Faculty Bibliography

BACKGROUND:Platelets and fresh frozen plasma (FFP) are frequently administered to critically ill patients. Considering the variability in indications and thresholds guiding these transfusions, a comprehensive review of current evidence was conducted to provide guidance to critical care practitioners. This CHEST guideline examined the literature on platelet transfusions in critically ill patients with thrombocytopenia, with and without active bleeding, as well as data on prophylactic platelet and FFP transfusions for common procedures in the critical care setting. STUDY DESIGN AND METHODS/METHODS:A panel of experts developed seven PICO questions addressing platelet and FFP transfusions in critically ill patients and performed a comprehensive evidence review. The panel applied the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach to assess the certainty of evidence, and to formulate and grade recommendations. A modified Delphi technique was used to reach consensus on the recommendations. RESULTS:The initial search identified a total of 7,172 studies, and after the initial screening, 100 articles were reviewed. Sixteen studies met inclusion criteria, comprising 1 randomized controlled trial and 15 observational studies. Overall, the certainty of the evidence for all questions was very low. The panel formulated seven conditional recommendations. CONCLUSIONS:In critically ill patients with thrombocytopenia or coagulopathy, a risk/benefit assessment should be made by providers prior to transfusion of platelets or FFP. Given the known risks of blood product transfusion, and the limited data regarding the benefits from platelet or FFP transfusion, most patients will benefit from avoiding transfusion of these blood products. In patients at high risk of bleeding, or where the bleeding complication may be catastrophic, transfusion should be considered.

BACKGROUND:Blood products frequently are administered to critically ill patients. Considering recent trials and practice variability, a comprehensive review of current evidence was deemed essential to offer pertinent guidance to critical care practitioners. This American College of Chest Physicians (CHEST) guidelines panel examined the literature on RBC transfusions among critically ill patients overall and specific subgroups, including patients with gastrointestinal bleeding, acute coronary syndrome (ACS), cardiac surgery, isolated troponin elevation, and septic shock, to provide evidence-based recommendations. STUDY DESIGN AND METHODS/METHODS:A panel of experts developed six Population, Intervention, Comparator, and Outcome questions addressing RBC transfusions in critically ill patients and performed a comprehensive evidence review. The panel applied the Grading of Recommendations, Assessment, Development, and Evaluations approach to assess the certainty of evidence and to formulate and grade recommendations. A modified Delphi technique was used to reach consensus on the recommendations. RESULTS:The initial search identified a total of 3,082 studies, and after the initial screening, 38 articles were reviewed. Among them, 23 studies met inclusion criteria, comprising 22 randomized controlled trials and one cohort study. Based on the analysis of these studies, the panel formulated two strong and four conditional recommendations. The overall quality of evidence for recommendations ranged from very low to moderate. CONCLUSIONS:In most critically ill patients, a restrictive strategy was preferable to a permissive approach because it does not increase the risk of death or complications, but does decrease RBC use significantly. Data from critically ill subpopulations also supported a restrictive approach, except in patients with ACS, for whom favoring a restrictive approach could increase adverse outcomes.

Stromal interaction molecule 1 (STIM1) is critical for store-operated Ca²⁺ entry (SOCE) and T cell activation. T helper 1 (T_H1) cells, which express T-bet (encoded by TBX21), mediate immunity to intracellular pathogens. Although SOCE is known to regulate other T_H lineages, its role in Th1 differentiation remains unclear. Here, we report a patient with an intronic loss-of-function mutation in STIM1, which abolishes SOCE and causes immunodeficiency. We demonstrate that SOCE promotes nuclear factor of activated T cells (NFAT) binding to conserved noncoding sequence (CNS)-12 in the TBX21 enhancer and enables NFAT to synergize with STAT1 to mediate TBX21 expression. While SOCE-deficient CD4⁺ T cells have reduced expression of TBX21 in the absence of interleukin-12 (IL-12), their expression of IL-12 receptors β1 and β2 is increased, sensitizing them to IL-12 signaling and allowing IL-12 to rescue T-bet expression. Our study reveals that the STIM1-SOCE-NFAT signaling axis is essential for the differentiation of Th1 cells depending on the cytokine milieu.

