The human gut is inhabited by a complex and metabolically active microbial ecosystem. While many studies focused on the effect of individual microbial taxa on human health, their overall metabolic ...potential has been under-explored. Using whole-metagenome shotgun sequencing data in 1,004 twins, we first observed that unrelated subjects share, on average, almost double the number of metabolic pathways (82%) than species (43%). Then, using 673 blood and 713 faecal metabolites, we found metabolic pathways to be associated with 34% of blood and 95% of faecal metabolites, with over 18,000 significant associations, while species showed less than 3,000 associations. Finally, we estimated that the microbiome was involved in a dialogue between 71% of faecal, and 15% of blood, metabolites. This study underlines the importance of studying the microbial metabolic potential rather than focusing purely on taxonomy to find therapeutic and diagnostic targets, and provides a unique resource describing the interplay between the microbiome and the systemic and faecal metabolic environments.
Summary
Background
Symptoms of SARS‐CoV‐2 infection have differed during the different waves of the pandemic but little is known about how cutaneous manifestations have changed.
Objectives
To ...investigate the diagnostic value, frequency and duration of cutaneous manifestations of SARS‐CoV‐2 infection and to explore their variations between the Delta and Omicron waves of the pandemic.
Methods
In this retrospective study, we used self‐reported data from 348 691 UK users of the ZOE COVID Study app, matched 1 : 1 for age, sex, vaccination status and self‐reported eczema diagnosis between the Delta and Omicron waves, to assess the diagnostic value, frequency and duration of five cutaneous manifestations of SARS‐CoV‐2 infection (acral, burning, erythematopapular and urticarial rash, and unusual hair loss), and how these changed between waves. We also investigated whether vaccination had any effect on symptom frequency.
Results
We show a significant association between any cutaneous manifestations and a positive SARS‐CoV‐2 test result, with a diagnostic value higher in the Delta compared with the Omicron wave (odds ratio 2·29, 95% confidence interval 2·22–2·36, P < 0·001; and odds ratio 1·29, 95% confidence interval 1·26–1·33, P < 0·001, respectively). Cutaneous manifestations were also more common with Delta vs. Omicron (17·6% vs. 11·4%, respectively) and had a longer duration. During both waves, cutaneous symptoms clustered with other frequent symptoms and rarely (in < 2% of the users) as first or only clinical sign of SARS‐CoV‐2 infection. Finally, we observed that vaccinated and unvaccinated users showed similar odds of presenting with a cutaneous manifestation, apart from burning rash, where the odds were lower in vaccinated users.
Conclusions
Cutaneous manifestations are predictive of SARS‐CoV‐2 infection, and their frequency and duration have changed with different variants. Therefore, we advocate for their inclusion in the list of clinically relevant COVID‐19 symptoms and suggest that their monitoring could help identify new variants.
What is already known about this topic?
Several studies during the wildtype COVID‐19 wave reported that patients presented with common skin‐related symptoms.
It has been observed that COVID‐19 symptoms differ among variants.
No study has focused on how skin‐related symptoms have changed across different variants.
What does this study add?
We showed, in a community‐based retrospective study including over 348 000 individuals, that the presence of cutaneous symptoms is predictive of SARS‐CoV‐2 infection during the Delta and Omicron waves and that this diagnostic value, along with symptom frequency and duration, differs between variants.
We showed that infected vaccinated and unvaccinated individuals reported similar skin‐related symptoms during the Delta and Omicron waves, with only burning rashes being less common after vaccination.
Odds ratios in adults testing positive for COVID‐19 of self‐reporting some of the typical COVID‐19 symptoms and skin signs of COVID‐19 infection. Results are based on 198 609 users of the ZOE COVID Study App that self‐reported their symptoms during the Delta wave and 198 609 users matched for age, sex, vaccination status and self‐reported eczema diagnosis that self‐reported their symptoms during the Omicron wave. The OR for anosmia (13·4, 95% confidence interval 13·1–13·8) is not shown for the Delta wave to improve visualization.
