Naturally occurring viruses of Drosophila reduce offspring number and lifespan

This is the final version. Available on open access from the Royal Society via the DOI in this recordData accessibility: Raw data and code at https://doi.org/10.6084/m9.figshare.22559866 [65]. Raw reads from total RNA sequencing are in the sequence read archive under the Bioproject PRJNA1010185. Supplementary material is available online [66].Drosophila remains a pre-eminent insect model system for host-virus interaction, but the host range and fitness consequences of the drosophilid virome are poorly understood. Metagenomic studies have reported approximately 200 viruses associated with Drosophilidae, but few isolates are available to characterize the Drosophila immune response, and most characterization has relied on injection and systemic infection. Here, we use a more natural infection route to characterize the fitness effects of infection and to study a wider range of viruses. We exposed laboratory Drosophila melanogaster to 23 naturally occurring viruses from wild-collected drosophilids. We recorded transmission rates along with two components of female fitness: survival and the lifetime number of adult offspring produced. Nine different viruses transmitted during contact with laboratory D. melanogaster, although for the majority, rates of transmission were less than 20%. Five virus infections led to a significant decrease in lifespan (D. melanogaster Nora virus, D. immigrans Nora virus, Muthill virus, galbut virus and Prestney Burn virus), and three led to a reduction in the total number of offspring. Our findings demonstrate the utility of the Drosophila model for community-level studies of host-virus interactions, and suggest that viral infection could be a substantial fitness burden on wild flies.Natural Environment Research Council (NERC

Phototesting and photoprotection in LE

Photosensitivity and induction of skin lesions following UV radiation is a common problem of patients with cutaneous and systemic forms of lupus erythematosus. The detrimental effect of UV radiation to patients with lupus erythematosus was already recognized in the last century. Skin lesions can now be provoked under standardized conditions allowing the diagnosis and classification of patients with photosensitive disorders. The aim of this review is to give an overview on the history, test procedure and test results in patients with lupus erythematosus

Characterizing the Initial Phase of Epidemic Growth on some Empirical Networks

A key parameter in models for the spread of infectious diseases is the basic reproduction number $R_0$, which is the expected number of secondary cases a typical infected primary case infects during its infectious period in a large mostly susceptible population. In order for this quantity to be meaningful, the initial expected growth of the number of infectious individuals in the large-population limit should be exponential. We investigate to what extent this assumption is valid by performing repeated simulations of epidemics on selected empirical networks, viewing each epidemic as a random process in discrete time. The initial phase of each epidemic is analyzed by fitting the number of infected people at each time step to a generalised growth model, allowing for estimating the shape of the growth. For reference, similar investigations are done on some elementary graphs such as integer lattices in different dimensions and configuration model graphs, for which the early epidemic behaviour is known. We find that for the empirical networks tested in this paper, exponential growth characterizes the early stages of the epidemic, except when the network is restricted by a strong low-dimensional spacial constraint, such as is the case for the two-dimensional square lattice. However, on finite integer lattices of sufficiently high dimension, the early development of epidemics shows exponential growth.Comment: To be included in the conference proceedings for SPAS 2017 (International Conference on Stochastic Processes and Algebraic Structures), October 4-6, 201

Peri- and Postnatal Effects of Prenatal Adenoviral VEGF Gene Therapy in Growth-Restricted Sheep

Uterine artery (UtA) adenovirus vector (Ad)-mediated over-expression of vascular endothelial growth factor (VEGF) enhances uterine blood flow in normal sheep pregnancy and increases fetal growth in the overnourished adolescent sheep model of fetal growth restriction (FGR). Herein we examined its impact on gestation length, neonatal survival, early postnatal growth and metabolism. Singleton-bearing ewes were evenly allocated to receive Ad.VEGF-A165(5 x 10(10)particles/ml, 10 ml, n =17) or Saline (10 ml, n = 16) injected into each UtA at laparotomy (0.6 gestation). Fetal growth was serially monitored (blind) by ultrasound until delivery. Lambs were weighed and blood-sampled weekly and a glucose tolerance test performed (68d postnatal age). Hepatic DNA/RNA was extracted at necropsy (83d postnatal age) to examine methylation status of eight somatotropic axis genes. ITALIC! IGF1mRNA and protein expression were measured by RT-PCR and radioimmunoassay, respectively. All pregnancies remained viable following Ad.VEGF-A165treatment. Fetal abdominal circumference and renal volume were greater in Ad.VEGF-A165versus Saline groups at 21/28 days (p ≤ 0.04) post-injection. At delivery, gestation length (p = 0.07), lamb birthweight (p = 0.08), umbilical girth (p = 0.06) and plasma glucose (p=0.09) tended to be greater in Ad.VEGF-A165treated lambs. Levels of neonatal intervention required to ensure survival was equivalent between groups. Absolute postnatal growth rate (p = 0.02), insulin area-under-the-curve (p = 0.04) and carcass weight at necropsy (p = 0.04) were increased by Ad.VEGF-A165treatment. There was no impact on markers of insulin sensitivity or methylation/expression of key genes involved in somatic growth. Ad.VEGF-A165gene therapy increased fetal growth in a sheep FGR model and lambs continued to thrive during the neonatal and early postnatal period