OBJECTIVE:We conducted a systematic review and meta-analysis to quantify the effect of attention-deficit/hyperactivity disorder (ADHD) medication on quality of life (QoL), and to understand whether this effect differs between stimulants and nonstimulants. METHOD/METHODS:February 2023 (https://med-adhd.org/), we identified randomized controlled trials (RCTs) of ADHD medications for individuals aged 6 years or more with a diagnosis of ADHD based on the DSM (from third to fifth editions) or the International Classification of Diseases (ICD; ninth or tenth revision), reporting data on QoL (measured with a validated scale). The risk of bias for each RCTs was assessed using the Cochrane Risk of Bias tool 2. Multilevel meta-analytic models were conducted with R 4.3.1. RESULTS:We included 17 RCTs (5,388 participants in total; 56% randomized to active medication) in the meta-analyses. We found that amphetamines (Hedge's g = 0.51, 95% CI = 0.08, 0.94), methylphenidate (0.38; 0.23, 0.54), and atomoxetine (0.30; 0.19, 0.40) were significantly more efficacious than placebo in improving QoL in people with ADHD, with moderate effect size. For atomoxetine, these effects were not moderated by the length of intervention, and did not differ between children/adolescents and adults. CONCLUSION/CONCLUSIONS:In addition to being efficacious in reducing ADHD core symptom severity, both stimulant and nonstimulant medications are efficacious in improving QoL in people with ADHD, albeit with lower effect sizes. Future research should explore whether, and to what degree, combining pharmacological and nonpharmacological interventions is likely to further improve QoL in people with ADHD. PLAIN LANGUAGE SUMMARY/CONCLUSIONS:From a prior dataset of a network meta-analysis, 17 randomized controlled trials (RCTs) were included in a meta-analysis to investigate if attention-deficit/hyperactivity disorder (ADHD) medication improves quality of life (QoL) in people with ADHD. The analysis showed that medications such as amphetamines, methylphenidate, and atomoxetine improved QoL compared to placebo, with moderate effect sizes. This study underscores the importance of ADHD medications, both stimulants and nonstimulants, not only in alleviating core ADHD symptoms but also in enhancing overall QoL for individuals with ADHD. STUDY PREREGISTRATION INFORMATION/UNASSIGNED:Effects of pharmacological treatment for ADHD on quality of life: a systematic review and meta-analysis; https://osf.io/; qvgps.

STUDY OBJECTIVE/OBJECTIVE:To determine whether preoperative LDL-C concentration affects the risk of perioperative major adverse cardiovascular or cerebrovascular events (MACCE) after noncardiac surgery. DESIGN/METHODS:Single center retrospective cohort study. SETTING/METHODS:Hospital (including medical and surgical floor, intensive care unit) and patient disposition location (including the patient's home or any other receiving facility). PATIENTS/METHODS:43,348 non-cardiac surgeries at NYU Langone Health between January 2016 and September 2020. INTERVENTIONS/METHODS:Patients were grouped based on preoperative LDL-C. MEASUREMENTS/METHODS:Complete serum lipid panel obtained within one year prior to the date of noncardiac surgery and rate of perioperative MACCE, defined as a composite of in-hospital non-fatal myocardial infarction, in-hospital acute ischemic stroke, myocardial injury after noncardiac surgery, and death from any cause within 30 days of surgery. MAIN RESULTS/RESULTS:Perioperative MACCE occurred in 1093 patients (2.5 %) overall. After multivariable adjustment, odds of MACCE were significantly lower in patients with higher (≥100 mg/dL) versus lower (<100 mg/dL) LDL-C (adjusted odds ratio [aOR] 0.783, 95 % CI, 0.660-0.926]). CONCLUSIONS:In a large cohort of patients undergoing non-cardiac surgery at a major academic health system in New York City, lower LDL-C concentrations were not associated with a lower incidence of perioperative MACCE. Further investigation into modifiable perioperative cardiovascular risk factors is needed to improve perioperative outcomes.

Clinical diagnosis typically incorporates physical examination, patient history, various laboratory tests, and imaging studies but makes limited use of the human immune system's own record of antigen exposures encoded by receptors on B cells and T cells. We analyzed immune receptor datasets from 593 individuals to develop MAchine Learning for Immunological Diagnosis, an interpretive framework to screen for multiple illnesses simultaneously or precisely test for one condition. This approach detects specific infections, autoimmune disorders, vaccine responses, and disease severity differences. Human-interpretable features of the model recapitulate known immune responses to severe acute respiratory syndrome coronavirus 2, influenza, and human immunodeficiency virus, highlight antigen-specific receptors, and reveal distinct characteristics of systemic lupus erythematosus and type-1 diabetes autoreactivity. This analysis framework has broad potential for scientific and clinical interpretation of immune responses.

