OBJECTIVES:To assess for the first time the safety and pharmacokinetics of an antiprogrammed cell death-ligand 1 immune checkpoint inhibitor (BMS-936559; Bristol-Myers Squibb, Princeton, NJ) and its ...effect on immune biomarkers in participants with sepsis-associated immunosuppression.
DESIGN:Randomized, placebo-controlled, dose-escalation.
SETTING:Seven U.S. hospital ICUs.
STUDY POPULATION:Twenty-four participants with sepsis, organ dysfunction (hypotension, acute respiratory failure, and/or acute renal injury), and absolute lymphocyte count less than or equal to 1,100 cells/μL.
INTERVENTIONS:Participants received single-dose BMS-936559 (10–900 mg; n = 20) or placebo (n = 4) infusions. Primary endpoints were death and adverse events; key secondary endpoints included receptor occupancy and monocyte human leukocyte antigen-DR levels.
MEASUREMENTS AND MAIN RESULTS:The treated group was older (median 62 yr treated pooled vs 46 yr placebo), and a greater percentage had more than 2 organ dysfunctions (55% treated pooled vs 25% placebo); other baseline characteristics were comparable. Overall mortality was 25% (10 mg dose2/4; 30 mg2/4; 100 mg1/4; 300 mg1/4; 900 mg0/4; placebo0/4). All participants had adverse events (75% grade 1–2). Seventeen percent had a serious adverse event (3/20 treated pooled, 1/4 placebo), with none deemed drug-related. Adverse events that were potentially immune-related occurred in 54% of participants; most were grade 1–2, none required corticosteroids, and none were deemed drug-related. No significant changes in cytokine levels were observed. Full receptor occupancy was achieved for 28 days after BMS-936559 (900 mg). At the two highest doses, an apparent increase in monocyte human leukocyte antigen-DR expression (> 5,000 monoclonal antibodies/cell) was observed and persisted beyond 28 days.
CONCLUSIONS:In this first clinical evaluation of programmed cell death protein-1/programmed cell death-ligand 1 pathway inhibition in sepsis, BMS-936559 was well tolerated, with no evidence of drug-induced hypercytokinemia or cytokine storm, and at higher doses, some indication of restored immune status over 28 days. Further randomized trials on programmed cell death protein-1/programmed cell death-ligand 1 pathway inhibition are needed to evaluate its clinical safety and efficacy in patients with sepsis.
IMPORTANCE: The death of a pediatric patient with sepsis motivated New York to mandate statewide sepsis treatment in 2013. The mandate included a 1-hour bundle of blood cultures, broad-spectrum ...antibiotics, and a 20-mL/kg intravenous fluid bolus. Whether completing the bundle elements within 1 hour improves outcomes is unclear. OBJECTIVE: To determine the risk-adjusted association between completing the 1-hour pediatric sepsis bundle and individual bundle elements with in-hospital mortality. DESIGN, SETTINGS, AND PARTICIPANTS: Statewide cohort study conducted from April 1, 2014, to December 31, 2016, in emergency departments, inpatient units, and intensive care units across New York State. A total of 1179 patients aged 18 years and younger with sepsis and septic shock reported to the New York State Department of Health who had a sepsis protocol initiated were included. EXPOSURES: Completion of a 1-hour sepsis bundle within 1 hour compared with not completing the 1-hour sepsis bundle within 1 hour. MAIN OUTCOMES AND MEASURES: Risk-adjusted in-hospital mortality. RESULTS: Of 1179 patients with sepsis reported at 54 hospitals (mean SD age, 7.2 6.2 years; male, 54.2%; previously healthy, 44.5%; diagnosed as having shock, 68.8%), 139 (11.8%) died. The entire sepsis bundle was completed in 1 hour in 294 patients (24.9%). Antibiotics were administered to 798 patients (67.7%), blood cultures were obtained in 740 patients (62.8%), and the fluid bolus was completed in 548 patients (46.5%) within 1 hour. Completion of the entire bundle within 1 hour was associated with lower risk-adjusted odds of in-hospital mortality (odds ratio OR, 0.59 95% CI, 0.38 to 0.93, P = .02; predicted risk difference RD, 4.0% 95% CI, 0.9% to 7.0%). However, completion of each individual bundle element within 1 hour was not significantly associated with lower risk-adjusted mortality (blood culture: OR, 0.73 95% CI, 0.51 to 1.06, P = .10; RD, 2.6% 95% CI, −0.5% to 5.7%; antibiotics: OR, 0.78 95% CI, 0.55 to 1.12, P = .18; RD, 2.1% 95% CI, −1.1% to 5.2%, and fluid bolus: OR, 0.88 95% CI, 0.56 to 1.37, P = .56; RD, 1.1% 95% CI, −2.6% to 4.8%). CONCLUSIONS AND RELEVANCE: In New York State following a mandate for sepsis care, completion of a sepsis bundle within 1 hour compared with not completing the 1-hour sepsis bundle within 1 hour was associated with lower risk-adjusted in-hospital mortality among patients with pediatric sepsis and septic shock.
Cellular biomolecular complexes including protein–protein, protein–RNA, and protein–DNA interactions regulate and execute most biological functions. In particular in brain, protein–protein ...interactions (PPIs) mediate or regulate virtually all nerve cell functions, such as neurotransmission, cell–cell communication, neurogenesis, synaptogenesis, and synaptic plasticity. Perturbations of PPIs in specific subsets of neurons and glia are thought to underly a majority of neurobiological disorders. Therefore, understanding biological functions at a cellular level requires a reasonably complete catalog of all physical interactions between proteins. An enzyme-catalyzed method to biotinylate proximal interacting proteins within 10 to 300 nm of each other is being increasingly used to characterize the spatiotemporal features of complex PPIs in brain. Thus, proximity labeling has emerged recently as a powerful tool to identify proteomes in distinct cell types in brain as well as proteomes and PPIs in structures difficult to isolate, such as the synaptic cleft, axonal projections, or astrocyte–neuron junctions. In this review, we summarize recent advances in proximity labeling methods and their application to neurobiology.
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•Exploring PPIs in brain is essential to understanding neurological disorders.•Overview of current PL methods used for PPI identification.•Application of in vitro and in vivo PL approaches in neurobiology.•Future perspectives of PL methods in neurobiology.
PL has emerged as a powerful tool to identify proteomes in distinct cell types in brain as well as proteomes and protein–protein interaction networks in structures difficult to isolate, such as the synaptic cleft, axonal projections, or astrocyte–neuron junctions. Here, we review recent advances in PL methods and their application to neurobiology.
According to Werner Sombart’s classic text Luxury and Capitalism, the status-seeking behavior of individuals may facilitate the development of capitalism and an early industrialization. In this ...study, we develop a growth-theoretic framework to formalize this hypothesis by introducing a status-seeking preference into the Schumpeterian growth model of endogenous takeoff. Then, we explore how this cultural preference affects the transition of an economy from pre-industrial stagnation to modern economic growth. We find that the effects of status-seeking behaviors evolve across different stages of economic development. Specifically, a stronger preference for status seeking causes an earlier takeoff and increases economic growth in the short run but has an overall negative effect on the steady-state equilibrium growth rate. Finally, we calibrate the model to US data to perform a quantitative analysis and also use cross-country data to estimate the effects of status-seeking preference on economic growth.
Agricultural revolution and industrialization Chu, Angus C.; Peretto, Pietro F.; Wang, Xilin
Journal of development economics,
September 2022, 2022-09-00, Letnik:
158
Journal Article
Recenzirano
Odprti dostop
This study explores how agricultural technology affects the endogenous takeoff of an economy in the Schumpeterian growth model. Due to the subsistence requirement for agricultural consumption, an ...improvement in agricultural technology reallocates labor from agriculture to the industrial sector. Therefore, agricultural improvement expands firm size in the industrial sector, which determines innovation and triggers an endogenous transition from stagnation to growth. Calibrating the model to data, we find that without the reallocation of labor from agriculture to the industrial sector in the early 19th century, the takeoff of the US economy would have been delayed by about four decades.
•Explore how agricultural technology affects the endogenous takeoff of an economy.•Due to subsistence consumption, agricultural technology improvement reallocates labor from agriculture to industry.•Agricultural improvement expands industrial firm size, which determines innovation and triggers an endogenous takeoff.•The reallocation of labor in the early 19th century sped up the takeoff of the US by four decades.
Herpes simplex virus (HSV) establishes a latent reservoir in neurons of human peripheral nerves. In this quiescent state, the viral genome persists as a circular, histone-associated episome, and ...transcription of viral lytic cycle genes is largely suppressed through epigenetic processes. Periodically, latent virus undergoes reactivation whereby lytic genes are activated and viral replication occurs. In this Gem, we review recent evidence that mechanisms governing the initial transcription of lytic genes are distinct from those of de novo infection and directly link reactivation to neuronal stress response pathways. We also discuss evidence that lytic cycle gene expression can be uncoupled from the full reactivation program, arguing for a less sharply bimodal definition of latency.
Intolerance to enteral nutrition is common in critically ill adults, and may result in significant morbidity including ileus, abdominal distension, vomiting and potential aspiration events. ...Prokinetic agents are prescribed to improve gastric emptying. However, the efficacy and safety of these agents in critically ill patients is not well-defined. Therefore, we conducted a systematic review and meta-analysis to determine the efficacy and safety of prokinetic agents in critically ill patients.
We searched MEDLINE, EMBASE, and Cochrane Library from inception up to January 2016. Eligible studies included randomized controlled trials (RCTs) of critically ill adults assigned to receive a prokinetic agent or placebo, and that reported relevant clinical outcomes. Two independent reviewers screened potentially eligible articles, selected eligible studies, and abstracted pertinent data. We calculated pooled relative risk (RR) for dichotomous outcomes and mean difference for continuous outcomes, with the corresponding 95 % confidence interval (CI). We assessed risk of bias using Cochrane risk of bias tool, and the quality of evidence using grading of recommendations assessment, development, and evaluation (GRADE) methodology.
