Lessons Learned from the First 10 Years of the Oaks and Prairies Joint Venture’s Grassland Restoration Incentive Program (GRIP)

The Oaks and Prairies Joint Venture (OPJV) was formed in 2008 as a public-private partnership of agencies and organizations working across jurisdictional boundaries in portions of Texas and Oklahoma, USA. The OPJV’s major focus is reversing declines of bird populations by supporting strategic habitat conservation (biological planning, conservation design, conservation delivery, mission-based monitoring, and assumption-driven research) for northern bobwhite (Colinus virginianus), grasslandobligate species, and their respective habitats. Our objective for this paper is to document and share a decade of lessons learned in developing a partnership-based native grassland conservation program to meet grassland bird conservation targets. We share lessons learned about how to manage partnership-based, large-scale habitat incentive programs to better target project locations and habitat practice types. To establish initial shared purpose, OPJV partners drew from population and habitat objectives in various state, national, and international bird conservation plans, stepped down to ecoregion levels, to establish the OPJV Grassland Bird Conservation Business Plan. The plan has 4 strategies directly contributing to the achievement of OPJV grassland bird biological objectives that are directly supported by OPJV staff or resources (or both). The overall objective for 2015–2025 was 619,978 ha (1,532,000 acres) improved within 40 focal counties, representing 1/3 of all counties in the OPJV. Our main strategy was to provide financial incentives through the OPJV Grassland Restoration Incentive Program (GRIP) to private landowners for conducting beneficial grassland bird habitat management practices. Since inception in 2013, GRIP has treated over 44,515 ha (110,000 acres) on private lands in Texas and Oklahoma, with the goal of maintaining highquality grassland bird habitat on treated hectares for ≥5 years. In 2017, OPJV partners working with USDA Natural Resources Conservation Service, began a 5-year, $6.1 million partnership to provide additional technical and financial assistance to private landowners interested in grassland conservation through the Regional Conservation Partnership Program (RCPP). A project scoring system was designed to strategically encourage individual projects to include prescribed fire—one of the lowest cost practices per hectare—as a recurring practice to maintain program-achieved grassland improvements. Post-inception of the RCPP, the area treated with prescribed fire increased from approximately 809 ha (2,000 acres)/year to 3,237 ha (8,000 acres)/ year, while maintaining average annual hectares of all other beneficial practices. Beginning in 2013, bird point count surveys were conducted annually to monitor northern bobwhite and grassland bird populations, including a subset of points under the National Bobwhite Conservation Initiative (NBCI) Coordinated Implementation Plan. To date, nearly 25,000 individual point counts have been performed in Texas (n = 20,111) and Oklahoma (n = 4,558). Working together, OPJV partners have made significant progress toward meeting grassland bird habitat and population objectives, while tracking progress and improving methods. However, there is still considerable work ahead

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

Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P <10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P <5 x 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.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

How and when post intensive care syndrome-family is measured: A scoping review

OBJECTIVES: Family members of Intensive Care Unit (ICU) patients can experience mental health difficulties. These are collectively described as Post Intensive Care Syndrome-Family (PICS-F). There are no standardised outcome measures to benchmark the impact of PICS-F. This scoping review aimed to map and characterise interventions, outcomes, and outcome instruments related to PICS-F.METHODS: Eight databases were searched in June 2023: Pubmed, CINAHL, Ovid Medline, EMBASE, PsycInfo, AMED, Emcare and Cochrane. The grey literature was also searched. Studies published after 2012 related to PICS-F were included. Search strategy included: (Population) family members of adult ICU patients, (Concept) PICS-F, (Context) ICU settings. Frequency analysis of outcomes was performed, and instruments were mapped to describe the characteristics.RESULTS: Of the identified 4848 records, 46 papers representing 44 unique studies met the inclusion criteria and were retained for analysis. In total, 8008 family members were represented across 15 countries in four continents worldwide. The number of studies reporting PICS-F interventions increased rapidly over the past 12 years and were performed in ICUs treating mixed conditions. Studies were randomised control trials (n = 33), before-and-after design (n = 6) and non-randomised trials (n = 5). A total of 18 outcome instruments were used measuring predominantly anxiety, with complicated grief measured only once. The identified instruments were mostly validated for clinical and disease specific populations but not validated among relatives of ICU patients.CONCLUSION: There is a plethora of instruments measuring PICS-F outcomes. No core outcome set is currently available for PICS-F. To reduce heterogeneity of how PICS-F is measured, a core outcome set with validated measurements is recommended to allow benchmarking and to document the impact of PICS-F interventions.IMPLICATIONS FOR CLINICAL PRACTICE: Recognising PICS-F symptoms and understanding how to assess them could help clinicians to develop interventions to improve family outcomes. Validated instruments are needed to evaluate these interventions.</p

