicizumab is a bispecific monoclonal antibody that bridges activated factor IX and factor X to replace the function of missing activated factor VIII, thereby restoring hemostasis. In a phase 3, multicenter trial, we investigated its use as prophylaxis in persons who have hemophilia A without factor VIII inhibitors. METHODS: We randomly assigned, in a 2:2:1 ratio, participants 12 years of age or older who had been receiving episodic treatment with factor VIII to receive a subcutaneous maintenance dose of emicizumab of 1.5 mg per kilogram of body weight per week (group A) or 3.0 mg per kilogram every 2 weeks (group B) or no prophylaxis (group C). The primary end point was the difference in rates of treated bleeding (group A vs. group C and group B vs. group C). Participants who had been receiving factor VIII prophylaxis received emicizumab at a maintenance dose of 1.5 mg per kilogram per week (group D); intraindividual comparisons were performed in those who had participated in a noninterventional study. RESULTS: A total of 152 participants were enrolled. The annualized bleeding rate was 1.5 events (95% confidence interval [CI], 0.9 to 2.5) in group A and 1.3 events (95% CI, 0.8 to 2.3) in group B, as compared with 38.2 events (95% CI, 22.9 to 63.8) in group C; thus, the rate was 96% lower in group A and 97% lower in group B (P<0.001 for both comparisons). A total of 56% of the participants in group A and 60% of those in group B had no treated bleeding events, as compared with those in group C, who all had treated bleeding events. In the intraindividual comparison involving 48 participants, emicizumab prophylaxis resulted in an annualized bleeding rate that was 68% lower than the rate with previous factor VIII prophylaxis (P<0.001). The most frequent adverse event was low-grade injection-site reaction. There were no thrombotic or thrombotic microangiopathy events, development of antidrug antibodies, or new development of factor VIII inhibitors. CONCLUSIONS: Emicizumab prophylaxis administered subcutaneously once weekly or every 2 weeks led to a significantly lower bleeding rate than no prophylaxis among persons with hemophilia A without inhibitors; more than half the participants who received prophylaxis had no treated bleeding events. In an intraindividual comparison, emicizumab therapy led to a significantly lower bleeding rate than previous factor VIII prophylaxis. (Funded by F. Hoffmann-La Roche and Chugai Pharmaceutical; HAVEN 3 ClinicalTrials.gov number, NCT02847637 .).

The scientific literature contains numerous descriptions of observed and potential effects of global climate change on species and ecosystems. In response to anticipated effects of climate change, conservation organizations and government agencies are developing "adaptation strategies" to facilitate the adjustment of human society and ecological systems to altered climate regimes. We reviewed the literature and climate-change adaptation plans that have been developed in United States, Canada, England, México, and South Africa and found 16 general adaptation strategies that relate directly to the conservation of biological diversity. These strategies can be grouped into four broad categories: land and water protection and management; direct species management; monitoring and planning; and law and policy. Tools for implementing these strategies are similar or identical to those already in use by conservationists worldwide (land and water conservation, ecological restoration, agrienvironment schemes, species translocation, captive propagation, monitoring, natural resource planning, and legislation/regulation). Although our review indicates natural resource managers already have many tools that can be used to address climate-change effects, managers will likely need to apply these tools in novel and innovative ways to meet the unprecedented challenges posed by climate change.

The Salafi movement (often referred to as the Wahhabis) includes such diverse figures as Osama bin Laden and the Mufti of Saudi Arabia and reflects a broad array of positions regarding issues related to politics and violence. This article explains the sources of unity that connect violent extremists with nonviolent puritans. Although Salafis share a common religious creed, they differ over their assessment of contemporary problems and thus how this creed should be applied. Differences over contextual interpretation have produced three major Salafi factions: purists, politicos, and jihadis.

