The scientific rationale and study protocol for the DPP3, Angiotensin II, and Renin Kinetics in Sepsis (DARK-Sepsis) randomized controlled trial: serum biomarkers to predict response to angiotensin II versus standard-of-care vasopressor therapy in the treatment of septic shock.

BACKGROUND: Data to support the use of specific vasopressors in septic shock are limited. Since angiotensin II (AT2) was approved by the Food and Drug Administration in 2017, multiple mechanistically distinct vasopressors are available to treat septic shock, but minimal data exist regarding which patients are most likely to benefit from each agent. Renin and dipeptidyl peptidase 3 (DPP3) are components of the renin-angiotensin-aldosterone system which have been shown to outperform lactate in predicting sepsis prognosis, and preliminary data suggest they could prove useful as biomarkers to guide AT2 use in septic shock. METHODS: The DARK-Sepsis trial is an investigator-initiated industry-funded, open-label, single-center randomized controlled trial of the use of AT2 versus standard of care (SOC) vasopressor therapy in patients admitted to the intensive care unit (ICU) with vasodilatory shock requiring norepinephrine ≥ 0.1 mcg/kg/min. In both groups, a series of renin and DPP3 levels will be obtained over the first 24 h of treatment with AT2 or SOC. The primary study outcome will be the ability of these biomarkers to predict response to vasopressor therapy, as measured by change in total norepinephrine equivalent dose of vasopressors at 3 h post-drug initiation or the equivalent timepoint in the SOC arm. To determine if the ability to predict vasopressor response is specific to AT2 therapy, the primary analysis will be the ability of baseline renin and DPP3 levels to predict vasopressor response adjusted for treatment arm (AT2 versus control) and Sequential Organ Failure Assessment (SOFA) scores. Secondary outcomes will include rates of acute kidney injury, need for mechanical ventilation and kidney replacement therapy, lengths of stay in the ICU and hospital, ICU and hospital mortality, and rates of prespecified adverse events. DISCUSSION: With an armamentarium of mechanistically distinct vasopressor agents now available, sub-phenotyping patients using biomarkers has the potential to improve septic shock outcomes by enabling treatment of the correct patient with the correct vasopressor at the correct time. However, this approach requires validation in a large definitive multicenter trial. The data generated through the DARK-Sepsis study will prove crucial to the optimal design and patient enrichment of such a pivotal trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT05824767. Registered on April 24, 2023.

Mere Nuisance or Growing Threat? The Physical and Economic Impact of High Tide Flooding on US Road Networks.

High tide flooding (HTF) already affects traffic in many US coastal areas, but the issue will worsen significantly in the future. While studies show that large storm surge events threaten to be ever more costly, less damaging, but more frequent HTF events remain understudied and potentially carry a comparable economic impact. This study advances our understanding of the risks and impacts of HTF on vulnerable traffic corridors using hourly tide gauge water levels, sea-level rise projections, and link-level spatial analysis. It is the first study to estimate HTF economic impacts for varying levels of intervention, including reasonably anticipated driver-initiated rerouting and ancillary protection of adjacent property. The 2020 annual national-level costs of $1.3 to $1.5 billion will increase to $28 to $37 billion in 2050 and $220 to $260 billion in 2100 for medium to high greenhouse gas (GHG) emissions scenarios, respectively. Total costs over the century are $1.0 to $1.3 trillion (discounted 3%). Additional cost-effective protection by building sea walls or raising road surfaces could significantly reduce 2100 costs to $61 to $78 billion, but there remain many barriers to adopting least-cost adaptation decisions, and these gains may only be realized with careful planning and information sharing.

Effects of Increasing Aridity on Ambient Dust and Public Health in the U.S. Southwest Under Climate Change.

The U.S. Southwest is projected to experience increasing aridity due to climate change. We quantify the resulting impacts on ambient dust levels and public health using methods consistent with the Environmental Protection Agency's Climate Change Impacts and Risk Analysis framework. We first demonstrate that U.S. Southwest fine (PM2.5) and coarse (PM2.5-10) dust levels are strongly sensitive to variability in the 2-month Standardized Precipitation-Evapotranspiration Index across southwestern North America. We then estimate potential changes in dust levels through 2099 by applying the observed sensitivities to downscaled meteorological output projected by six climate models following an intermediate (Representative Concentration Pathway 4.5, RCP4.5) and a high (RCP8.5) greenhouse gas concentration scenario. By 2080-2099 under RCP8.5 relative to 1986-2005 in the U.S. Southwest: (1) Fine dust levels could increase by 57%, and fine dust-attributable all-cause mortality and hospitalizations could increase by 230% and 360%, respectively; (2) coarse dust levels could increase by 38%, and coarse dust-attributable cardiovascular mortality and asthma emergency department visits could increase by 210% and 88%, respectively; (3) climate-driven changes in dust concentrations can account for 34-47% of these health impacts, with the rest due to increases in population and baseline incidence rates; and (4) economic damages of the health impacts could total $47 billion per year additional to the 1986-2005 value of $13 billion per year. Compared to national-scale climate impacts projected for other U.S. sectors using the Climate Change Impacts and Risk Analysis framework, dust-related mortality ranks fourth behind extreme temperature-related mortality, labor productivity decline, and coastal property loss.

Usefulness of CRP and ESR in predicting septic joints.

OBJECTIVE: To determine whether erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), or a combination of both was better in diagnosing a septic joint. METHODS: A retrospective chart review was done in all patients who had serum assays for ESR or CRP as well as joint fluid analysis over a two-year period. Based on lab and operative findings, patients (cohorts) were categorized as having normal, inflammatory, or septic joints. Sensitivities (SEN), specificities (SP), positive and negative predictive values (PPV, NPV) were obtained using our lab's positive cutoffs of 15 for ESR and 0.8 for CRP. Contingency tables were used for comparisons between predictor variables and the presence of septic joints. Receiver operator curves (ROC) were obtained for CRPs and ESRs. RESULTS: Of 163 patients, 72 had inflammatory joints, 44 had septic joints, and 47 were normal. Fifteen admitted to drug use and 43 to alcohol consumption. There were 120 males and 42 females. The mean CRP for septic joints was 13, 8.5 for inflammatory joints, and 6 for normal. The mean ESR for septic joints was 57, 48 for inflammatory joints, and 43 for normal joints. By univariate analysis, drug use and elevated CRPs were significantly associated with septic joints while alcohol use, ESRs, and gender were not. A regression model with 4 variables indicated that drug use and CRP were predictive of septic joint; alcohol and ESR were not. CONCLUSION: CRP is helpful in determining the presence of a septic joint; ESR is not.