Measuring Post Intensive Care Syndrome-Family: A scoping review

Scoping Review question: How is Post Intensive Care Syndrome-Family evaluated in family members of adult ICU patients? Aim: To collate and characterise the interventions and measurement tools in clinical studies relating to PICS-F. Objectives: 1. To identify and map the outcomes measured in studies related to PICS-F. 2. To describe the characteristics of outcome measurement tools, including the timepoints and frequency of the assessments, and the validity of the measurement tools used in studies related to PICS-F outcomes 3. To map the common characteristics of clinical studies related to PICS-F including the study design, intervention, settings, and disease group of patients

Early intravenous beta-blockade with esmolol in adults with severe traumatic brain injury (EBB-TBI): Protocol for a phase 2a intervention design study

AbstractTraumatic brain injury is a leading cause of death and disability worldwide. Interventions that mitigate secondary brain injury have the potential to improve outcomes for patients and reduce the impact on communities and society. Increased circulating catecholamines are associated with worse outcomes and there is supportive animal data and indications in human studies of benefit from beta-blockade after severe traumatic brain injury. Here we present the protocol for a dose-finding study using esmolol in adults commenced within 24 hours of severe traumatic brain injury. Esmolol has practical advantages and theoretical benefits as a neuroprotective agent in this setting, but these must be balanced against the known risk of secondary injury from hypotension. The aim of this study is to determine a dose schedule for esmolol, using the continual reassessment method, that combines a clinically significant reduction in heart rate as a surrogate for catecholamine drive with maintenance of cerebral perfusion pressure. The maximum tolerated dosing schedule for esmolol can then be tested for patient benefit in subsequent randomised controlled trials. Trial registration: ISRCTN, ISRCTN11038397, registered retrospectively 07/01/2021 https://www.isrctn.com/ISRCTN1103839

Early intravenous Beta-Blockade with esmolol in adults with severe Traumatic Brain Injury (EBB-TBI): A phase 2a intervention design study

BackgroundTargeted beta-blockade after severe traumatic brain injury may reduce secondary brain injury by attenuating the sympathoadrenal response. The potential role and optimal dose for esmolol, a selective, short-acting, titratable beta-1 beta-blocker as a safe, putative early therapy after major traumatic brain injury has not been assessed.MethodsWe conducted a single centre, open-label, dose finding study, using an adaptive model-based design. Adults (18 years or older) with severe traumatic brain injury and intracranial pressure monitoring received esmolol within 24 hours of injury to reduce heart rate by 15% from baseline of the preceding 4 hours while ensuring cerebral perfusion pressure (CPP) was maintained above 60mmHg. In cohorts of three the starting dose and dose increments were escalated according to pre-specified plan in the absence of dose-limiting toxicity. Dose-limiting toxicity (DLT) was defined as failure to maintain CPP triggering cessation of esmolol infusion. The primary outcome was the maximum tolerated dose-schedule of esmolol, defined as that associated with less than 10% probability of dose-limiting toxicity. Secondary outcomes include 6-month mortality and 6-month extended Glasgow Outcome Scale.ResultsSixteen patients (6 (37.5%) female; mean age 36 years (standard deviation 13 years) with a median Glasgow Coma Scalecore of 6.5 (interquartile range 5 – 7) received esmolol. The optimal starting dose of esmolol was 10 micrograms per kilogram per minute, with increments every 30 minutes of 5 mcg.kg.min-1, as it was the highest dose with less than 10% estimated probability of dose-limiting toxicity (7%). All-cause mortality was 12.5% at 6 months (corresponding to standardised mortality ratio of 0.63). One dose limiting toxicity event and no serious adverse haemodynamic effects were seen. ConclusionEsmolol administration, titrated to a heart rate reduction of 15%, is feasible within 24 hours of severe traumatic brain injury. The probability of dose-limiting toxicity requiring withdrawal of esmolol when using the optimised schedule is low

JLSC Board Editorial 2019

Many of us were hired to work toward systems where knowledge is open, equitable, transparent, and diverse. At the same time, our hiring institutions can be ambivalent about change, and we ourselves sometimes fall short of the ideals we espouse. One antidote for burnout and disillusionment is to build a durable, continuing community that can survive and do good work despite setbacks and failures. As JLSC editors, the three of us—Anne, Jennifer, and Rebekah—plan to continue facilitating the conversations that make this community a sustainable reality. The editorials below all engage with the idea of community. We hope that their thoughts and critiques will encourage all of us to think about our own communities and work to improve them.status: Published onlin