Individual goods and social goods compared, 27. — Quantitative measurement of social goods, 28. — Ideal output of social goods, 30. — Individual voting on outputs, 32. — Individual voting on increments to existing outputs, 40. — Alternatives to voting, 42. — Distributing the cost of social goods, 44. — Social goods not equally available to all voters, 47.

OBJECTIVE: A treatment plan to be used in patients with peritoneal carcinomatosis was devised and tested as a Phase II study. BACKGROUND: Peritoneal carcinomatosis from appendical or colorectal cancer has been regarded as a fatal clinical entity. Treatment protocols have not been reported previously. METHODS: The authors used cytoreductive surgery and intraperitoneal chemotherapy to treat 181 consecutive patients with peritoneal carcinomatosis. There were 51 patients with colorectal cancer and 130 patients with appendiceal cancer. Mean follow-up is 24 months, with a range of 0 to 149 months. RESULTS: Clinical features that showed prognostic significance included appendiceal versus colorectal primary tumors (p = 0.0001), grade 1 versus grades 2 and 3 histopathology (p = 0.0003), complete versus incomplete cytoreductions (p = 0.0001), lymph node-negative versus lymph node-positive primary tumors (p = 0.0001), and volume of peritoneal carcinomatosis present preoperatively for colon cancer (p = 0.0006). Features with no statistical prognostic significance included preoperative tumor volume for appendiceal cancer, age, sex, number of cycles of chemotherapy, operative time, complications, blood loss, and institution providing treatment. From these prognostic features, four prognostic groups were identified, and 3-year survival was estimated by the product-limit survival method. Group I patients (n = 76) were those with grade 1 histology, no lymph node metastases, and complete cytoreductions (survival at 3 years = 99%). Group II patients (n = 23) were those with grade 2 or 3 histology, no lymph node metastases, and complete cytoreductions (65%). Group III patients (n = 24) had any histology, lymph node metastases, and complete cytoreductions (66%). Group IV patients (n = 58) had incomplete cytoreductions (20%).

BACKGROUND: Ian Taylor introduced the angiosome concept, separating the body into distinct three-dimensional blocks of tissue fed by source arteries. Understanding the angiosomes of the foot and ankle and the interaction among their source arteries is clinically useful in surgery of the foot and ankle, especially in the presence of peripheral vascular disease. METHODS: In 50 cadaver dissections of the lower extremity, arteries were injected with methyl methacrylate in different colors and dissected. Preoperatively, each reconstructive patient's vascular anatomy was routinely analyzed using a Doppler instrument and the results were evaluated. RESULTS: There are six angiosomes of the foot and ankle originating from the three main arteries and their branches to the foot and ankle. The three branches of the posterior tibial artery each supply distinct portions of the plantar foot. The two branches of the peroneal artery supply the anterolateral portion of the ankle and rear foot. The anterior tibial artery supplies the anterior ankle, and its continuation, the dorsalis pedis artery, supplies the dorsum of the foot. Blood flow to the foot and ankle is redundant, because the three major arteries feeding the foot have multiple arterial-arterial connections. By selectively performing a Doppler examination of these connections, it is possible to quickly map the existing vascular tree and the direction of flow. CONCLUSIONS: Detailed knowledge of the vascular anatomy of the foot and ankle allows the plastic surgeon to plan vascularly sound reconstructions, the foot and ankle surgeon to design safe exposures of the underlying skeleton, and the vascular surgeon to choose the most effective revascularization for a given wound.

Nervous system involvement by sarcoidosis has been considered rare, yet more than 400 cases have been reported. We present 23 additional cases here, including 14 with autopsies, and we review the literature. The overall frequency of neurologic involvement is 5%. Patients usually have other stigmata of sarcoidosis; however, neurologic dysfunction is frequently the presenting finding. The protean manifestations of central nervous system (CNS) involvement usually occur in the early phase of the disease, while those of peripheral nervous system and skeletal muscle involvement are characteristically seen in the chronic stages. Basal granulomatous meningitis causes most of the CNS manifestations either by infiltration or compression of adjacent structures. Steroids are the mainstay of therapy, and the overall response is quite variable. The course is also variable, being transient in some and chronic in others. The prognosis is better with peripheral than with central nervous system involvement.

The human reference genome is the most widely used resource in human genetics and is due for a major update. Its current structure is a linear composite of merged haplotypes from more than 20 people, with a single individual comprising most of the sequence. It contains biases and errors within a framework that does not represent global human genomic variation. A high-quality reference with global representation of common variants, including single-nucleotide variants, structural variants and functional elements, is needed. The Human Pangenome Reference Consortium aims to create a more sophisticated and complete human reference genome with a graph-based, telomere-to-telomere representation of global genomic diversity. Here we leverage innovations in technology, study design and global partnerships with the goal of constructing the highest-possible quality human pangenome reference. Our goal is to improve data representation and streamline analyses to enable routine assembly of complete diploid genomes. With attention to ethical frameworks, the human pangenome reference will contain a more accurate and diverse representation of global genomic variation, improve gene-disease association studies across populations, expand the scope of genomics research to the most repetitive and polymorphic regions of the genome, and serve as the ultimate genetic resource for future biomedical research and precision medicine.

Klopp, Calvin T. M.D.; Alford, T. Crandall M.D.; Bateman, Jeanne M.D.; Berry, G. Neill M.D.; Winship, T. M.D. Author Information

The presence of airways obstruction identify in middle-aged male smokers at increased risk for lung cancer. This hypothesis was tested in a sample of patients with moderate to severe obstruction from the Intermittent Positive Pressure Breathing Trial and a sample of patients with no obstruction to moderate obstruction from the Johns Hopkins Lung Project, all of whom were followed for the development of lung cancer. On follow-up, the risk of developing lung cancer was found to be associated with entry values for age, smoking, and ventilatory status by linear, proportional hazard, and log-linear adjustment techniques. Among cigarette smokers, the presence of airways obstruction was more of an indicator for the subsequent development of lung cancer than was age or the level of smoking. The risk for lung cancer also increased in proportion to the degree of airways obstruction. These data suggest that smokers with ventilatory obstruction are at greater risk for lung cancer than are smokers without obstruction.

ABSTRACT From the approach of the geological oceanographer, this paper attempts to develop rational lines of reasoning for hindcasting how nature disposed of sediments brought into a lake or ocean at a particular place and time. By assuming the ocean to be a currentless, tideless, wave-free basin, jet theory as developed by Tollmien and subsequent workers is utilized in determining the magnitude and interrelations of limnological and oceanographic phenomena observed off mouths of sediment-laden rivers. To do this, the basic theory of jets is modified by introducing a rotating fluid system and postulating a hydraulic head at the orifice. If a delta is defined as a sedimentary deposit built by jet flow into or within a permanent body of water, these modifications allow for the existence of three basic types of deltaic deposits, depending on the density contrast between entraining and entrained fluids. Examples of these different types of inflow are cited from the Mississippi Delta region. In the case of hyperpycnal inflow (inflow more dense), it is suggested that turbidity currents carrying coarse-grained material during glacial stages eroded the Mississippi Submarine Canyon and supplied the material for the submarine delta off the canyon’s mouth. Homopycnal inflow (inflow equally dense), which gives rise to the deltaic deposit characterized by classical top-, fore-, and bottom-set beds, is described for the Lake Ponchartrain, Louisiana, area when the Bonnet Carre Floodway is in operation and for crevasses in the Lower Mississippi River. Hypopycnal inflow (inflow less dense) is discussed in some detail, including such aspects as flocculation effects, lunate bar development at river mouths, development of distributaries and flank depressions, the seaward movement of river water upon leaving the river’s mouths, and effects of the earth’s rotation. Modifying effects of wind, waves, and tides on deltaic deposits are discussed briefly.