The effect of icepack cooling on skin and muscle temperature at rest and after exercise

Objective. To compare cooling of skin, subcutaneous fat and muscle, produced by an icepack, at rest and after short-duration exhaustive exercise. Methods. Eight male subjects were studied. With the subject supine, hypodermic needle-tip thermistors were inserted into the subcutaneous fat and the mid-portion of the left rectus femoris, to a depth of 1 cm plus the adipose thickness at the site, and a temperature probe was placed on the skin overlying the needle tips. A pack of crushed ice was applied for 15 minutes and temperatures were recorded before, during, and for 45 minutes after icepack application. Thereafter, subjects underwent a ramped, treadmill, VO2max test, an icepack was applied after temperature probes were inserted into the right leg and measurements were made as before. Results. After the treadmill run, skin (Sk), subcutaneous (SC) and muscle (Ms) temperatures (mean ± standard deviation (SD)) were 0.9 ± 1.3, 1.0 ± 0.7 and 1.3 ± 0.8°C higher than at rest. After 15 minutes of icepack cooling, temperatures fell in the exercised limb by 22.7 ± 1.5°C (Sk), 13.5 ± 4.2°C (SC) and 9.3 ± 5.5°C (Ms) and in the control limb by 20.7 ± 2.9°C (Sk), 11.4 ± 2.0°C (SC) and 8.7 ± 2.6°C (Ms). The reductions in temperature were significant in both the control and exercised limbs. Forty-five minutes after icepack cooling, muscle temperature was still approximately 5°C lower in both the rested and exercised muscle (p < 0.001). Individual variations in response to cooling were noted. Conclusions. Cooling of superficial muscle occurs after high-intensity exercise. The degree of cooling is not uniform. This may be due to differences in the sympathetic response to cooling, influencing haemodynamic and thermoregulatory changes after exercise. This needs further investigation. South African Journal of Sports Medicine Vol. 18 (3) 2006: pp. 60-6

Microbial ligand costimulation drives neutrophilic steroid-refractory asthma

Funding: The authors thank the Wellcome Trust (102705) and the Universities of Aberdeen and Cape Town for funding. This research was also supported, in part, by National Institutes of Health GM53522 and GM083016 to DLW. KF and BNL are funded by the Fonds Wetenschappelijk Onderzoek, BNL is the recipient of an European Research Commission consolidator grant and participates in the European Union FP7 programs EUBIOPRED and MedALL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

The effect of icepack cooling on skin and muscle temperature at rest and after exercise

Objective. To compare cooling of skin, subcutaneous fat and muscle, produced by an icepack, at rest and after short-duration exhaustive exercise. Methods. Eight male subjects were studied. With the subject supine, hypodermic needle-tip thermistors were inserted into the subcutaneous fat and the mid-portion of the left rectus femoris, to a depth of 1 cm plus the adipose thickness at the site, and a temperature probe was placed on the skin overlying the needle tips. A pack of crushed ice was applied for 15 minutes and temperatures were recorded before, during, and for 45 minutes after icepack application. Thereafter, subjects underwent a ramped, treadmill, VO2max test, an icepack was applied after temperature probes were inserted into the right leg and measurements were made as before. Results. After the treadmill run, skin (Sk), subcutaneous (SC) and muscle (Ms) temperatures (mean ± standard deviation (SD)) were 0.9 ± 1.3, 1.0 ± 0.7 and 1.3 ± 0.8°C higher than at rest. After 15 minutes of icepack cooling, temperatures fell in the exercised limb by 22.7 ± 1.5°C (Sk), 13.5 ± 4.2°C (SC) and 9.3 ± 5.5°C (Ms) and in the control limb by 20.7 ± 2.9°C (Sk), 11.4 ± 2.0°C (SC) and 8.7 ± 2.6°C (Ms). The reductions in temperature were significant in both the control and exercised limbs. Forty-five minutes after icepack cooling, muscle temperature was still approximately 5°C lower in both the rested and exercised muscle (p < 0.001). Individual variations in response to cooling were noted. Conclusions. Cooling of superficial muscle occurs after high-intensity exercise. The degree of cooling is not uniform. This may be due to differences in the sympathetic response to cooling, influencing haemodynamic and thermoregulatory changes after exercise. This needs further investigation. South African Journal of Sports Medicine Vol. 18 (3) 2006: pp. 60-6

