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

Sectoral Transformations in Neo-Patrimonial Rentier States: Tourism Development and State Policy in Egypt

This article challenges claims that liberalising state regulated markets in developing countries may induce lasting economic development. The analysis of the rise of tourism in Egypt during the last three decades suggests that the effects of liberalisation and structural adjustment are constrained by the neo-patrimonial character of the Egyptian political system. Since the decline of oil rent revenues during the 1980s tourism development was the optimal strategy to compensate for the resulting fiscal losses. Increasing tourism revenues have helped in coping with macroeconomic imbalances and in avoiding more costly adjustment of traditional economic sectors. Additionally, they provided the private elite with opportunities to generate large profits. Therefore, sectoral transformations due to economic liberalisation in neo-patrimonial Rentier states should be described as a process, which has led to the diversification of external rent revenues, rather than to a general downsizing of the Rentier character of the economy

A Multicenter, Randomized, Placebo‐Controlled Trial of Atorvastatin for the Primary Prevention of Cardiovascular Events in Patients With Rheumatoid Arthritis

Objective: Rheumatoid arthritis (RA) is associated with increased cardiovascular event (CVE) risk. The impact of statins in RA is not established. We assessed whether atorvastatin is superior to placebo for the primary prevention of CVEs in RA patients. Methods: A randomized, double‐blind, placebo‐controlled trial was designed to detect a 32% CVE risk reduction based on an estimated 1.6% per annum event rate with 80% power at P 50 years or with a disease duration of >10 years who did not have clinical atherosclerosis, diabetes, or myopathy received atorvastatin 40 mg daily or matching placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, transient ischemic attack, or any arterial revascularization. Secondary and tertiary end points included plasma lipids and safety. Results: A total of 3,002 patients (mean age 61 years; 74% female) were followed up for a median of 2.51 years (interquartile range [IQR] 1.90, 3.49 years) (7,827 patient‐years). The study was terminated early due to a lower than expected event rate (0.70% per annum). Of the 1,504 patients receiving atorvastatin, 24 (1.6%) experienced a primary end point, compared with 36 (2.4%) of the 1,498 receiving placebo (hazard ratio [HR] 0.66 [95% confidence interval (95% CI) 0.39, 1.11]; P = 0.115 and adjusted HR 0.60 [95% CI 0.32, 1.15]; P = 0.127). At trial end, patients receiving atorvastatin had a mean ± SD low‐density lipoprotein (LDL) cholesterol level 0.77 ± 0.04 mmoles/liter lower than those receiving placebo (P < 0.0001). C‐reactive protein level was also significantly lower in the atorvastatin group than the placebo group (median 2.59 mg/liter [IQR 0.94, 6.08] versus 3.60 mg/liter [IQR 1.47, 7.49]; P < 0.0001). CVE risk reduction per mmole/liter reduction in LDL cholesterol was 42% (95% CI −14%, 70%). The rates of adverse events in the atorvastatin group (n = 298 [19.8%]) and placebo group (n = 292 [19.5%]) were similar. Conclusion: Atorvastatin 40 mg daily is safe and results in a significantly greater reduction of LDL cholesterol level than placebo in patients with RA. The 34% CVE risk reduction is consistent with the Cholesterol Treatment Trialists’ Collaboration meta‐analysis of statin effects in other populations

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

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

ODT’s OTIA III Bridge Program: Three Years of Environmental Stewardship

The purpose of the environmental stewardship framework is to deliver projects that are sensitive to their communities and landscape while streamlining the permitting process. After three years of implementation, we have successfully maintained the collaborative approach with regulatory partners. This has been critical to our success in avoidance and minimization of project impacts.The OTIA III State Bridge Delivery Program (the Program) is part of the Oregon Department of Transportation’s (ODOT) 10-year, $3 billion Oregon Transportation Investment Act (OTIA) program. OTIA funds will repair or replace hundreds of bridges, pave and maintain city and county roads, improve and expand interchanges, add new capacity to Oregon’s highway system, and remove freight bottlenecks statewide.Oregon Bridge Delivery Partners (OBDP), a joint venture formed by HDR Engineering Inc. and Fluor Enterprises Inc., is a private-sector firm that has contracted with the ODOT to manage the$1.3 billion state bridge program. OBDP has developed a framework to integrate the myriad of tools developed for the Program, including environmental performance standards, a joint batched-programmatic biological opinion, environmental and engineering baseline reports, and a web-based GIS. The purpose of this framework is to identify environmental concerns early in the project development process and communicate these concerns to design teams and regulatory agencies to promote environmental stewardship through impact avoidance and minimization.Innovative and creative use of technology has been a keystone to the framework. Environmental professionals input the relevant environmental data for a project in a comprehensive, on-line Pre-Construction Assessment (PCA) form. The data are used to identify project challenges (e.g., archaeological sites or wetlands within the project footprint) and compile electronic reports to the regulatory agencies. Environmental metrics, such as exempted T&amp;E species “take” and wetland fill quantities are tracked using the GIS database. One framework meets the needs of many stakeholders.Now, after almost three years of execution, OBDP and ODOT have some great successes and lessons learned to share. OBDP have continued to adapt and develop tools to be successful – as well as shift the Program operating structure. The focus of this presentation will be on the framework that has been utilized to maintain compliance and strive for environmental excellence

The first tetrapod from the mid-Miocene Clarkia lagerstätte (Idaho, USA)

The Clarkia lagerstätte (Latah Formation) of Idaho is well known for its beautifully preserved plant fossils as well as a fauna of insects and fish. Here we present the first known tetrapod fossil from these deposits. This specimen, recovered from the lower anoxic zone of the beds, is preserved as a carbonaceous film of a partial skeleton associated with a partial lower incisor and some tooth fragments. The morphology of the teeth indicates that the first tetrapod reported from Clarkia is a rodent. Its skeletal morphology as well as its bunodont and brachydont dentition suggests that it is a member of the squirrel family (Sciuridae). It is a large specimen that cannot be assigned to a known genus. Instead, it appears to represent the first occurrence of a new taxon with particularly gracile postcranial morphology likely indicative of an arboreal ecology. This new specimen is a rare glimpse into the poorly known arboreal mammal fossil record of the Neogene. It supports a greater taxonomic and ecological diversity of Miocene Sciuridae than previously recognized and offers new lines of inquiry in the paleoecological research enabled by the unique preservation conditions of the Clarkia biota