Abatacept Pharmacokinetics and Exposure Response in Patients Hospitalized With COVID-19: A Secondary Analysis of the ACTIV-1 IM Randomized Clinical Trial

IMPORTANCE: The pharmacokinetics of abatacept and the association between abatacept exposure and outcomes in patients with severe COVID-19 are unknown. OBJECTIVE: To characterize abatacept pharmacokinetics, relate drug exposure with clinical outcomes, and evaluate the need for dosage adjustments. DESIGN, SETTING, AND PARTICIPANTS: This study is a secondary analysis of data from the ACTIV-1 (Accelerating COVID-19 Therapeutic Interventions and Vaccines) Immune Modulator (IM) randomized clinical trial conducted between October 16, 2020, and December 31, 2021. The trial included hospitalized adults who received abatacept in addition to standard of care for treatment of COVID-19 pneumonia. Data analysis was performed between September 2022 and February 2024. EXPOSURE: Single intravenous infusion of abatacept (10 mg/kg with a maximum dose of 1000 mg). MAIN OUTCOMES AND MEASURES: Mortality at day 28 was the primary outcome of interest, and time to recovery at day 28 was the secondary outcome. Drug exposure was assessed using the projected area under the serum concentration time curve over 28 days (AUC0-28). Logistic regression modeling was used to analyze the association between drug exposure and 28-day mortality, adjusted for age, sex, and disease severity. The association between time to recovery and abatacept exposure was examined using Fine-Gray modeling with death as a competing risk, and was adjusted for age, sex, and disease severity. RESULTS: Of the 509 patients who received abatacept, 395 patients with 848 serum samples were included in the population pharmacokinetic analysis. Their median age was 55 (range, 19-89) years and most (250 [63.3%]) were men. Abatacept clearance increased with body weight and more severe disease activity at baseline. Drug exposure was higher in patients who survived vs those who died, with a median AUC0-28 of 21 428 (range, 8462-43 378) mg × h/L vs 18 262 (range, 9628-27 507) mg × h/L (P \u3c .001). Controlling for age, sex, and disease severity, an increase of 5000 units in AUC0-28 was associated with lower odds of mortality at day 28 (OR, 0.52 [95% CI, 0.35-0.79]; P = .002). For an AUC0-28 of 19 400 mg × h/L or less, there was a higher probability of recovery at day 28 (hazard ratio, 2.63 [95% CI, 1.70-4.08] for every 5000-unit increase; P \u3c .001). Controlling for age, sex, and disease severity, every 5000-unit increase in AUC0-28 was also associated with lower odds of a composite safety event at 28 days (OR, 0.46 [95% CI, 0.33-0.63]; P \u3c .001). Using the dosing regimen studied in the ACTIV-1 IM trial, 121 of the 395 patients (30.6%) would not achieve an abatacept exposure of at least 19 400 mg × h/L, particularly at the extremes of body weight. Using a modified, higher-dose regimen, only 12 patients (3.0%) would not achieve the hypothesized target abatacept exposure. CONCLUSIONS AND RELEVANCE: In this study, patients who were hospitalized with severe COVID-19 and achieved higher projected abatacept exposure had reduced mortality and a higher probability of recovery with fewer safety events. However, abatacept clearance was high in this population, and the current abatacept dosing (10 mg/kg intravenously with a maximum of 1000 mg) may not achieve optimal exposure in all patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04593940

Averting biodiversity collapse in tropical forest protected areas

The rapid disruption of tropical forests probably imperils global biodiversity more than any other contemporary phenomenon¹⁻³. With deforestation advancing quickly, protected areas are increasingly becoming final refuges for threatened species and natural ecosystem processes. However, many protected areas in the tropics are themselves vulnerable to human encroachment and other environmental stresses⁴⁻⁹. As pressures mount, it is vital to know whether existing reserves can sustain their biodiversity. A critical constraint in addressing this question has been that data describing a broad array of biodiversity groups have been unavailable for a sufficiently large and representative sample of reserves. Here we present a uniquely comprehensive data set on changes over the past 20 to 30 years in 31 functional groups of species and 21 potential drivers of environmental change, for 60 protected areas stratified across the world’s major tropical regions. Our analysis reveals great variation in reserve ‘health’: about half of all reserves have been effective or performed passably, but the rest are experiencing an erosion of biodiversity that is often alarmingly widespread taxonomically and functionally. Habitat disruption, hunting and forest-product exploitation were the strongest predictors of declining reserve health. Crucially, environmental changes immediately outside reserves seemed nearly as important as those inside in determining their ecological fate, with changes inside reserves strongly mirroring those occurring around them. These findings suggest that tropical protected areas are often intimately linked ecologically to their surrounding habitats, and that a failure to stem broad-scale loss and degradation of such habitats could sharply increase the likelihood of serious biodiversity declines.Keywords: Ecology, Environmental scienc

