Prognostic modeling studies of the Keweenaw Current in Lake Superior. Part II: Simulation,

ABSTRACT The formation and evolution of the Keweenaw Current in Lake Superior were examined using a nonorthogonalcoordinate primitive equation numerical model. The model was initialized by the monthly averaged temperature field observed in June and September 1973 and run prognostically under different forcing conditions with and without winds. As a Rossby adjustment problem, the model predicted the formation of a well-defined coastal current jet within an inertial period of 16.4 h after the current field adjusted to the initial temperature field. The magnitude and direction of this current jet varied with the cross-shelf temperature gradient and wind velocity. It tended to intensify during northeastward (downwelling favorable) winds, and to lessen, or even reverse, during southwestward to northwestward (upwelling favorable) or southeastward (downwelling favorable) winds. In a case with strong stratification and without external atmospheric forcings, a well-defined clockwise warm-core eddy formed near the northeastern coast of the Keweenaw Peninsula as a result of baroclinic instability. A warmcore eddy was detected recently from satellite surface temperature images, the shape and location of which were very similar to those of the model-predicted eddy. The energy budget analysis suggested that the eddy kinetic energy grew exponentially over a timescale of 7 days. Growth was due to a rapid energy transfer from available eddy potential energy. The subsequent decline of the eddy kinetic energy was the result of turbulent diffusion, transfer from the eddy kinetic energy to mean kinetic energy, and outward net energy flux

A Modeling Study of Benthic Detritus Flux\u27s Impacts on Heterotrophic Processes in Lake Michigan

Effects of sediment resuspension-induced benthic detrital flux on the heterotrophic part of the microbial food web in Lake Michigan were examined using a three-dimensional (3-D) coupled biological and physical model. The model was driven by the realistic meteorological forcing observed in March 1999. Wind-induced surface wave dynamics were incorporated into the physical model to generate the bottom flux. The model-generated benthic detrital flux was assumed to be proportional to the difference between model-calculated and critical stresses at the bottom. The model results indicate that detrital flux at the bottom was a key factor causing a significant increase of phosphorus and detritus concentrations in the nearshore region of the springtime plume. Inside the plume the sediment-resuspended bottom detritus flux could directly enhance heterotrophic production, while outside the plume, detrital flux from river discharge might have a direct contribution to the high abundance of bacteria and microzooplankton in the nearshore region. Model-data comparison on cross-shore transects near Chicago, Gary, St. Joseph, and Racine suggests that other physical and biological processes may play a comparative role as the bottom detritus flux in terms of the spatial distribution of bacteria and microzoplankton. A more complete microbial food web model needs to be developed to simulate the heterotrophic process in southern Lake Michigan

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

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

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

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

Documenting complex surface temperature patterns from advanced very high resolution radiometer (AVHRR) imagery of Saginaw Bay, Lake Huron

Interannual differences in nutrient concentrations, phytoplankton densities, and the dispersal of zooplankton and fish life history stages (e.g., planktonic larvae, resting eggs) in embayments often are contingent upon bay and coastal water exchange and movements. However, predicting water mass exchange is difficult in that many factors influence the circulation of waters within bays. The central theme of this contribution is that circulation phenomena derived from simple models can be identified and classified using satellite-obtained lake surface temperature maps, and the incidence of events related to gross temperature regime (season) and winds (shorter-term perturbations). To illustrate this potential, the high sampling frequency of AVHRR imagery was used to examine seasonal surface temperature patterns between Saginaw Bay and Lake Huron over a 3-year period. Linear regressions of CoastWatch IMGMAP and OCNMAP daytime sea surface temperature (SST) algorithms against shipboard bulk temperatures were highly significant, with r2 values of 0.98 and 0.94. Synoptic reconnaissance of lake surface temperatures from AVHRR verified many previously known general seasonal events, yet provided much better spatial coverage. The thermal bar persisted in the bay for approximately 6 weeks from late April until mid-June. The combination of shallow depths and impounded river discharges caused inner bay waters to warm more rapidly than outer bay and open lake waters. A thermal gradient of 6 to 10°C persisted between the inner bay and Lake Huron waters throughout the summer. The persistence of major spatial thermal gradients restricted mixing of inner bay waters with the outer bay and open lake, whereas inner and outer bay temperatures converged during fall months, increasing the likelihood of mixing. However, frequent wind-induced effects can cause circulation reversals and move surface waters in quite complex patterns across the bay. AVHRR image classification confirms the sensitivity of inner bay waters to wind stress-related circulation, aiding interpretations of historical data sets

A non-orthogonal primitive equation coastal ocean circulation model: Application to Lake Superior

A non-orthogonal coordinate primitive equation model has been developed for the study of the Keweenaw Current in Lake Superior. This model provides a more accurate fitting of the coastline. A comparison with a curvilinear orthogonal model shows that the non-orthogonal transformation model provided a better simulation of the current jet in the near-shore region. Accurate fitting of both bathymetry and irregular coastlines plays an essential role in capturing the magnitude of the Keweenaw Current and cross-shelf structure of the thermal bar near the coast. The formation of the Keweenaw Current and thermal front was directly driven by a westerly or southwesterly wind and seasonal development of stratification over steep bottom topography. Under a condition with accurate fitting of steep bathymetry, failure to resolve the irregular geometry of the coastline can result in an underestimation of the magnitude of the Keweenaw Current by about 20 cm/s

Response of Lake Superior to mesoscale wind forcing: A comparison between currents driven by QuikSCAT and buoy winds

The satellite scatterometer QuikSCAT wind field has been available every 12 hours on Lake Superior since 19 July 1999. The wind data cover most of the interior area of the lake with a spatial resolution of about 25 km. Driving the three-dimensional Lake Superior circulation model by the QuikSCAT winds, we resimulated the 1999 seasonal variability of currents in Lake Superior. A comparison was made with our previous simulation results, which relied on the wind field interpolated from moored buoys and land-based meteorological stations. The model driven by QuikSCAT winds improved the simulation of the spatial coverage area of the cold band during upwelling favorable wind events and the current jet during downwelling favorable wind events observed along the Keweenaw coast in July-October 1999. A statistical analysis shows that these improvements were mainly reflected in the low-frequency variation of the long-shore current, even though the overall deviation between computed and observed surface temperature and currents was measurably reduced. This study suggests that the wind field constructed from either moored buoys plus land-based meteorological stations or QuikSCAT is not sufficient to provide a reliable and accurate simulation of coastal currents and stratification in Lake Superior. A mesoscale meteorological model assimilated with observed winds on all the available weather measurement sites or stations or QuikSCAT is needed to provide an accurate meteorological forcing for the Lake Superior physical model. Copyright 2004 by the American Geophysical Union