Linked Comment: M. Grau‐Pérez and I. Garcia‐Doval. Br J Dermatol 2022; 187:839.
Plain language summary available online
Tobacco smoking is known to impact circulating levels of major immune cells populations, but its effect on specific immune cell subsets remains poorly understood. Here, using high-resolution data ...from 223 healthy women (25 current and 198 never smokers), we investigated the association between smoking status and 35,651 immune traits capturing immune cell subset frequencies. Our results confirmed that active tobacco smoking is associated with increased frequencies of circulating CD8+ T cells expressing the CD25 activation marker. Moreover, we identified novel associations between smoking status and relative abundances of CD8+ CD25+ memory T cells, CD8+ memory T cells expressing the CCR4 chemokine receptor, and CD4+CD8+ (double-positive) CD25+ T cells. We also observed, in current smokers, a decrease in the relative frequencies of CD4+ T cells expressing the CD38 activation marker and an increase in class-switched memory B cell isotypes IgA, IgG, and IgE. Finally, using data from 135 former female smokers, we showed that the relative frequencies of immune traits associated with active smoking are usually completely restored after smoking cessation, with the exception of subsets of CD8+ and CD8+ memory T cells, which persist partially altered. Our results are consistent with previous findings and provide further evidence on how tobacco smoking shapes leukocyte cell subsets proportion toward chronic inflammation.
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of melanoma and other cancers. However, no reliable biomarker of survival or response has entered the clinic to identify those ...patients with melanoma who are most likely to benefit from ICIs. Glycosylation affects proteins and lipids' structure and functions. Tumours are characterized by aberrant glycosylation which may contribute to their progression and hinder an effective antitumour immune response.
We aim at identifying novel glyco-markers of response and survival by leveraging the N-glycome of total serum proteins collected in 88 ICI-naive patients with advanced melanoma from two European countries. Samples were collected before and during ICI treatment.
We observe that responders to ICIs present with a pre-treatment N-glycome profile significantly shifted towards higher abundancy of low-branched structures containing lower abundances of antennary fucose, and that this profile is positively associated with survival and a better predictor of response than clinical variables alone.
While changes in serum protein glycosylation have been previously implicated in a pro-metastatic melanoma behaviour, we show here that they are also associated with response to ICI, opening new avenues for the stratification of patients and the design of adjunct therapies aiming at improving immune response.
Inflammation can modulate tumour growth and progression, and influence clinical response to treatment. We investigated the potential of circulating inflammatory proteins for response stratification ...of immune checkpoint inhibitor (ICI) therapy for advanced melanoma.
Study subjects were 87 patients with unresectable stage III or IV cutaneous melanoma from the multiple centres across the United Kingdom (UK) and the Netherlands (NL) who received ipilimumab, nivolumab, or pembrolizumab, or a combination of ipilimumab and nivolumab. Serum samples were collected before and during ICI therapy at follow-up visits scheduled every third week over a 12-week period. We performed targeted quantification of 92 proteins involved in inflammation and tested for association of their pre-treatment and on-treatment levels, as well as longitudinal changes, with overall response rate, progression-free survival, and overall survival.
We observed consistently higher pre-treatment levels of interleukin-6 (IL-6), hepatocyte growth factor (HGF), and monocyte chemotactic protein 2 (MCP-2), in non-responders compared to responders (meta-analysis p=3.31 × 10−4, 2.29 × 10−4, and 1.02 × 10−3, respectively). Patients' stratification according to the median value of IL-6, HGF, and MCP-2 highlighted a cumulative negative effect of pre-treatment levels of the three proteins on response (p=1.13 × 10−2), with overall response rate among patients presenting with combined elevated IL-6, HGF, and MCP-2 levels being three-fold lower (26.7%) compared to patients with none of the three proteins elevated (80.0%, p=9.22 × 10−3). Longitudinal data analysis showed that on-treatment changes in circulating inflammatory proteins are not correlated with response.