The vulnerabilities of agricultural land and food production to future water scarcity

Rapidly increasing populations coupled with increased food demand requires either an expansion of agriculturalland or sufficient production gains from current resources. However, in a changing world, reduced wateravailability might undermine improvements in crop and grass productivity and may disproportionately affectdifferent parts of the world. Using multi-model studies, the potential trends, risks and uncertainties to land useand land availability that may arise from reductions in water availability are examined here. In addition, theimpacts of different policy interventions on pressures from emerging risks are examined.Results indicate that globally, approximately 11% and 10% of current crop- and grass-lands could be vul-nerable to reduction in water availability and may lose some productive capacity, with Africa and the MiddleEast, China, Europe and Asia particularly at risk. While uncertainties remain, reduction in agricultural land areaassociated with dietary changes (reduction of food waste and decreased meat consumption) offers the greatestbuffer against land loss and food insecurity

Characterisation of Innate Fungal Recognition in the Lung

The innate recognition of fungi by leukocytes is mediated by pattern recognition receptors (PRR), such as Dectin-1, and is thought to occur at the cell surface triggering intracellular signalling cascades which lead to the induction of protective host responses. In the lung, this recognition is aided by surfactant which also serves to maintain the balance between inflammation and pulmonary function, although the underlying mechanisms are unknown. Here we have explored pulmonary innate recognition of a variety of fungal particles, including zymosan, Candida albicans and Aspergillus fumigatus, and demonstrate that opsonisation with surfactant components can limit inflammation by reducing host-cell fungal interactions. However, we found that this opsonisation does not contribute directly to innate fungal recognition and that this process is mediated through non-opsonic PRRs, including Dectin-1. Moreover, we found that pulmonary inflammatory responses to resting Aspergillus conidia were initiated by these PRRs in acidified phagolysosomes, following the uptake of fungal particles by leukocytes. Our data therefore provides crucial new insights into the mechanisms by which surfactant can maintain pulmonary function in the face of microbial challenge, and defines the phagolysosome as a novel intracellular compartment involved in the innate sensing of extracellular pathogens in the lung

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Genetic mechanisms of critical illness in Covid-19.

Host-mediated lung inflammation is present,1 and drives mortality,2 in critical illness caused by Covid-19. Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development.3 Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study(GWAS) in 2244 critically ill Covid-19 patients from 208 UK intensive care units (ICUs). We identify and replicate novel genome-wide significant associations, on chr12q24.13 (rs10735079, p=1.65 [Formula: see text] 10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), on chr19p13.2 (rs2109069, p=2.3 [Formula: see text] 10-12) near the gene encoding tyrosine kinase 2 (TYK2), on chr19p13.3 (rs2109069, p=3.98 [Formula: see text] 10-12) within the gene encoding dipeptidyl peptidase 9 (DPP9), and on chr21q22.1 (rs2236757, p=4.99 [Formula: see text] 10-8) in the interferon receptor gene IFNAR2. We identify potential targets for repurposing of licensed medications: using Mendelian randomisation we found evidence in support of a causal link from low expression of IFNAR2, and high expression of TYK2, to life-threatening disease; transcriptome-wide association in lung tissue revealed that high expression of the monocyte/macrophage chemotactic receptor CCR2 is associated with severe Covid-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms, and mediators of inflammatory organ damage in Covid-19. Both mechanisms may be amenable to targeted treatment with existing drugs. Large-scale randomised clinical trials will be essential before any change to clinical practice

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation.

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease