Coronavirus disease (COVID-19) is a global threat to health. Its inflammatory characteristics are incompletely understood.
To define the cytokine profile of COVID-19 and to identify evidence of ...immunometabolic alterations in those with severe illness.
Levels of IL-1β, IL-6, IL-8, IL-10, and sTNFR1 (soluble tumor necrosis factor receptor 1) were assessed in plasma from healthy volunteers, hospitalized but stable patients with COVID-19 (COVID
patients), patients with COVID-19 requiring ICU admission (COVID
patients), and patients with severe community-acquired pneumonia requiring ICU support (CAP
patients). Immunometabolic markers were measured in circulating neutrophils from patients with severe COVID-19. The acute phase response of AAT (alpha-1 antitrypsin) to COVID-19 was also evaluated.
IL-1β, IL-6, IL-8, and sTNFR1 were all increased in patients with COVID-19. COVID
patients could be clearly differentiated from COVID
patients, and demonstrated higher levels of IL-1β, IL-6, and sTNFR1 but lower IL-10 than CAP
patients. COVID-19 neutrophils displayed altered immunometabolism, with increased cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, HIF-1α (hypoxia-inducible factor-1α), and lactate. The production and sialylation of AAT increased in COVID-19, but this antiinflammatory response was overwhelmed in severe illness, with the IL-6:AAT ratio markedly higher in patients requiring ICU admission (
< 0.0001). In critically unwell patients with COVID-19, increases in IL-6:AAT predicted prolonged ICU stay and mortality, whereas improvement in IL-6:AAT was associated with clinical resolution (
< 0.0001).
The COVID-19 cytokinemia is distinct from that of other types of pneumonia, leading to organ failure and ICU need. Neutrophils undergo immunometabolic reprogramming in severe COVID-19 illness. Cytokine ratios may predict outcomes in this population.
The Beck Depression Inventory II (BDI-II) has been suspected of overestimating the level of depression in individuals that endure chronic pain. Using a sample (N = 345) of male military veterans with ...chronic pain enrolled in an outpatient treatment program, a factor analysis on the BDI-II revealed a "Somatic Complaints" factor along with 2 other factors we labeled "Negative Rumination" and "Mood." Standardized scores were provided for each BDI-II factor score, Total score, and Total minus Somatic score. The internal consistency reliabilities (Gilmer-Feldt and alpha coefficients) for all scores were found to be clinically acceptable. Item-Total score correlations found that all of the BDI-II items were good discriminators (r > .30). We conclude that the normative data provided in this study should help control for somatic responding by male chronic pain veterans on the BDI-II. We highly recommend that clinicians and researchers use the norm-referenced method when interpreting BDI-II scores from individuals suffering from chronic pain.
We describe a new behavior of planktonic ciliates. The field-collected tintinnid Eutintinnus inquilinus attached with its lorica to a range of surfaces, including particulate aggregates. Most ...tintinnids remained attached with the aboral end of their lorica when well fed. On starvation, many tintinnids detached and resumed a free-swimming life. We hypothesize that the adhesive property of the lorica has evolved as an adaptation to attach to suspended aggregates or other seston particles. Attached E. inquilinus have a feeding rate that is 80% higher than free-swimming individuals because of the change in the fluid dynamics of the feeding current for attached E. inquilinus, which leads to steeper velocity gradients and higher flow rates close to the lorica. This mechanism will also operate for swimming suspension feeders attached to smaller particles that significantly increase the hydrodynamic drag. Selection for traits that enhance the velocity gradients in feeding currents of small plankton may be common and may partly shape behavioral patterns and functional morphology. When exposed to the calanoid copepod Acartia clausi, populations of E. inquilinus were less susceptible to predation than another Eutintinnus species of similar morphology but that were entirely free swimming.
Radioactive radon is an inert gas that can migrate from soils and rocks and accumulate in enclosed areas, such as homes and underground mines. Studies of miners show that exposure to radon decay ...products causes lung cancer. Consequently, it is of public health interest to estimate accurately the consequences of daily, low-level exposure in homes to this known carcinogen. Epidemiologic studies of residential radon exposure are burdened by an inability to estimate exposure accurately, low total exposure, and subsequent small excess risks. As a result, the studies have been inconclusive to date. Estimates of the hazard posed by residential radon have been based on analyses of data on miners, with recent estimates based on a pooling of four occupational cohort studies of miners, including 360 lung cancer deaths.
To more fully describe the lung cancer risk in radon-exposed miners, we pooled original data from 11 studies of radon-exposed underground miners, conducted a comprehensive analysis, and developed models for estimating radon-associated lung cancer risk.
