A Model for Assessing the Visual Resources of River Basins as an Aid to Making Landuse Planning Decisions

The visual quality of a river basin and its associated properties can be identified, evaluated and integrated into the landscape planning process. The model developed provides a quantitative methodology for determining visual quality on the basis of available Geographic Information System factors. These factors are utilized to develop the preference attributes, COLOR, FORM, TEXTURE and LINE, which are associated with the assessment of visual quality. The preference attributes are then combined through a decision making process into a continuum of DISTINCTIVE, GOOD, AVERAGE and MINIMAL visual quality and is expressed digitally in map format. By providing visual quality information in a digital format it can be treated as a discrete component of the planning process similar to physical, cultural and economic attributes

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

A roadmap for development of neuro-oscillations as translational biomarkers for treatment development in neuropsychopharmacology

New treatment development for psychiatric disorders depends critically upon the development of physiological measures that can accurately translate between preclinical animal models and clinical human studies. Such measures can be used both as stratification biomarkers to define pathophysiologically homogeneous patient populations and as target engagement biomarkers to verify similarity of effects across preclinical and clinical intervention. Traditional "time-domain" event-related potentials (ERP) have been used translationally to date but are limited by the significant differences in timing and distribution across rodent, monkey and human studies. By contrast, neuro-oscillatory responses, analyzed within the "time-frequency" domain, are relatively preserved across species permitting more precise translational comparisons. Moreover, neuro-oscillatory responses are increasingly being mapped to local circuit mechanisms and may be useful for investigating effects of both pharmacological and neuromodulatory interventions on excitatory/inhibitory balance. The present paper provides a roadmap for development of neuro-oscillatory responses as translational biomarkers in neuropsychiatric treatment development

Natural killer cell–mediated inflammation resolution is disabled in severe asthma

Severe asthma is typically characterized by chronic airway inflammation that is refractory to corticosteroids and associated with excess morbidity. Patients were recruited into the National Heart, Lung, and Blood Institute-sponsored Severe Asthma Research Program and comprehensively phenotyped by bronchoscopy. Bronchoalveolar lavage (BAL) cells were analyzed by flow cytometry. Compared with healthy individuals (n = 21), patients with asthma (n = 53) had fewer BAL natural killer (NK) cells. Patients with severe asthma (n = 29) had a marked increase in the ratios of CD4+ T cells to NK cells and neutrophils to NK cells. BAL NK cells in severe asthma were skewed toward the cytotoxic CD56dim subset, with significantly increased BAL fluid levels of the cytotoxic mediator granzyme A. The numbers of BAL CD56dim NK cells and CCR6-CCR4- T helper 1-enriched CD4+ T cells correlated inversely with lung function [forced expiratory volume in 1 s (FEV1) % predicted] in asthma. Relative to cells from healthy controls, peripheral blood NK cells from asthmatic patients had impaired killing of K562 myeloid target cells despite releasing more cytotoxic mediators. Ex vivo exposure to dexamethasone markedly decreased blood NK cell lysis of target cells and cytotoxic mediator release. NK cells expressed airway lipoxin A4/formyl peptide receptor 2 receptors, and in contrast to dexamethasone, lipoxin A4-exposed NK cells had preserved functional responses. Together, our findings indicate that the immunology of the severe asthma airway is characterized by decreased NK cell cytotoxicity with increased numbers of target leukocytes, which is exacerbated by corticosteroids that further disable NK cell function. These failed resolution mechanisms likely contribute to persistent airway inflammation in severe asthma

Preventing asthma in high risk kids (PARK) with omalizumab: Design, rationale, methods, lessons learned and adaptation.

Asthma remains one of the most important challenges to pediatric public health in the US. A large majority of children with persistent and chronic asthma demonstrate aeroallergen sensitization, which remains a pivotal risk factor associated with the development of persistent, progressive asthma throughout life. In individuals with a tendency toward Type 2 inflammation, sensitization and exposure to high concentrations of offending allergens is associated with increased risk for development of, and impairment from, asthma. The cascade of biological responses to allergens is primarily mediated through IgE antibodies and their production is further stimulated by IgE responses to antigen exposure. In addition, circulating IgE impairs innate anti-viral immune responses. The latter effect could magnify the effects of another early life exposure associated with increased risk of the development of asthma – viral infections. Omalizumab binds to circulating IgE and thus ablates antigen signaling through IgE-related mechanisms. Further, it has been shown restore IFN-α response to rhinovirus and to reduce asthma exacerbations during the viral season. We therefore hypothesized that early blockade of IgE and IgE mediated responses with omalizumab would prevent the development and reduce the severity of asthma in those at high risk for developing asthma. Herein, we describe a double-blind, placebo-controlled trial of omalizumab in 2–3 year old children at high risk for development of asthma to prevent the development and reduce the severity of asthma. We describe the rationale, methods, and lessons learned in implementing this potentially transformative trial aimed at prevention of asthma