Our findings are in line with an increasing body of evidence that the pro-inflammatory cytokine IL-6 can influence response to ICI in advanced melanoma, and further support a role of circulating HGF and MCP-2 levels as prognostic biomarkers as suggested by previous smaller studies. Inflammatory proteins may serve as predictive biomarkers of ICI response and valuable targets for combination therapy.
This work was supported by the Seerave Foundation and Dutch Cancer Society.
Rosenkranz (
2021
) devised two bimodal epistemic logics: an idealized one and a realistic one. The former is shown to be sound with respect to a class of neighborhood frames called
i-frames
. ...Rosenkranz designed a specific i-frame able to invalidate a series of undesired formulas, proving that these are not theorems of the idealized logic. Nonetheless, an unwanted formula and an unwanted rule of inference are not invalidated. Invalidating the former guarantees the distinction between the two modal operators characteristic of the logic, while invalidating the latter is crucial in order to deal with the problem of logical omniscience. In this paper, I present an i-frame able to invalidate all the undesired formulas already invalidated by Rosenkranz, together with the missing formula and rule of inference.
Abstract Leveraging whole genome sequencing data of 1751 individuals from the UK and 2587 Qatari subjects, we suggest here an association of rare variants mapping to the sour taste-associated gene ...KCNJ2 with reduced low-density lipoprotein cholesterol (LDL-C, P = 2.10 × 10 −12 ) and with a 22% decreased dietary trans-fat intake. This study identifies a novel candidate rare locus for LDL-C, adding insights into the genetic architecture of a complex trait implicated in cardiovascular disease.
The received view says that possibility is the dual of necessity: a proposition is (metaphysically, logically, epistemically etc.) possible iff it is not the case that its negation is ...(metaphysically, logically, epistemically etc., respectively) necessary. This reading is usually taken for granted by modal logicians and indeed seems plausible when dealing with logical or metaphysical possibility. But what about epistemic possibility? We argue that the dual definition of epistemic possibility in terms of epistemic necessity generates tension
when reasoning about non-idealized agents
and is a problem of concern for most
hyperintensional
epistemic logics that alleviate the problem of logical omniscience. The tension is particularly evident when knowledge is taken as a primitive to define other epistemic concepts, such as justification and belief, as done in the knowledge-first tradition. We propose a non-dual interpretation of epistemic possibility, employing a hyperintensionality filter similar to the one that makes the corresponding epistemic necessity operator hyperintensional. We employ the proposed semantics to model Stalnaker’s belief as epistemic possibility of knowledge and provide a sound and complete axiomatization for a hyperintensional version of his bimodal logic of knowledge and belief.
X-chromosome inactivation (XCI) silences one X in female cells to balance sex-differences in X-dosage. A subset of X-linked genes escape XCI, but the extent to which this phenomenon occurs and how it ...varies across tissues and in a population is as yet unclear. To characterize incidence and variability of escape across individuals and tissues, we conducted a transcriptomic study of escape in adipose, skin, lymphoblastoid cell lines and immune cells in 248 healthy individuals exhibiting skewed XCI. We quantify XCI escape from a linear model of genes' allelic fold-change and XIST-based degree of XCI skewing. We identify 62 genes, including 19 lncRNAs, with previously unknown patterns of escape. We find a range of tissue-specificity, with 11% of genes escaping XCI constitutively across tissues and 23% demonstrating tissue-restricted escape, including cell type-specific escape across immune cells of the same individual. We also detect substantial inter-individual variability in escape. Monozygotic twins share more similar escape than dizygotic twins, indicating that genetic factors may underlie inter-individual differences in escape. However, discordant escape also occurs within monozygotic co-twins, suggesting environmental factors also influence escape. Altogether, these data indicate that XCI escape is an under-appreciated source of transcriptional differences, and an intricate phenotype impacting variable trait expressivity in females.
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