Allyl Derivatives of Sympathomimetic Amines

The allyl group was substituted on the side chains of benzedrine and ephedrine in the belief that these derivatives would antagonize the parent compounds. Their antagonistic effect was clearly demonstrated; the action was believed to be due to reaction at the receptors in the muscles

Gulf Stream recirculation experiment - Part II

This report presents trajectories and time series of velocity, pressure, and temperature for twelve neutrally-buoyant floats launched during the Gulf Stream Recirculation EXperiment (GUSREX) and two from earlier experiments, that continued to operate after May 1982. These float data were obtained from Autonomous Listening Stations (ALSs) deployed from May 1982 to August 1985.Funding was provided by the national Science Foundation under Grant Numbers OCE 81-09145 and OCE 81-1746

SOFAR float trajectories in the tropical Atlantic 1989-1992

Neutrally buoyant SOFAR floats at nominal depths of 800 m, 1800 m, and 3300 m were tracked acoustically for 3.7 years in the vicinity of the western boundary and the equator of the Atlantic Ocean. Trajectories and summaries from the whole experiment are shown along with detailed trajectories from the second setting of the listening stations, October 1990 to September 1992. Some highlights are mentioned below. Trajectories at 1800 m revealed a swift narrow southward flowing deep western boundary current (DWBC) extending from 7°N across the equator. Two floats directly crossed the equator in the DWBC and went to 10°S. Two other floats left the DWBC near the equator and drifted eastward. Three floats entered the DWBC from the equatorial current system and drifted southward. No obvious DWBC or swift equatorial currents were observed by the 3300 m floats. The 800 m floats plus some surface drifters measured seven anticyclonic eddies as they translated northwestward along the coast of South America in a band from the equator to 12°N. One of the floats (28) entered the Caribbean where tracking stopped. This float was again tracked as it drifted across the mid-Atlantic Ridge and entered the Canary Basin near 34°N 28°W after a gap of 2.7 years. We infer that this float went westward though the Caribbean and northeastward in the Gulf Stream. Float 17 drifted northward from 10°N to 22°N in an eastern boundary current off the coast of West Africa. Floats between 6°N-6°S (roughly) drifted long distances zonally in the equatorial current system.Funding was provided by the National Science Foundation through Grants Nos. OCE85-21082, OCE85-17375, and OCE91-14656

North Brazil Current Rings Experiment : RAFOS float data report : November 1998 – June 2000

Twenty-one RAFOS floats were tracked at depths of 200-1000 meters in and around several North Brazil Current Rings between November 1998 and June 2000. This was part of an experiment to study the role of these current rings in transporting upper level South Atlantic water across the equatorial-tropical gyre boundary into the North Atlantic subtropical gyre. The float trajectories in combination with surface drifters and satellite imagery reveal the sometimes complex life histories of several rings and their fate as they collide with the Lesser Antilles Islands. This report describes the float trajectories, the velocity, temperature, and depth time series, and a preliminary analysis of the float data.Funding was provided by the National Science Foundation under Grant No. OCE-9729765 and OCE-0136477

SOFAR float trajectories from an experiment to measure the Atlantic cross equatorial flow (1989-1990)

Neutrally buoyant SOFAR floats at nominal depths of 800, 1800, and 3300 m were tracked for 21 months in the vicinity of western boundary currents near 6N and at several sites in the Atlantic near 11N and along the equator. Trajectories at 1800 m show a swift (>50 cm/sec), narrow (100 km wide) southward-flowing Deep Western Boundary Current (DWBC) extending from 7N to the equator. At times (February-March 1989) DWBC water turned eastward and flowed along the equator and at other times (August-September 1990) the DWBC crossed the equator and continued southward. The mean velocity near the equator was eastward from February 1989 to February 1990 and westward from March 1990 to November 1990. Thus the cross-equatorial flow in the DWBC appeared to be linked to the direction of equatorial currents which varied over periods of more than a year. No obvious DWBC nor swift equatorial current was observed by 3300 m floats. Eight-hundred-meter floats revealed a northwestward intermediate level western boundary current although flow patterns were complicated. Three floats that significantly contributed to the northwestward flow looped in anticyclonic eddies that translated up the coast at 8 cm/sec. Six 800 m floats drifted eastward along the equator between 5S and 6N at a mean velocity of 11 cm/sec; one reached 5W in the Gulf of Guinea, suggesting that the equatorial current extended at least 35-40° along the equator. Three of these floats reversed direction near the end of the tracking period, implying low frequency fluctuations.Funding was provided by the National Science Foundation through Grant Nos. OCE-8521082, OCE-8517375, and OCE-9114656

Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach

Background The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain. Methods and Findings We conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs that replicated across cohorts; BMI-related differential methylation was associated with concurrent changes in the expression of genes in lipid metabolism pathways. Genetic instrumental variable analysis of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to sterol regulatory element binding transcription factor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci was found to be secondary to differences in BMI. However, the cross-sectional nature of the data limits definitive causal determination. Conclusions We present robust associations of BMI with differential DNA methylation at numerous loci in blood cells. BMI-related DNA methylation and gene expression provide mechanistic insights into the relationship between DNA methylation, obesity, and adiposity-related diseases

Phase 1 Trials of rVSV Ebola Vaccine in Africa and Europe.