We pooled original data from 11 cohort studies of radon-exposed underground miners, including 65,000 men and more than 2700 lung cancer deaths, and fit various relative risk (RR) regression models.
The RR relationship for cumulative radon progeny exposure was consistently linear in the range of miner exposures, suggesting that exposures at lower levels, such as in homes, would carry some risk. The exposure-response trend for never-smokers was threefold the trend for smokers, indicating a greater RR for exposure in never-smokers. The RR from exposure diminished with time since the exposure occurred. For equal total exposure, exposures of long duration (and low rate) were more harmful than exposures of short duration (and high rate).
In the miners, about 40% of all lung cancer deaths may be due to radon progeny exposure, 70% of lung cancer deaths in never-smokers, and 39% of lung cancer deaths in smokers. In the United States, 10% of all lung cancer deaths might be due to indoor radon exposure, 11% of lung cancer deaths in smokers, and 30% of lung cancer deaths in never-smokers. This risk model estimates that reducing radon in all homes exceeding the U. S. Environmental Protection Agency's recommended action level may reduce lung cancer deaths about 2%-4%. These estimates should be interpreted with caution, because concomitant exposures of miners to agents such as arsenic or diesel exhaust may modify the radon effect and, when considered together with other differences between homes and mines, might reduce the generalizability of findings in miners.
IMPORTANCE: Use of antibiotics for the treatment of appendicitis is safe and has been found to be noninferior to appendectomy based on self-reported health status at 30 days. Identifying patient ...characteristics associated with a greater likelihood of appendectomy within 30 days in those who initiate antibiotics could support more individualized decision-making. OBJECTIVE: To assess patient factors associated with undergoing appendectomy within 30 days of initiating antibiotics for appendicitis. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study using data from the Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) randomized clinical trial, characteristics among patients who initiated antibiotics were compared between those who did and did not undergo appendectomy within 30 days. The study was conducted at 25 US medical centers; participants were enrolled between May 3, 2016, and February 5, 2020. A total of 1552 participants with acute appendicitis were randomized to antibiotics (776 participants) or appendectomy (776 participants). Data were analyzed from September 2020 to July 2021. EXPOSURES: Appendectomy vs antibiotics. MAIN OUTCOMES AND MEASURES: Conditional logistic regression models were fit to estimate associations between specific patient factors and the odds of undergoing appendectomy within 30 days after initiating antibiotics. A sensitivity analysis was performed excluding participants who underwent appendectomy within 30 days for nonclinical reasons. RESULTS: Of 776 participants initiating antibiotics (mean SD age, 38.3 13.4 years; 286 37% women and 490 63% men), 735 participants had 30-day outcomes, including 154 participants (21%) who underwent appendectomy within 30 days. After adjustment for other factors, female sex (odds ratio OR, 1.53; 95% CI, 1.01-2.31), radiographic finding of wider appendiceal diameter (OR per 1-mm increase, 1.09; 95% CI, 1.00-1.18), and presence of appendicolith (OR, 1.99; 95% CI, 1.28-3.10) were associated with increased odds of undergoing appendectomy within 30 days. Characteristics that are often associated with increased risk of complications (eg, advanced age, comorbid conditions) and those clinicians often use to describe appendicitis severity (eg, fever: OR, 1.28; 95% CI, 0.82-1.98) were not associated with odds of 30-day appendectomy. The sensitivity analysis limited to appendectomies performed for clinical reasons provided similar results regarding appendicolith (adjusted OR, 2.41; 95% CI, 1.49-3.91). CONCLUSIONS AND RELEVANCE: This cohort study found that presence of an appendicolith was associated with a nearly 2-fold increased risk of undergoing appendectomy within 30 days of initiating antibiotics. Clinical characteristics often used to describe severity of appendicitis were not associated with odds of 30-day appendectomy. This information may help guide more individualized decision-making for people with appendicitis.
A classical hallmark of acute inflammation is neutrophil infiltration of tissues, a multi-step process that involves sequential cell-cell interactions of circulating leukocytes with interleukin ...(IL)-1- or tumor necrosis factor-α (TNF)-activated microvascular endothelial cells (ECs) and pericytes (PCs) that form the wall of the postcapillary venules. The initial infiltrating cells accumulate perivascularly in close proximity to PCs. IL-17, a pro-inflammatory cytokine that acts on target cells via a heterodimeric receptor formed by IL-17RA and IL-17RC subunits, also promotes neutrophilic inflammation but its effects on vascular cells are less clear. We report that both cultured human ECs and PCs strongly express IL-17RC and, while neither cell type expresses much IL-17RA, PCs express significantly more than ECs. IL-17, alone or synergistically with TNF, significantly alters inflammatory gene expression in cultured human PCs but not ECs. RNA-seq analysis identifies many IL-17-induced transcripts in PCs encoding proteins known to stimulate neutrophil-mediated immunity. Conditioned media (CM) from IL-17-activated PCs, but not ECs, induce pertussis toxin-sensitive neutrophil polarization, likely mediated by PC-secreted chemokines, and also stimulate neutrophil production of pro-inflammatory molecules, including TNF, IL-1α, IL-1β, and IL-8. Furthermore, IL-17-activated PCs but not ECs can prolong neutrophil survival by producing G-CSF and GM-CSF, delaying the mitochondria outer membrane permeabilization and caspase 9 activation. Importantly, neutrophils exhibit enhanced phagocytic capacity after activation by CM from IL-17-treated PCs. We conclude that PCs, not ECs, are the major target of IL-17 within the microvessel wall and that IL-17-activated PCs can modulate neutrophil functions within the perivascular tissue space.
Endothelial cells (ECs) line the lumen of the entire vascular system and actively regulate blood flow; maintain blood fluidity; control water, solute, and macromolecular transfer between blood and ...tissue; and modulate circulating immune cell recruitment and activation. These vital functions, combined with the broad anatomic distribution of ECs, implicate them in all forms of critical illness. The present article discusses how ECs adapt and break down during the course of critical illness. We first review the biology of ECs, highlighting the vascular segmental differences and their specific roles in the maintenance of homeostasis. We then discuss how ECs acquire new functions to restore local and systemic homeostasis (activation) as well as how breakdowns in EC functions (dysfunction) contribute to local and systemic pathologic responses, with clinical correlations. Lastly, how these processes have been studied in critically ill children is discussed.
Chronic granulomatous disease (CGD) is a congenital disorder in which phagocytes cannot generate superoxide (O2
-) and other microbial oxidants due to mutations in any one of four components of the ...O2
--generating complex, NADPH oxidase. We report here a female CGD patient in whom a missense mutation in one of these components, the p22-phox subunit of the neutrophil membrane cytochrome bwhere phox indicates phagocyte oxidase (used to designate protein components of the phagocyte NADPH oxidase) results in a nonfunctional oxidase and failure of neutrophils to produce O2
-in response to phorbol 12-myristrate 13-acetate. Cytochrome b in the patient's neutrophils was normal in appearance and abundance as determined by visible spectroscopy and by immunoblots of the gp91 and p22 subunits. However, the neutrophil plasma membranes were devoid of activity in the cell-free oxidase activation system, whereas the cytosol functioned normally. We postulated that the patient was homozygous for a mutation in p22 that results in the synthesis of normal levels of a nonfunctional cytochrome b. A single-base substitution (C → A) was found in the patient's mononuclear cell p22-phox cDNA that predicts a nonconservative Pro → Gln substitution at residue 156. The same mutation was also identified in all clones sequenced from patient genomic DNA, demonstrating homozygosity for the mutant allele. An antipeptide antibody against p22 residues 153-164 was found to bind only to permeabilized neutrophils, indicating that the mutation occurs in a cytoplasmic domain. These studies establish that this domain of p22-phox is cytoplasmic and that mutations in this region can have profound effects on cytochrome b function.
Abstract
Ciliate microzooplankton are important grazers in most pelagic ecosystems and among them, tintinnids, with their largely species‐specific loricas, allow relatively easy assessment of ...questions of diversity and distributions. Herein, we present the results of a survey of species records of tintinnids from the Southern Ocean (locations below 40°S) reported in 56 publications yielding 2,047 species records (synonyms included) from 402 locations. The 192 species reported can be parsed into two main groups: 32 endemic Southern Ocean species, known only from 40°S and further south, and a second group of 181 widespread species, forms with extensive geographic ranges extending into the Southern Ocean. Widespread species reported from the Southern Ocean can be further divided into a group of 81 species, each recorded multiple times in the Southern Ocean waters and 70 apparent “stray” species which have only been found but once. The endemic and widespread species of the Southern Ocean show both distinct distributional patterns and morphological differences. The assemblage of Southern Ocean endemics is found mostly within the
A
ntarctic zone delimited by the average location of the Polar Front and contains a relatively large portion of wide‐mouthed forms. We give suggestions for future study.
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