Thirteen RCTs (enrolling 1341 patients) met our inclusion criteria. Prokinetic agents significantly reduced feeding intolerance (RR 0.73, 95 % CI 0.55, 0.97; P = 0.03; moderate certainty), which translated to 17.3 % (95 % CI 5, 26.8 %) absolute reduction in feeding intolerance. Prokinetics also reduced the risk of developing high gastric residual volumes (RR 0.69; 95 % CI 0.52, 0.91; P = 0.009; moderate quality) and increased the success of post-pyloric feeding tube placement (RR 1.60, 95 % CI 1.17, 2.21; P = 0.004; moderate quality). There was no significant improvement in the risk of vomiting, diarrhea, intensive care unit (ICU) length of stay or mortality. Prokinetic agents also did not significantly increase the rate of diarrhea.
There is moderate-quality evidence that prokinetic agents reduce feeding intolerance in critically ill patients compared to placebo or no intervention. However, the impact on other clinical outcomes such as pneumonia, mortality, and ICU length of stay is unclear.
In this survey, we provide a selective review of the literature on inflation, innovation, and economic growth. The relationship between economic growth and inflation is a fundamental question in ...economics. Most studies in this literature explore this relationship in capital‐based growth models. This survey reviews a recent branch of this literature on inflation and innovation‐driven growth. Specifically, we use a canonical monetary Schumpeterian growth model to demonstrate the effects of inflation on innovation and the macroeconomy via different channels. We find that the cash‐in‐advance constraints on consumption and R&D investment have drastically different implications on the macroeconomic effects of inflation.
To elucidate the underlying physiological mechanisms of muscle synergies, we investigated long-range functional connectivity by cortico-muscular (CMC), intermuscular (IMC) and cortico-synergy (CSC) ...coherence. Fourteen healthy participants executed an isometric upper limb task in synergy-tuned directions. Cortical activity was recorded using 32-channel electroencephalography (EEG) and muscle activity using 16-channel electromyography (EMG). Using non-negative matrix factorisation (NMF), we calculated muscle synergies from two different tasks. A preliminary multidirectional task was used to identify synergy-preferred directions (PDs). A subsequent coherence task, consisting of generating forces isometrically in the synergy PDs, was used to assess the functional connectivity properties of synergies. Overall, we were able to identify four different synergies from the multidirectional task. A significant alpha band IMC was consistently present in all extracted synergies. Moreover, IMC alpha band was higher between muscles with higher weights within a synergy. Interestingly, CSC alpha band was also significantly higher across muscles with higher weights within a synergy. In contrast, no significant CMC was found between the motor cortex area and synergy muscles. The presence of a shared input onto synergistic muscles within a synergy supports the idea of neurally derived muscle synergies that build human movement. Our findings suggest cortical modulation of some of the synergies and the consequential existence of shared input between muscles within cortically modulated synergies.
•Review article examining quantitative neuroproteomics studies (2008–2013).•We discuss 2D-gel and MS based methods for relative and absolute quantitation.•We discuss proteomic studies of psychiatric ...diseases and neurodegenerative diseases.•We list neuroproteomic studies in table format according to quantitative method utilized.•We discuss future directions and challenges for neuroproteomics studies.
The field of proteomics is undergoing rapid development in a number of different areas including improvements in mass spectrometric platforms, peptide identification algorithms and bioinformatics. In particular, new and/or improved approaches have established robust methods that not only allow for in-depth and accurate peptide and protein identification and modification, but also allow for sensitive measurement of relative or absolute quantitation. These methods are beginning to be applied to the area of neuroproteomics, but the central nervous system poses many specific challenges in terms of quantitative proteomics, given the large number of different neuronal cell types that are intermixed and that exhibit distinct patterns of gene and protein expression. This review highlights the recent advances that have been made in quantitative neuroproteomics, with a focus on work published over the last five years that applies emerging methods to normal brain function as well as to various neuropsychiatric disorders including schizophrenia and drug addiction as well as of neurodegenerative diseases including Parkinson’s disease and Alzheimer’s disease. While older methods such as two-dimensional polyacrylamide electrophoresis continued to be used, a variety of more in-depth MS-based approaches including both label (ICAT, iTRAQ, TMT, SILAC, SILAM), label-free (label-free, MRM, SWATH) and absolute quantification methods, are rapidly being applied to neurobiological investigations of normal and diseased brain tissue as well as of cerebrospinal fluid (CSF). While the biological implications of many of these studies remain to be clearly established, that there is a clear need for standardization of experimental design and data analysis, and that the analysis of protein changes in specific neuronal cell types in the central nervous system remains a serious challenge, it appears that the quality and depth of the more recent quantitative proteomics studies is beginning to shed light on a number of aspects of neuroscience that relates to normal brain function as well as of the changes in protein expression and regulation that occurs in neuropsychiatric and neurodegenerative disorders.
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