Determinants of host susceptibility to murine respiratory syncytial virus (RSV) disease identify a role for the innate immunity scavenger receptor MARCO gene in human infants

AbstractBackgroundRespiratory syncytial virus (RSV) is the global leading cause of lower respiratory tract infection in infants. Nearly 30% of all infected infants develop severe disease including bronchiolitis, but susceptibility mechanisms remain unclear.MethodsWe infected a panel of 30 inbred strains of mice with RSV and measured changes in lung disease parameters 1 and 5days post-infection and they were used in genome-wide association (GWA) studies to identify quantitative trait loci (QTL) and susceptibility gene candidates.FindingsGWA identified QTLs for RSV disease phenotypes, and the innate immunity scavenger receptor Marco was a candidate susceptibility gene; targeted deletion of Marco worsened murine RSV disease. We characterized a human MARCO promoter SNP that caused loss of gene expression, increased in vitro cellular response to RSV infection, and associated with increased risk of disease severity in two independent populations of children infected with RSV.InterpretationTranslational integration of a genetic animal model and in vitro human studies identified a role for MARCO in human RSV disease severity. Because no RSV vaccines are approved for clinical use, genetic studies have implications for diagnosing individuals who are at risk for severe RSV disease, and disease prevention strategies (e.g. RSV antibodies)

Genome sequencing and population genomic analyses provide insights into the adaptive landscape of silver birch

Silver birch (Betula pendula) is a pioneer boreal tree that can be induced to flower within 1 year. Its rapid life cycle, small (440-Mb) genome, and advanced germplasm resources make birch an attractive model for forest biotechnology. We assembled and chromosomally anchored the nuclear genome of an inbred B. pendula individual. Gene duplicates from the paleohexaploid event were enriched for transcriptional regulation, whereas tandem duplicates were overrepresented by environmental responses. Population resequencing of 80 individuals showed effective population size crashes at major points of climatic upheaval. Selective sweeps were enriched among polyploid duplicates encoding key developmental and physiological triggering functions, suggesting that local adaptation has tuned the timing of and cross-talk between fundamental plant processes. Variation around the tightly-linked light response genes PHYC and FRS10 correlated with latitude and longitude and temperature, and with precipitation for PHYC. Similar associations characterized the growth-promoting cytokinin response regulator ARR1, and the wood development genes KAK and MED5A.Peer reviewe

Author Correction: Genome sequencing and population genomic analyses provide insights into the adaptive landscape of silver birch.

In the version of this article initially published, there was a mistake in the calculation of the nucleotide mutation rate per site per generation: 1 × 10−9 mutations per site per generation was used, whereas 9.5 × 10−9 was correct. This error affects the interpretation of population-size changes over time and their possible correspondence with known geological events, as shown in the original Fig. 4 and supporting discussion in the text, as well as details in the Supplementary Note. Neither the data themselves nor any other results are affected. Figure 4 has been revised accordingly. Images of the original and corrected figure panels are shown in the correction notice

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Determinants of host susceptibility to murine respiratory syncytial virus (RSV) disease identify a role for the innate immunity scavenger receptor MARCO gene in human infants

Background: Respiratory syncytial virus (RSV) is the global leading cause of lower respiratory tract infection in infants. Nearly 30% of all infected infants develop severe disease including bronchiolitis, but susceptibility mechanisms remain unclear. Methods: We infected a panel of 30 inbred strains of mice with RSV and measured changes in lung disease parameters 1 and 5 days post-infection and they were used in genome-wide association (GWA) studies to identify quantitative trait loci (QTL) and susceptibility gene candidates. Findings: GWA identified QTLs for RSV disease phenotypes, and the innate immunity scavenger receptor Marco was a candidate susceptibility gene; targeted deletion of Marco worsened murine RSV disease. We characterized a human MARCO promoter SNP that caused loss of gene expression, increased in vitro cellular response to RSV infection, and associated with increased risk of disease severity in two independent populations of children infected with RSV. Interpretation Translational integration of a genetic animal model and in vitro human studies identified a role for MARCO in human RSV disease severity. Because no RSV vaccines are approved for clinical use, genetic studies have implications for diagnosing individuals who are at risk for severe RSV disease, and disease prevention strategies (e.g. RSV antibodies)

The Development of Cutaneous Neurofibromas

Cutaneous neurofibromas are the hallmarks of neurofibromatosis type 1 (NF1). They are composed of multiple cell types, and traditionally they are believed to arise from small nerve tributaries of the skin. A key finding in the context of this view has been that subpopulations of tumor Schwann cells harbor biallelic inactivation of the NF1 gene (NF1−/−). In the present study, our aim was to clarify further the pathogenesis of cutaneous neurofibromas. First, we detected cells expressing multipotency-associated biomarkers in cutaneous neurofibromas. Second, we developed a method for isolating and expanding multipotent neurofibroma-derived precursor cells (NFPs) from dissociated human cutaneous neurofibromas and used it to analyze their growth and differentiation potential. In analogy to solitary cells resident in neurofibromas, NFPs were found to express nestin and had the potential to differentiate to, at least, Schwann cells, neurons, epithelial cells, and adipocytes. Mutation analysis of the NFPs revealed that their genotype was NF1+/−. The results led us to speculate that the development of cutaneous neurofibromas includes the recruitment of multipotent NF1+/− precursor cells. These cells may be derived from the multipotent cells of the hair roots, which often are intimately associated with microscopic neurofibromas

Current evidence on the impact of medication optimization or pharmacological interventions on frailty or aspects of frailty: a systematic review of randomized controlled trials

Background Frailty and adverse drug effects are linked in the fact that polypharmacy is correlated with the severity of frailty; however, a causal relation has not been proven in older people with clinically manifest frailty. Methods A literature search was performed in Medline to detect prospective randomized controlled trials (RCTs) testing the effects of pharmacological interventions or medication optimization in older frail adults on comprehensive frailty scores or partial aspects of frailty that were published from January 1998 to October 2019. Results Twenty-five studies were identified, 4 on comprehensive frailty scores and 21 on aspects of frailty. Two trials on comprehensive frailty scores showed positive results on frailty although the contribution of medication review in a multidimensional approach was unclear. In the studies on aspects related to frailty, ten individual drug interventions showed improvement in physical performance, muscle strength or body composition utilizing alfacalcidol, teriparatide, piroxicam, testosterone, recombinant human chorionic gonadotropin, or capromorelin. There were no studies examining negative effects of drugs on frailty. Conclusion So far, data on a causal relationship between drugs and frailty are inconclusive or related to single-drug interventions on partial aspects of frailty. There is a clear need for RCTs on this topic that should be based on a comprehensive, internationally consistent and thus reproducible concept of frailty assessment