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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Of 2600 randomized patients, after removal of those who declined or had withdrawn consent, 2463 (95%) were included in the analysis of the primary outcome (mean [SD] age 75 years [7 years]; 1387 [57%] men).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 -
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 -
Immunity Jul 2022Lung-resident memory B cells (MBCs) provide localized protection against reinfection in respiratory airways. Currently, the biology of these cells remains largely...
Lung-resident memory B cells (MBCs) provide localized protection against reinfection in respiratory airways. Currently, the biology of these cells remains largely unexplored. Here, we combined influenza and SARS-CoV-2 infection with fluorescent-reporter mice to identify MBCs regardless of antigen specificity. We found that two main transcriptionally distinct subsets of MBCs colonized the lung peribronchial niche after infection. These subsets arose from different progenitors and were both class switched, somatically mutated, and intrinsically biased in their differentiation fate toward plasma cells. Combined analysis of antigen specificity and B cell receptor repertoire segregated these subsets into "bona fide" virus-specific MBCs and "bystander" MBCs with no apparent specificity for eliciting viruses generated through an alternative permissive process. Thus, diverse transcriptional programs in MBCs are not linked to specific effector fates but rather to divergent strategies of the immune system to simultaneously provide rapid protection from reinfection while diversifying the initial B cell repertoire.
Topics: Animals; B-Lymphocytes; COVID-19; Immunologic Memory; Lung; Memory B Cells; Mice; Reinfection; SARS-CoV-2
PubMed: 35768001
DOI: 10.1016/j.immuni.2022.06.002 -
Annals of the American Thoracic Society Feb 2022
Topics: Humans; Hypercapnia; Respiration, Artificial; Respiratory Distress Syndrome
PubMed: 35103567
DOI: 10.1513/AnnalsATS.202108-997ED -
Pathogens (Basel, Switzerland) Nov 2022Zika virus (ZIKV) is an arthropod-borne virus that belongs to the family, genus and was first isolated 1947 in Uganda, Africa, from the serum of a sentinel Rhesus... (Review)
Review
Zika virus (ZIKV) is an arthropod-borne virus that belongs to the family, genus and was first isolated 1947 in Uganda, Africa, from the serum of a sentinel Rhesus monkey. Since its discovery, the virus was responsible for major outbreaks in several different countries, being linked to severe complications in pregnant women, neonatal birth defects and the congenital zika syndrome. Maternal-fetal transmission of ZIKV can occur in all trimesters of pregnancy, and the role of the placenta and its cells in these cases is yet to be fully understood. The decidua basalis and chorionic villi, maternal-fetal components of the placenta, contain a rich immunological infiltrate composed by Hofbauer cells, mastocytes, dendritic cells and macrophages, primary cells of the innate immune response that have a role that still needs to be better investigated in ZIKV infection. Recent studies have already described several histopathological features and the susceptibility and permissiveness of placenta cells to infection by the Zika virus. In this review, we address some of the current knowledge on the innate immune responses against ZIKV, especially in the placenta.
PubMed: 36558744
DOI: 10.3390/pathogens11121410 -
Neuroscience and Biobehavioral Reviews Jan 2024Smoking continues to be a leading cause of preventable disease and death worldwide. Nicotine dependence generates a lifelong propensity towards cravings and relapse,... (Review)
Review
Smoking continues to be a leading cause of preventable disease and death worldwide. Nicotine dependence generates a lifelong propensity towards cravings and relapse, presenting an ongoing challenge for the development of treatments. Accumulating evidence supports a role for epigenetics in the development and maintenance of addiction to many drugs of abuse, however, the involvement of epigenetics in nicotine dependence is less clear. Here we review evidence that nicotine interacts with epigenetic mechanisms to enable the maintenance of nicotine-seeking across time. Research across species suggests that nicotine increases permissive histone acetylation, decreases repressive histone methylation, and modulates levels of DNA methylation and noncoding RNA expression throughout the brain. These changes are linked to the promoter regions of genes critical for learning and memory, reward processing and addiction. Pharmacological manipulation of enzymes that catalyze core epigenetic modifications regulate nicotine reward and associative learning, demonstrating a functional role of epigenetic modifications in nicotine dependence. These findings are consistent with nicotine promoting an overall permissive chromatin state at genes important for learning, memory and reward. By exploring these links through next-generation sequencing technologies, epigenetics provides a promising avenue for future interventions to treat nicotine dependence.
Topics: Humans; Histones; Nicotine; Tobacco Use Disorder; Epigenesis, Genetic; DNA Methylation
PubMed: 38070842
DOI: 10.1016/j.neubiorev.2023.105505 -
Blood Feb 2021
Topics: HLA-DP beta-Chains; Humans; Unrelated Donors
PubMed: 33599759
DOI: 10.1182/blood.2020009266 -
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 -
The European Respiratory Journal Dec 2022SARS-CoV-2 has caused devastating effects with over 550 million infections by July 2022 and approximately 6.4 million deaths [1]. Societal and economic impacts will...
SARS-CoV-2 has caused devastating effects with over 550 million infections by July 2022 and approximately 6.4 million deaths [1]. Societal and economic impacts will reverberate for years, with continuous evolution of SARS-CoV-2 as it persistently spreads through the human population as exemplified by reduced activity of vaccines and monoclonals against Omicron BA.4 or BA.5 subvariants [2]. A greater understanding of pathogenesis and more tailored therapeutic approaches are therefore essential.
Topics: Humans; SARS-CoV-2; COVID-19; Angiotensin-Converting Enzyme 2; Permissiveness; Lung; Inflammation; Macrophages
PubMed: 36028257
DOI: 10.1183/13993003.01521-2022