A National Survey on the Current Status of General Internal Medicine Residency Education in Geriatric Medicine

OBJECTIVES: The dramatic increase in the U.S. elderly population expected over the coming decades will place a heavy strain on the current health care system. General internal medicine (GIM) residents need to be prepared to take care of this population. In this study, we document the current and future trends in geriatric education in GIM residency programs. DESIGN, SETTING, PARTICIPANTS: An original survey was mailed to all the GIM residency directors in the United States (N = 390). RESULTS: A 53% response rate was achieved (n = 206). Ninety-three percent of GIM residencies had a required geriatrics curriculum. Seventy one percent of the programs required 13 to 36 half days of geriatric medicine clinical training during the 3-year residency, and 29% required 12 half days or less of clinical training. Nursing homes, outpatient geriatric assessment centers, and nongeriatric ambulatory settings were the predominant training sites for geriatrics in GIM. Training was most often offered in a block format. The average number of physician faculty available to teach geriatrics was 6.4 per program (2.8 full-time equivalents). Conflicting time demands with other curricula was ranked as the most significant barrier to geriatric education. CONCLUSIONS: A required geriatric medicine curriculum is now included in most GIM residency programs. Variability in the amount of time devoted to geriatrics exists across GIM residencies. Residents in some programs spend very little time in specific, required geriatric medicine clinical experiences. The results of this survey can guide the development of future curricular content and structure. Emphasizing geriatrics in GIM residencies helps ensure that these residents are equipped to care for the expanding aging population

High-Sensitivity C-Reactive Protein is a Prognostic Biomarker of Six-Month Disability after Traumatic Brain Injury: Results from the TRACK-TBI Study

Systemic inflammation impacts outcome after traumatic brain injury (TBI), but most TBI biomarker studies have focused on brain-specific proteins. C-reactive protein (CRP) is a widely used biomarker of inflammation with potential as a prognostic biomarker after TBI. The Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study prospectively enrolled TBI patients within 24 h of injury, as well as orthopedic injury and uninjured controls; biospecimens were collected at enrollment. A subset of hospitalized participants had blood collected on day 3, day 5, and 2 weeks. High-sensitivity CRP (hsCRP) and glial fibrillary acidic protein (GFAP) were measured. Receiver operating characteristic analysis was used to evaluate the prognostic ability of hsCRP for 6-month outcome, using the Glasgow Outcome Scale-Extended (GOSE). We included 1206 TBI subjects, 122 orthopedic trauma controls (OTCs), and 209 healthy controls (HCs). Longitudinal biomarker sampling was performed in 254 hospitalized TBI subjects and 19 OTCs. hsCRP rose between days 1 and 5 for TBI and OTC subjects, and fell by 2 weeks, but remained elevated compared with HCs (p < 0.001). Longitudinally, hsCRP was significantly higher in the first 2 weeks for subjects with death/severe disability (GOSE <5) compared with those with moderate disability/good recovery (GOSE ≥5); AUC was highest at 2 weeks (AUC = 0.892). Combining hsCRP and GFAP at 2 weeks produced AUC = 0.939 for prediction of disability. Serum hsCRP measured within 2 weeks of TBI is a prognostic biomarker for disability 6 months later. hsCRP may have utility as a biomarker of target engagement for anti-inflammatory therapies

Prophylaxis of postoperative endophthalmitis following cataract surgery: Results of the ESCRS multicenter study and identification of risk factors

Purpose: To identify risk factors and describe the effects of antibiotic prophylaxis on the incidence of postoperative endophthalmitis after cataract surgery based on analysis of the findings of the European Society of Cataract & Refractive Surgeons (ESCRS) multicenter study. Setting: Twenty-four ophthalmology units in Austria, Belgium, Germany, Italy, Poland, Portugal, Spain, Turkey, and the United Kingdom. Methods: A prospective randomized partially masked multicenter cataract surgery study recruited 16 603 patients. The study was based on a 2 × 2 factorial design, with intracameral cefuroxime and topical perioperative levofloxacin factors resulting in 4 treatment groups. The comparison of case and non-case data was performed using multivariable logistic regression analyses. Odds ratios (ORs) associated with treatment effects and other risk factors were estimated. Results: Twenty-nine patients presented with endophthalmitis, of whom 20 were classified as having proven infective endophthalmitis. The absence of an intracameral cefuroxime prophylactic regimen at 1 mg in 0.1 mL normal saline was associated with a 4.92-fold increase (95% confidence interval [CI], 1.87-12.9) in the risk for total postoperative endophthalmitis. In addition, the use of clear corneal incisions (CCIs) compared to scleral tunnels was associated with a 5.88-fold increase (95% CI, 1.34-25.9) in risk and the use of silicone intraocular lens (IOL) optic material compared to acrylic with a 3.13-fold increase (95% CI, 1.47-6.67). The presence of surgical complications increased the risk for total endophthalmitis 4.95-fold (95% CI, 1.68-14.6), and more experienced surgeons were more likely to be associated with endophthalmitis cases. When considering only proven infective endophthalmitis cases, the absence of cefuroxime and the use of silicone IOL optic material were significantly associated with an increased risk, and there was evidence that men were more predisposed to infection (OR, 2.70; 95% CI, 1.07-6.8). Conclusions: Use of intracameral cefuroxime at the end of surgery reduced the occurrence of postoperative endophthalmitis. Additional risk factors associated with endophthalmitis after cataract surgery included CCIs and the use of silicone IOLs. © 2007 ASCRS and ESCRS

Averting biodiversity collapse in tropical forest protected areas

The rapid disruption of tropical forests probably imperils global biodiversity more than any other contemporary phenomenon. With deforestation advancing quickly, protected areas are increasingly becoming final refuges for threatened species and natural ecosystem processes. However, many protected areas in the tropics are themselves vulnerable to human encroachment and other environmental stresses. As pressures mount, it is vital to know whether existing reserves can sustain their biodiversity. A critical constraint in addressing this question has been that data describing a broad array of biodiversity groups have been unavailable for a sufficiently large and representative sample of reserves. Here we present a uniquely comprehensive data set on changes over the past 20 to 30 years in 31 functional groups of species and 21 potential drivers of environmental change, for 60 protected areas stratified across the world’s major tropical regions. Our analysis reveals great variation in reserve ‘health’: about half of all reserves have been effective or performed passably, but the rest are experiencing an erosion of biodiversity that is often alarmingly widespread taxonomically and functionally. Habitat disruption, hunting and forest-product exploitation were the strongest predictors of declining reserve health. Crucially, environmental changes immediately outside reserves seemed nearly as important as those inside in determining their ecological fate, with changes inside reserves strongly mirroring those occurring around them. These findings suggest that tropical protected areas are often intimately linked ecologically to their surrounding habitats, and that a failure to stem broad-scale loss and degradation of such habitats could sharply increase the likelihood of serious biodiversity declines.William F. Laurance, D. Carolina Useche, Julio Rendeiro, Margareta Kalka, Corey J. A. Bradshaw, Sean P. Sloan, Susan G. Laurance, Mason Campbell, Kate Abernethy, Patricia Alvarez, Victor Arroyo-Rodriguez, Peter Ashton, Julieta Benítez-Malvido, Allard Blom, Kadiri S. Bobo, Charles H. Cannon, Min Cao, Richard Carroll, Colin Chapman, Rosamond Coates, Marina Cords, Finn Danielsen, Bart De Dijn, Eric Dinerstein, Maureen A. Donnelly, David Edwards, Felicity Edwards, Nina Farwig, Peter Fashing, Pierre-Michel Forget, Mercedes Foster, George Gale, David Harris, Rhett Harrison, John Hart, Sarah Karpanty, W. John Kress, Jagdish Krishnaswamy, Willis Logsdon, Jon Lovett, William Magnusson, Fiona Maisels, Andrew R. Marshall, Deedra McClearn, Divya Mudappa, Martin R. Nielsen, Richard Pearson, Nigel Pitman, Jan van der Ploeg, Andrew Plumptre, John Poulsen, Mauricio Quesada, Hugo Rainey, Douglas Robinson, Christiane Roetgers, Francesco Rovero, Frederick Scatena, Christian Schulze, Douglas Sheil, Thomas Struhsaker, John Terborgh, Duncan Thomas, Robert Timm, J. Nicolas Urbina-Cardona, Karthikeyan Vasudevan, S. Joseph Wright, Juan Carlos Arias-G., Luzmila Arroyo, Mark Ashton, Philippe Auzel, Dennis Babaasa, Fred Babweteera, Patrick Baker, Olaf Banki, Margot Bass, Inogwabini Bila-Isia, Stephen Blake, Warren Brockelman, Nicholas Brokaw, Carsten A. Brühl, Sarayudh Bunyavejchewin, Jung-Tai Chao, Jerome Chave, Ravi Chellam, Connie J. Clark, José Clavijo, Robert Congdon, Richard Corlett, H. S. Dattaraja, Chittaranjan Dave, Glyn Davies, Beatriz de Mello Beisiegel, Rosa de Nazaré Paes da Silva, Anthony Di Fiore, Arvin Diesmos, Rodolfo Dirzo, Diane Doran-Sheehy, Mitchell Eaton, Louise Emmons, Alejandro Estrada, Corneille Ewango, Linda Fedigan, François Feer, Barbara Fruth, Jacalyn Giacalone Willis, Uromi Goodale, Steven Goodman, Juan C. Guix, Paul Guthiga, William Haber, Keith Hamer, Ilka Herbinger, Jane Hill, Zhongliang Huang, I Fang Sun, Kalan Ickes, Akira Itoh, Natália Ivanauskas, Betsy Jackes, John Janovec, Daniel Janzen, Mo Jiangming, Chen Jin, Trevor Jones, Hermes Justiniano, Elisabeth Kalko, Aventino Kasangaki, Timothy Killeen, Hen-biau King, Erik Klop, Cheryl Knott, Inza Koné, Enoka Kudavidanage, José Lahoz da Silva Ribeiro, John Lattke, Richard Laval, Robert Lawton, Miguel Leal, Mark Leighton, Miguel Lentino, Cristiane Leonel, Jeremy Lindsell, Lee Ling-Ling, K. Eduard Linsenmair, Elizabeth Losos, Ariel Lugo, Jeremiah Lwanga, Andrew L. Mack, Marlucia Martins, W. Scott McGraw, Roan McNab, Luciano Montag, Jo Myers Thompson, Jacob Nabe-Nielsen, Michiko Nakagawa, Sanjay Nepal, Marilyn Norconk, Vojtech Novotny, Sean O'Donnell, Muse Opiang, Paul Ouboter, Kenneth Parker, N. Parthasarathy, Kátia Pisciotta, Dewi Prawiradilaga, Catherine Pringle, Subaraj Rajathurai, Ulrich Reichard, Gay Reinartz, Katherine Renton, Glen Reynolds, Vernon Reynolds, Erin Riley, Mark-Oliver Rödel, Jessica Rothman, Philip Round, Shoko Sakai, Tania Sanaiotti, Tommaso Savini, Gertrud Schaab, John Seidensticker, Alhaji Siaka, Miles R. Silman, Thomas B. Smith, Samuel Soares de Almeida, Navjot Sodhi, Craig Stanford, Kristine Stewart, Emma Stokes, Kathryn E. Stoner, Raman Sukumar, Martin Surbeck, Mathias Tobler, Teja Tscharntke, Andrea Turkalo, Govindaswamy Umapathy, Merlijn van Weerd, Jorge Vega Rivera, Meena Venkataraman, Linda Venn, Carlos Verea, Carolina Volkmer de Castilho, Matthias Waltert, Benjamin Wang, David Watts, William Weber, Paige West, David Whitacre, Ken Whitney, David Wilkie, Stephen Williams, Debra D. Wright, Patricia Wright, Lu Xiankai, Pralad Yonzon & Franky Zamzan