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JAMA Mar 2020Vasopressors are commonly administered to intensive care unit (ICU) patients to raise blood pressure. Balancing risks and benefits of vasopressors is a challenge,... (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
Vasopressors are commonly administered to intensive care unit (ICU) patients to raise blood pressure. Balancing risks and benefits of vasopressors is a challenge, particularly in older patients.
OBJECTIVE
To determine whether reducing exposure to vasopressors through permissive hypotension (mean arterial pressure [MAP] target, 60-65 mm Hg) reduces mortality at 90 days in ICU patients aged 65 years or older with vasodilatory hypotension.
DESIGN, SETTING, AND PARTICIPANTS
A multicenter, pragmatic, randomized clinical trial was conducted in 65 ICUs in the United Kingdom and included 2600 randomized patients aged 65 years or older with vasodilatory hypotension (assessed by treating clinician). The study was conducted from July 2017 to March 2019, and follow-up was completed in August 2019.
INTERVENTIONS
Patients were randomized 1:1 to vasopressors guided either by MAP target (60-65 mm Hg, permissive hypotension) (n = 1291) or according to usual care (at the discretion of treating clinicians) (n = 1307).
MAIN OUTCOME AND MEASURES
The primary clinical outcome was all-cause mortality at 90 days.
RESULTS
Of 2600 randomized patients, after removal of those who declined or had withdrawn consent, 2463 (95%) were included in the analysis of the primary outcome (mean [SD] age 75 years [7 years]; 1387 [57%] men). Patients randomized to the permissive hypotension group had lower exposure to vasopressors compared with those in the usual care group (median duration 33 hours vs 38 hours; difference in medians, -5.0; 95% CI, -7.8 to -2.2 hours; total dose in norepinephrine equivalents median, 17.7 mg vs 26.4 mg; difference in medians, -8.7 mg; 95% CI, -12.8 to -4.6 mg). At 90 days, 500 of 1221 (41.0%) in the permissive hypotension compared with 544 of 1242 (43.8%) in the usual care group had died (absolute risk difference, -2.85%; 95% CI, -6.75 to 1.05; P = .15) (unadjusted relative risk, 0.93; 95% CI, 0.85-1.03). When adjusted for prespecified baseline variables, the odds ratio for 90-day mortality was 0.82 (95% CI, 0.68 to 0.98). Serious adverse events were reported for 79 patients (6.2%) in the permissive care group and 75 patients (5.8%) in the usual care group. The most common serious adverse events were acute renal failure (41 [3.2%] vs 33 [2.5%]) and supraventricular cardiac arrhythmia (12 [0.9%] vs 13 [1.0%]).
CONCLUSIONS AND RELEVANCE
Among patients 65 years or older receiving vasopressors for vasodilatory hypotension, permissive hypotension compared with usual care did not result in a statistically significant reduction in mortality at 90 days. However, the confidence interval around the point estimate for the primary outcome should be considered when interpreting the clinical importance of the study.
TRIAL REGISTRATION
isrctn.org Identifier: ISRCTN10580502.
Topics: Acute Kidney Injury; Aged; Aged, 80 and over; Atrial Premature Complexes; Cognition Disorders; Confidence Intervals; Female; Hospital Mortality; Humans; Hypotension; Intensive Care Units; Kaplan-Meier Estimate; Male; Vasoconstrictor Agents
PubMed: 32049269
DOI: 10.1001/jama.2020.0930 -
British Journal of Anaesthesia Nov 2023Intraoperative hypotension is associated with adverse postoperative outcomes; however these findings are supported only by observational studies. The aim of this... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Intraoperative hypotension is associated with adverse postoperative outcomes; however these findings are supported only by observational studies. The aim of this meta-analysis of randomised trials was to compare the postoperative effects permissive management with targeted management of intraoperative blood pressure.
METHODS
We searched PubMed, Cochrane, and Embase up to June 2023 for studies comparing permissive (mean arterial pressure ≤60 mm Hg) with targeted (mean arterial pressure >60 mm Hg) intraoperative blood pressure management. Primary outcome was all-cause mortality at the longest follow-up available. Secondary outcomes were atrial fibrillation, myocardial infarction, acute kidney injury, delirium, stroke, number of patients requiring transfusion, time on mechanical ventilation, and length of hospital stay.
RESULTS
We included 10 randomised trials including a total of 9359 patients. Mortality was similar between permissive and targeted blood pressure management groups (89/4644 [1.9%] vs 99/4643 [2.1%], odds ratio 0.88, 95% confidence interval [CI], 0.65-1.18, P=0.38, I=0% with nine studies included). Atrial fibrillation (102/3896 [2.6%] vs 130/3887 [3.3%] odds ratio 0.71, 95% CI 0.53-0.96, P=0.03, I=0%), and length of hospital stay (mean difference -0.20 days, 95% CI -0.26 to -0.13, P<0.001, I=0%) were reduced in the permissive management group. No significant differences were found in subgroup analysis for cardiac and noncardiac surgery.
CONCLUSION
Pooled randomised evidence shows that a target intraoperative mean arterial pressure ≤60 mm Hg is not associated with increased mortality; nevertheless it is surprisingly associated with a reduced rate of atrial fibrillation and of length of hospital stay.
SYSTEMATIC REVIEW PROTOCOL
PROSPERO CRD42023393725.
Topics: Humans; Arterial Pressure; Atrial Fibrillation; Blood Pressure; Hypotension; Postoperative Complications; Randomized Controlled Trials as Topic
PubMed: 37739903
DOI: 10.1016/j.bja.2023.08.026 -
Cell Chemical Biology May 2022The metabolic oxidative degradation of cellular lipids severely restricts replication of hepatitis C virus (HCV), a leading cause of chronic liver disease, but little is...
The metabolic oxidative degradation of cellular lipids severely restricts replication of hepatitis C virus (HCV), a leading cause of chronic liver disease, but little is known about the factors regulating this process in infected cells. Here we show that HCV is restricted by an iron-dependent mechanism resembling the one triggering ferroptosis, an iron-dependent form of non-apoptotic cell death, and mediated by the non-canonical desaturation of oleate to Mead acid and other highly unsaturated fatty acids by fatty acid desaturase 2 (FADS2). Genetic depletion and ectopic expression experiments show FADS2 is a key determinant of cellular sensitivity to ferroptosis. Inhibiting FADS2 markedly enhances HCV replication, whereas the ferroptosis-inducing compound erastin alters conformation of the HCV replicase and sensitizes it to direct-acting antiviral agents targeting the viral protease. Our results identify FADS2 as a rate-limiting factor in ferroptosis, and suggest the possibility of pharmacologically manipulating the ferroptosis pathway to attenuate viral replication.
Topics: Antiviral Agents; Fatty Acid Desaturases; Fatty Acids, Unsaturated; Ferroptosis; Hepacivirus; Hepatitis C, Chronic; Humans; Iron; Permissiveness; Virus Replication
PubMed: 34520742
DOI: 10.1016/j.chembiol.2021.07.022 -
Science (New York, N.Y.) Sep 2021Melanoma can arise only from cells with a permissive chromatin landscape.
Melanoma can arise only from cells with a permissive chromatin landscape.
Topics: Oncogenes
PubMed: 34516853
DOI: 10.1126/science.abl4510 -
Current Opinion in Psychology Apr 2021Regulatory approvals for Epidiolex (purified cannabidiol) in the treatment of childhood drug resistant epilepsy have set a precedent for the use of cannabinoids as a... (Review)
Review
Regulatory approvals for Epidiolex (purified cannabidiol) in the treatment of childhood drug resistant epilepsy have set a precedent for the use of cannabinoids as a prescribed medicine. Two common reasons cited for the use and prescription of cannabis-based products are pain and insomnia. Unlike drug resistant epilepsy, the level of evidence of efficacy in pain is poorly developed. The lowest quality trials with the greatest methodological shortcomings suggest some benefit, a level of evidence that is inconsistent with widespread prescribing. The evidence in insomnia is scant. Ongoing trial development and critical review of the literature should not be overshadowed by increasing permissiveness towards cannabis use and anecdotal reports of efficacy.
Topics: Cannabidiol; Cannabinoids; Cannabis; Drug Resistant Epilepsy; Humans; Pain
PubMed: 32652488
DOI: 10.1016/j.copsyc.2020.06.002 -
Annals of the American Thoracic Society Feb 2022
Topics: Humans; Hypercapnia; Respiration, Artificial; Respiratory Distress Syndrome
PubMed: 35103567
DOI: 10.1513/AnnalsATS.202108-997ED -
Current Opinion in Immunology Oct 2023Macrophages function as tissue-immune sentinels and mediate key antimicrobial responses against bacterial pathogens. Yet, they can also act as a cellular niche for... (Review)
Review
Macrophages function as tissue-immune sentinels and mediate key antimicrobial responses against bacterial pathogens. Yet, they can also act as a cellular niche for intracellular bacteria, such as Salmonella enterica, to persist in infected tissues. Macrophages exhibit heterogeneous activation or polarization, states that are linked to differential antibacterial responses and bacteria permissiveness. Remarkably, recent studies demonstrate that Salmonella and other intracellular bacteria inject virulence effectors into the cellular cytoplasm to skew the macrophage polarization state and reprogram these immune cells into a permissive niche. Here, we review mechanisms of macrophage reprogramming by Salmonella and highlight manipulation of macrophage polarization as a shared bacterial pathogenesis strategy. In addition, we discuss how the interplay of bacterial effector mechanisms, microenvironmental signals, and ontogeny may shape macrophage cell states and functions. Finally, we propose ideas of how further research will advance our understanding of macrophage functional diversity and immunobiology.
Topics: Humans; Macrophages; Bacteria; Virulence
PubMed: 37437470
DOI: 10.1016/j.coi.2023.102367 -
Acta Biomaterialia Apr 2021Biomaterial matrices must permit tissue growth and maturation for the success of tissue regeneration strategies. Naturally, this accommodation is achieved via the... (Review)
Review
Biomaterial matrices must permit tissue growth and maturation for the success of tissue regeneration strategies. Naturally, this accommodation is achieved via the dynamic remodeling of a cell's extracellular matrix (ECM). Synthetically, hydrolytic or enzymatic degradation are often engineered into materials for this purpose. More recently, supramolecular interactions have been used to provide a biomimetic and tunable mechanism to facilitate tissue formation via their dynamic and reversible non-covalent interactions. By engineering the mechanical and bioactive properties of a material, supramolecular chemists are able to design permissivity into the construct and facilitate tissue integration in-vivo. Furthermore, via the reversibility of non-covalent interactions, injectability and responsiveness can be designed for enhanced delivery and spatio-temporal control. In this review, we delineate the basic considerations needed when designing permissive supramolecular hydrogels for tissue engineering with an eye toward tissue growth and integration. We highlight three archetypal hydrogel systems that have shown well-documented tissue integration in vivo, and provide avenues to assess tissue in-growth. Careful design and assessment of the biomedical potential of a supramolecular hydrogels can inspire the creation of robust and dynamic implants for new tissue engineering applications.
Topics: Biocompatible Materials; Extracellular Matrix; Hydrogels; Tissue Engineering
PubMed: 33508507
DOI: 10.1016/j.actbio.2021.01.034 -
Molecular and Cellular Biochemistry Feb 2022Histones are classically known to organize the eukaryotic DNA into chromatin. They are one of the key players in regulating transcriptionally permissive and... (Review)
Review
Histones are classically known to organize the eukaryotic DNA into chromatin. They are one of the key players in regulating transcriptionally permissive and non-permissive states of the chromatin. Nevertheless, their context-dependent appearance within the cytoplasm and systemic circulation has also been observed. The past decade has also witnessed few scientific communications on the existence of vesicle-associated histones. Diverse groups have attempted to determine the significance of these extra-nuclear histones so far, with many of those studies still underway. Of note amongst these are interactions of extra-nuclear or free histones with cellular membranes, mediated by mutual cationic and anionic natures, respectively. It is here aimed to consolidate the mechanism of formation of extra-nuclear histones; implications of histone-induced membrane destabilization and explore the mechanisms of their association/release with extracellular vesicles, along with the functional aspects of these extra-nuclear histones in cell and systemic physiology.
Topics: Animals; Cell Membrane; Extracellular Vesicles; Histones; Humans
PubMed: 34796445
DOI: 10.1007/s11010-021-04300-4 -
Trends in Microbiology Mar 2024Many pathogens are hard to eradicate, even in the absence of genetically detectable antimicrobial resistance mechanisms and despite proven antibiotic susceptibility. The... (Review)
Review
Many pathogens are hard to eradicate, even in the absence of genetically detectable antimicrobial resistance mechanisms and despite proven antibiotic susceptibility. The fraction of clonal bacteria that temporarily elude effective antibiotic treatments is commonly known as 'antibiotic persisters.' Over the past decade, there has been a growing body of research highlighting the pivotal role played by the cellular host in the development of persisters. In parallel, this research has also sought to elucidate the molecular mechanisms underlying the formation of intracellular antibiotic persisters and has demonstrated a prominent role for the bacterial stress response. However, questions remain regarding the conditions leading to the formation of stress-induced persisters among a clonal population of intracellular bacteria and despite an ostensibly uniform environment. In this opinion, following a brief review of the current state of knowledge regarding intracellular antibiotic persisters, we explore the ways in which macrophage functional heterogeneity and bacterial phenotypic heterogeneity may contribute to the emergence of these persisters. We propose that the degree of mismatch between the macrophage permissiveness and the bacterial preparedness to invade and thrive intracellularly may explain the formation of stress-induced nonreplicating intracellular persisters.
PubMed: 38443279
DOI: 10.1016/j.tim.2024.02.009