BACKGROUND: The replication-competent recombinant vesicular stomatitis virus (rVSV)-based vaccine expressing a Zaire ebolavirus (ZEBOV) glycoprotein was selected for rapid safety and immunogenicity testing before its use in West Africa. METHODS: We performed three open-label, dose-escalation phase 1 trials and one randomized, double-blind, controlled phase 1 trial to assess the safety, side-effect profile, and immunogenicity of rVSV-ZEBOV at various doses in 158 healthy adults in Europe and Africa. All participants were injected with doses of vaccine ranging from 300,000 to 50 million plaque-forming units (PFU) or placebo. RESULTS: No serious vaccine-related adverse events were reported. Mild-to-moderate early-onset reactogenicity was frequent but transient (median, 1 day). Fever was observed in up to 30% of vaccinees. Vaccine viremia was detected within 3 days in 123 of the 130 participants (95%) receiving 3 million PFU or more; rVSV was not detected in saliva or urine. In the second week after injection, arthritis affecting one to four joints developed in 11 of 51 participants (22%) in Geneva, with pain lasting a median of 8 days (interquartile range, 4 to 87); 2 self-limited cases occurred in 60 participants (3%) in Hamburg, Germany, and Kilifi, Kenya. The virus was identified in one synovial-fluid aspirate and in skin vesicles of 2 other vaccinees, showing peripheral viral replication in the second week after immunization. ZEBOV-glycoprotein-specific antibody responses were detected in all the participants, with similar glycoprotein-binding antibody titers but significantly higher neutralizing antibody titers at higher doses. Glycoprotein-binding antibody titers were sustained through 180 days in all participants. CONCLUSIONS: In these studies, rVSV-ZEBOV was reactogenic but immunogenic after a single dose and warrants further evaluation for safety and efficacy. (Funded by the Wellcome Trust and others; ClinicalTrials.gov numbers, NCT02283099, NCT02287480, and NCT02296983; Pan African Clinical Trials Registry number, PACTR201411000919191.)

The genetic determinants of recurrent somatic mutations in 43,693 blood genomes

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences

Trends in Use of Medication to Treat Opioid Use Disorder During the COVID-19 Pandemic in 10 State Medicaid Programs

Federal and state agencies granted temporary regulatory waivers to prevent disruptions in access to medication for opioid use disorder (MOUD) during the COVID-19 pandemic, including expanding access to telehealth for MOUD. Little is known about changes in MOUD receipt and initiation among Medicaid enrollees during the pandemic.To examine changes in receipt of any MOUD, initiation of MOUD (in-person vs telehealth), and the proportion of days covered (PDC) with MOUD after initiation from before to after declaration of the COVID-19 public health emergency (PHE).This serial cross-sectional study included Medicaid enrollees aged 18 to 64 years in 10 states from May 2019 through December 2020. Analyses were conducted from January through March 2022.Ten months before the COVID-19 PHE (May 2019 through February 2020) vs 10 months after the PHE was declared (March through December 2020).Primary outcomes included receipt of any MOUD and outpatient initiation of MOUD via prescriptions and office- or facility-based administrations. Secondary outcomes included in-person vs telehealth MOUD initiation and PDC with MOUD after initiation.Among a total of 8 167 497 Medicaid enrollees before the PHE and 8 181 144 after the PHE, 58.6% were female in both periods and most enrollees were aged 21 to 34 years (40.1% before the PHE; 40.7% after the PHE). Monthly rates of MOUD initiation, representing 7% to 10% of all MOUD receipt, decreased immediately after the PHE primarily due to reductions in in-person initiations (from 231.3 per 100 000 enrollees in March 2020 to 171.8 per 100 000 enrollees in April 2020) that were partially offset by increases in telehealth initiations (from 5.6 per 100 000 enrollees in March 2020 to 21.1 per 100 000 enrollees in April 2020). Mean monthly PDC with MOUD in the 90 days after initiation decreased after the PHE (from 64.5% in March 2020 to 59.5% in September 2020). In adjusted analyses, there was no immediate change (odds ratio [OR], 1.01; 95% CI, 1.00-1.01) or change in the trend (OR, 1.00; 95% CI, 1.00-1.01) in the likelihood of receipt of any MOUD after the PHE compared with before the PHE. There was an immediate decrease in the likelihood of outpatient MOUD initiation (OR, 0.90; 95% CI, 0.85-0.96) and no change in the trend in the likelihood of outpatient MOUD initiation (OR, 0.99; 95% CI, 0.98-1.00) after the PHE compared with before the PHE.In this cross-sectional study of Medicaid enrollees, the likelihood of receipt of any MOUD was stable from May 2019 through December 2020 despite concerns about potential COVID-19 pandemic–related disruptions in care. However, immediately after the PHE was declared, there was a reduction in overall MOUD initiations, including a reduction in in-person MOUD initiations that was only partially offset by increased use of telehealth

Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium

Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10−8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations