We sought to determine whether temporal changes in the lower airway microbiome are associated with ventilator-associated pneumonia (VAP) in children.Using a multicentre prospective study of children ...aged 31 days to 18 years requiring mechanical ventilation support for >72 h, daily tracheal aspirates were collected and analysed by sequencing of the 16S rRNA gene. VAP was assessed using 2008 Centers for Disease Control and Prevention paediatric criteria. The association between microbial factors and VAP was evaluated using joint longitudinal time-to-event modelling, matched case-control comparisons and unsupervised clustering.Out of 366 eligible subjects, 66 (15%) developed VAP at a median of 5 (interquartile range 3-5) days post intubation. At intubation, there was no difference in total bacterial load (TBL), but Shannon diversity and the relative abundance of
, Lactobacillales and
were lower for VAP subjects
non-VAP subjects. However, higher TBL on each sequential day was associated with a lower hazard (hazard ratio 0.39, 95% CI 0.23-0.64) for developing VAP, but sequential values of diversity were not associated with VAP. Similar findings were observed from the matched analysis and unsupervised clustering. The most common dominant VAP pathogens included
species (19%),
(14%) and
/
(10%).
and
were also identified as dominant organisms in several subjects.In mechanically ventilated children, changes over time in microbial factors were marginally associated with VAP risk, although these changes were not suitable for predicting VAP in individual patients. These findings suggest that focusing exclusively on pathogen burden may not adequately inform VAP diagnosis.
Objectives
Fatigue is prevalent in people with inflammatory rheumatic and musculoskeletal diseases (I-RMDs) and recognised as one of the most challenging symptoms to manage. The existence of multiple ...factors associated with driving and maintaining fatigue, and the evidence about what improves fatigue has led to a multifaceted approach to its management. However, there are no recommendations for fatigue management in people with I-RMDs. This lack of guidance is challenging for those living with fatigue and health professionals delivering clinical care. Therefore, our aim was to develop EULAR recommendations for the management of fatigue in people with I-RMDs.
Methods
A multidisciplinary taskforce comprising 26 members from 14 European countries was convened, and two systematic reviews were conducted. The taskforce developed the recommendations based on the systematic review of evidence supplemented with taskforce members’ experience of fatigue in I-RMDs.
Results
Four overarching principles (OAPs) and four recommendations were developed. OAPs include health professionals’ awareness that fatigue encompasses multiple biological, psychological and social factors which should inform clinical care. Fatigue should be monitored and assessed, and people with I-RMDs should be offered management options. Recommendations include offering tailored physical activity and/or tailored psychoeducational interventions and/or, if clinically indicated, immunomodulatory treatment initiation or change. Patient-centred fatigue management should consider the individual’s needs and preferences, their clinical disease activity, comorbidities and other psychosocial and contextual factors through shared decision-making.
Conclusions
These 2023 EULAR recommendations provide consensus and up-to-date guidance on fatigue management in people with I-RMDs.
An excessive amount of adipose tissue may contribute to sarcopenia and may be one mechanism underlying accelerated loss of muscle mass and strength with aging. We therefore examined the association ...of baseline total body fat with changes in leg lean mass, muscle strength, and muscle quality over 7 years of follow-up and whether this link was explained by adipocytokines and insulin resistance.
Data were from 2,307 men and women, aged 70-79 years, participating in the Health, Aging, and Body Composition study. Total fat mass was acquired from dual energy X-ray absorptiometry. Leg lean mass was assessed by dual energy X-ray absorptiometry in Years 1, 2, 3, 4, 5, 6, and 8. Knee extension strength was measured by isokinetic dynamometer in Years 1, 2, 4, 6, and 8. Muscle quality was calculated as muscle strength divided by leg lean mass.
Every SD greater fat mass was related to 1.3 kg more leg lean mass at baseline in men and 1.5 kg in women (p < .01). Greater fat mass was also associated with a greater decline in leg lean mass in both men and women (0.02 kg/year, p < .01), which was not explained by higher levels of adipocytokines and insulin resistance. Larger fat mass was related to significantly greater muscle strength but significantly lower muscle quality at baseline (p < .01). No significant differences in decline of muscle strength and quality were found.
High fatness was associated with lower muscle quality, and it predicts accelerated loss of lean mass. Prevention of greater fatness in old age may decrease the loss of lean mass and maintain muscle quality and thereby reducing disability and mobility impairments.
Innate immune receptors that form complexes with secondary receptors, activating multiple signalling pathways, modulate cellular activation and play essential roles in regulating homeostasis and ...immunity. We have previously identified a variety of bovine C-type lectin-like receptors that possess similar functionality than their human orthologues. Mincle (
), a heavily glycosylated monomer, is involved in the recognition of the mycobacterial component Cord factor (trehalose 6,6'-dimycolate). Here we characterise the bovine homologue of Mincle (boMincle), and demonstrate that the receptor is structurally and functionally similar to the human orthologue (huMincle), although there are some notable differences. In the absence of cross-reacting antibodies, boMincle-specific antibodies were created and used to demonstrate that, like the human receptor, boMincle is predominantly expressed by myeloid cells. BoMincle surface expression increases during the maturation of monocytes to macrophages. However, boMincle mRNA transcripts were also detected in granulocytes, B cells, and T cells. Finally, we show that boMincle binds to isolated bovine CD4
T cells in a specific manner, indicating the potential to recognise endogenous ligands. This suggests that the receptor might also play a role in homeostasis in cattle.