Pathogenic Enterobacter species are of increasing clinical concern due to the multidrug-resistant nature of these bacteria, including resistance to carbapenem antibiotics. Our understanding of Enterobacter virulence is limited, hindering the development of new prophylactics and therapeutics targeting infections caused by Enterobacter species. In this study, we assessed the virulence of contemporary clinical Enterobacter hormaechei isolates in a mouse model of intraperitoneal infection and used comparative genomics to identify genes promoting virulence. Through mutagenesis and complementation studies, we found two porin-encoding genes, ompC and ompD, to be required for E. hormaechei virulence. These porins imported clinically relevant carbapenems into the bacteria, and thus loss of OmpC and OmpD desensitized E. hormaechei to the antibiotics. Our genomic analyses suggest porin-related genes are frequently mutated in E. hormaechei, perhaps due to the selective pressure of antibiotic therapy during infection. Despite the importance of OmpC and OmpD during infection of immunocompetent hosts, we found the two porins to be dispensable for virulence in a neutropenic mouse model. Moreover, porin loss provided a fitness advantage during carbapenem treatment in an ex vivo human whole blood model of bacteremia. Our data provide experimental evidence of pathogenic Enterobacter species gaining antibiotic resistance via loss of porins and argue antibiotic therapy during infection of immunocompromised patients is a conducive environment for the selection of porin mutations enhancing the multidrug-resistant profile of these pathogens.

The mediodorsal (MD) thalamus is a critical partner for the prefrontal cortex (PFC) in cognitive control. Accumulating evidence has shown that the MD regulates task uncertainty in decision making and enhance cognitive flexibility. However, the computational mechanism of this cognitive process remains unclear. Here we trained biologically-constrained computational models to delineate the mechanistic role of MD in context-dependent decision making. We show that the addition of a feedforward MD structure to the recurrent PFC increases robustness to low cueing signal-to-noise ratio, enhances working memory, and enables rapid context switching. Incorporating genetically identified thalamocortical connectivity and interneuron cell types into the model replicates key neurophysiological findings in task-performing animals. Our model reveals computational mechanisms and geometric interpretations of MD in regulating cue uncertainty and context switching to enable cognitive flexibility. Our model makes experimentally testable predictions linking cognitive deficits with disrupted thalamocortical connectivity, prefrontal excitation-inhibition imbalance and dysfunctional inhibitory cell types.

INTRODUCTION/BACKGROUND:Law enforcement seizure data can indicate potential shifts in drug availability. We examined trends in the size of illicit fentanyl seizures in the United States from 2018 through 2023. METHODS:Using national High Intensity Drug Trafficking Areas data, we examined trends in the weight of fentanyl powder and number of fentanyl-containing pills per seizure with a focus on federal and other common state-level weight cutoffs that indicate various levels of trafficking (e.g., 1-4 g, 40-399 g, ≥400 g). RESULTS:Between 2018 and 2023, the plurality of fentanyl powder seizures weighed 40-399 g (27.7%), followed by seizures weighing 4-39 g (25.8%), 1-4 g (18.6%), ≥400 g (17.4%), and <1 g (10.4%). During this period, there was a decrease in the percentage weighing ≥400 g (annual percentage change [APC] = -5.3, 95% confidence interval [CI] -9.4, -1.0) and an increase in the percentage weighing 1-4 g (APC = 5.6, 95% CI 3.2, 8.1). With respect to fentanyl pill seizures, the plurality contained 40-399 pills (10 = 1 g; 25.4%), followed by 400-3999 (21.8%), <10 pills (20.4%), 10-39 pills (18.6%) and ≥4000 pills (13.8%). During this period, there was a decrease in seizures of <10 pills (APC = -12.6, 95% CI -23.2, -0.7) and increases in seizures containing 400-3999 (APC = 14.0, 95% CI 5.3, 23.1) and ≥4000 pills (APC = 12.6, 95% CI 7.4, 17.8). DISCUSSION AND CONCLUSIONS/CONCLUSIONS:The size of fentanyl seizures varies greatly, with a sizeable portion legally classified as drug trafficking. While the weight of fentanyl powder seizures is decreasing, the size of pill seizures is increasing. The increasing availability of fentanyl pills in particular needs to be monitored to inform prevention and harm reduction efforts.