This study examines the impact of corporate characteristics on climate change governance among 100 of the world’s largest companies, with 1400 observations in the fiscal year 2020. We consider ...variables such as company location, size, profitability, female board representation, years of reporting using Task Force on Climate-Related Financial Disclosures (TCFD) guidelines, the inclusion of UN Global Compact and Global Reporting Initiative (GRI) information, Dow Jones Sustainability Index (DJSI) membership, MSCI ESG ratings, and the presence of a climate transition plan, a sustainability executive, and a sustainability board committee. Applying a multi-theoretical framework, we employ correlation analysis and univariate and multiple linear regressions to assess the relationships. Our findings reveal positive correlations between climate governance and the presence of a climate transition plan, MSCI ratings, DJSI membership, and the existence of a sustainability executive. Additionally, companies located in developed countries exhibit significantly higher levels of climate change governance. These results hold across various scenarios, offering valuable insights for researchers, academics, business leaders, practitioners, and regulators. With the growing importance of climate change reporting, understanding the key contributing factors for effective climate governance is crucial for organizations seeking to address this critical issue.
Summary
Background
There is no cure or firm clinical recommendations for the treatment of vitiligo. One of the main issues is the heterogeneity of outcome measures used in randomized controlled ...trials for vitiligo.
Objectives
To define successful repigmentation from the patients’ point of view and to propose how and when repigmentation should be evaluated in clinical trials in vitiligo.
Methods
We conducted three workshops with patients with vitiligo and their parents or caregivers. Workshop 1 was held at World Vitiligo Day (Detroit, MI), workshop 2 at the University of Texas Southwestern Medical Center and workshop 3 at the Vitiligo and Pigmentation Institute of Southern California, University of California.
Results
Seventy‐three participants were recruited. Consensus on the following questions was achieved unanimously: (i) the definition of ‘successful repigmentation’ was 80–100% of repigmentation of a target lesion and (ii) both an objective and a subjective scale to measure repigmentation should be used.
Conclusions
This was the largest patients’ outcomes workshop. We followed the guidance from the CSG‐COUSIN and the Vitiligo Global Issues Consensus Group. Our recommendations to use percentage of repigmentation quartiles (0–25%, 26–50%, 51–79%, 80–100%) and the Vitiligo Noticeability Scale are based on the best available current evidence. A limitation of the research is that the workshops were conducted only in the U.S.A., due to pre‐existing organisational support and the availability of funding.
What's already known about this topic?
There are no firm clinical recommendations for the treatment of vitiligo.
One of the main issues is the heterogeneity of outcome measures used in randomized controlled trials for vitiligo.
What does this study add?
Based on international consensus and the best available evidence, repigmentation should be assessed by measuring the percentage of repigmentation in quartiles (0–25%, 26–50%, 51–79%, 80–100%).
The cosmetic acceptability of results should also be assessed, for example using the Vitiligo Noticeability Scale.
Respond to this article
Linked Comment: Wolkerstorfer. Br J Dermatol 2019; 180:454–455.
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Channelling of glucose via glycogen, known as the glycogen shunt, may play an important role in the metabolism of brain tumours, especially in hypoxic conditions. We aimed to dissect the role of ...glycogen degradation in glioblastoma (GBM) response to ionising radiation (IR). Knockdown of the glycogen phosphorylase liver isoform (PYGL), but not the brain isoform (PYGB), decreased clonogenic growth and survival of GBM cell lines and sensitised them to IR doses of 10-12 Gy. Two to five days after IR exposure of PYGL knockdown GBM cells, mitotic catastrophy and a giant multinucleated cell morphology with senescence-like phenotype developed. The basal levels of the lysosomal enzyme alpha-acid glucosidase (GAA), essential for autolysosomal glycogen degradation, and the lipidated forms of gamma-aminobutyric acid receptor-associated protein-like (GABARAPL1 and GABARAPL2) increased in shPYGL U87MG cells, suggesting a compensatory mechanism of glycogen degradation. In response to IR, dysregulation of autophagy was shown by accumulation of the p62 and the lipidated form of GABARAPL1 and GABARAPL2 in shPYGL U87MG cells. IR increased the mitochondrial mass and the colocalisation of mitochondria with lysosomes in shPYGL cells, thereby indicating reduced mitophagy. These changes coincided with increased phosphorylation of AMP-activated protein kinase and acetyl-CoA carboxylase 2, slower ATP generation in response to glucose loading and progressive loss of oxidative phosphorylation. The resulting metabolic deficiencies affected the availability of ATP required for mitosis, resulting in the mitotic catastrophy observed in shPYGL cells following IR. PYGL mRNA and protein levels were higher in human GBM than in normal human brain tissues and high PYGL mRNA expression in GBM correlated with poor patient survival. In conclusion, we show a major new role for glycogen metabolism in GBM cancer. Inhibition of glycogen degradation sensitises GBM cells to high-dose IR indicating that PYGL is a potential novel target for the treatment of GBMs.
Mycobacterium tuberculosis is characterised by limited genomic diversity, which makes the application of whole genome sequencing particularly attractive for clinical and epidemiological ...investigation. However, in order to confidently infer transmission events, an accurate knowledge of the rate of change in the genome over relevant timescales is required.
We attempted to estimate a molecular clock by sequencing 199 isolates from epidemiologically linked tuberculosis cases, collected in the Netherlands spanning almost 16 years.
Multiple analyses support an average mutation rate of ~0.3 SNPs per genome per year. However, all analyses revealed a very high degree of variation around this mean, making the confirmation of links proposed by epidemiology, and inference of novel links, difficult. Despite this, in some cases, the phylogenetic context of other strains provided evidence supporting the confident exclusion of previously inferred epidemiological links.
This in-depth analysis of the molecular clock revealed that it is slow and variable over short time scales, which limits its usefulness in transmission studies. However, the superior resolution of whole genome sequencing can provide the phylogenetic context to allow the confident exclusion of possible transmission events previously inferred via traditional DNA fingerprinting techniques and epidemiological cluster investigation. Despite the slow generation of variation even at the whole genome level we conclude that the investigation of tuberculosis transmission will benefit greatly from routine whole genome sequencing.
Several studies have linked dietary patterns to insulin sensitivity and systemic inflammation, which affect risk of multiple chronic diseases. The purpose of this study was to investigate the dietary ...patterns of a cohort of older adults, and to examine relationships of dietary patterns with markers of insulin sensitivity and systemic inflammation.
The Health, Aging and Body Composition (Health ABC) Study is a prospective cohort study of 3075 older adults. In Health ABC, multiple indicators of glucose metabolism and systemic inflammation were assessed. Food intake was estimated with a modified Block food frequency questionnaire. In this study, dietary patterns of 1751 participants with complete data were derived by cluster analysis.
Six clusters were identified, including a 'healthy foods' cluster, characterized by higher intake of low-fat dairy products, fruit, whole grains, poultry, fish and vegetables. In the main analysis, the 'healthy foods' cluster had significantly lower fasting insulin and homeostasis model assessment of insulin resistance values than the 'breakfast cereal' and 'high-fat dairy products' clusters, and lower fasting glucose than the 'high-fat dairy products' cluster (P≤0.05). No differences were found in 2-h glucose. With respect to inflammation, the 'healthy foods' cluster had lower interleukin-6 than the 'sweets and desserts' and 'high-fat dairy products' clusters, and no differences were seen in C-reactive protein or tumor necrosis factor-α.
A dietary pattern high in low-fat dairy products, fruit, whole grains, poultry, fish and vegetables may be associated with greater insulin sensitivity and lower systemic inflammation in older adults.
Background.
Diagnostic criteria for sarcopenia from appendicular lean mass (ALM), strength, and performance have been proposed, but little is known regarding the progression of sarcopenia.
We ...examined the time course of sarcopenia and determinants of transitioning toward and away from sarcopenia.
Methods.
ALM, gait speed, and grip strength were assessed seven times over 9 years in 2,928 initially well-functioning adults aged 70–79. Low ALM was defined as less than 7.95 kg/m2 (men) or less than 6.24 kg/m2 (women), low performance as gait speed less than 1.0 m/s, low strength as grip strength less than 30 kg (men) or less than 20 kg (women). Presarcopenia was defined as low ALM and sarcopenia as low ALM with low performance or low strength. Hidden Markov modeling was used to characterize states of ALM, strength, and performance and model transitions leading to sarcopenia and death. Determinants of transitioning toward and away from sarcopenia were examined with logistic regression.
Results.
Initially, 54% of participants had normal ALM, strength, and performance; 21% had presarcopenia; 5% had sarcopenia; and 20% had intermediate characteristics. Of participants with normal ALM, strength, and performance, 1% transitioned to presarcopenia and none transitioned to sarcopenia. The greatest transition to sarcopenia (7%) was in presarcopenic individuals. Low-functioning and sarcopenia states were more likely to lead to death (12% and 13%). Higher body mass index (p < .001) and pain (p = .05) predicted transition toward sarcopenia, whereas moderate activity predicted transition from presarcopenia to more normal states (p = .02).
Conclusions.
Pain, physical activity, and body mass index, potentially modifiable factors, are determinants of transitions. Promotion of health approaching old age is important as few individuals transition away from their initial state.
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