Geographic access to high capability severe acute respiratory failure centers in the United States

Objective: Optimal care of adults with severe acute respiratory failure requires specific resources and expertise. We sought to measure geographic access to these centers in the United States. Design: Cross-sectional analysis of geographic access to high capability severe acute respiratory failure centers in the United States. We defined high capability centers using two criteria: (1) provision of adult extracorporeal membrane oxygenation (ECMO), based on either 2008-2013 Extracorporeal Life Support Organization reporting or provision of ECMO to 2010 Medicare beneficiaries; or (2) high annual hospital mechanical ventilation volume, based 2010 Medicare claims. Setting: Nonfederal acute care hospitals in the United States. Measurements and Main Results: We defined geographic access as the percentage of the state, region and national population with either direct or hospital-transferred access within one or two hours by air or ground transport. Of 4,822 acute care hospitals, 148 hospitals met our ECMO criteria and 447 hospitals met our mechanical ventilation criteria. Geographic access varied substantially across states and regions in the United States, depending on center criteria. Without interhospital transfer, an estimated 58.5% of the national adult population had geographic access to hospitals performing ECMO and 79.0% had geographic access to hospitals performing a high annual volume of mechanical ventilation. With interhospital transfer and under ideal circumstances, an estimated 96.4% of the national adult population had geographic access to hospitals performing ECMO and 98.6% had geographic access to hospitals performing a high annual volume of mechanical ventilation. However, this degree of geographic access required substantial interhospital transfer of patients, including up to two hours by air. Conclusions: Geographic access to high capability severe acute respiratory failure centers varies widely across states and regions in the United States. Adequate referral center access in the case of disasters and pandemics will depend highly on local and regional care coordination across political boundaries. © 2014 Wallace et al

Nighttime intensivist staffing and the timing of death among ICU decedents: A retrospective cohort study

Introduction: Intensive care units (ICUs) are increasingly adopting 24-hour intensivist physician staffing. Although nighttime intensivist staffing does not consistently reduce mortality, it may affect other outcomes such as the quality of end-of-life care.Methods: We conducted a retrospective cohort study of ICU decedents using the 2009-2010 Acute Physiology and Chronic Health Evaluation clinical information system linked to a survey of ICU staffing practices. We restricted the analysis to ICUs with high-intensity daytime staffing, in which the addition of nighttime staffing does not influence mortality. We used multivariable regression to assess the relationship between nighttime intensivist staffing and two separate outcomes potentially related to the quality of end-of-life care: time from ICU admission to death and death at night.Results: Of 30,456 patients admitted to 27 high-intensity daytime staffed ICUs, 3,553 died in the hospital within 30 days. After adjustment for potential confounders, admission to an ICU with nighttime intensivist staffing was associated with a shorter duration between ICU admission and death (adjusted difference: -2.5 days, 95% CI -3.5 to -1.5, p-value < 0.001) and a decreased odds of nighttime death (adjusted odds ratio: 0.75, 95% CI 0.60 to 0.94, p-value 0.011) compared to admission to an ICU without nighttime intensivist staffing.Conclusions: Among ICU decedents, nighttime intensivist staffing is associated with reduced time between ICU admission and death and reduced odds of nighttime death. © 2013 Reineck et al.; licensee BioMed Central Ltd

Attainment of treat-to-target endpoints in SLE patients with high disease activity in the atacicept phase 2b ADDRESS II study

OBJECTIVE Low disease activity (LDA) and remission are emerging treat-to-target (T2T) endpoints in SLE. However, the rates at which these endpoints are met in patients with high disease activity (HDA) are unknown. Atacicept, which targets B lymphocyte stimulator and a proliferation-inducing ligand, improved disease outcomes in SLE patients with HDA (SLEDAI-2K ≥10) at baseline in the phase 2b ADDRESS II study. This is a post hoc analysis of T2T endpoints in these patients. METHODS Patients received weekly atacicept (75 or 150 mg s.c.) or placebo for 24 weeks (1:1:1 randomization). Attainment of three T2T endpoints, LDA (SLEDAI-2K ≤ 2), Lupus Low Disease Activity State (LLDAS) and remission (clinical SLEDAI-2K = 0, prednisone-equivalent ≤5mg/day and Physician’s Global Assessment <0.5), was assessed and compared with SLE Responder Index (SRI)-4 and SRI-6 response. RESULTS Of 306 randomized patients, 158 (51.6%) had baseline HDA. At week 24, 37 (23.4%) HDA patients attained LDA, 25 (15.8%) LLDAS and 17 (10.8%) remission. Each of these endpoints was more stringent than SRI-4 (n = 87; 55.1%) and SRI-6 (n = 67; 42.4%). Compared with placebo (n = 52), at week 24, patients treated with atacicept 150 mg (n = 51) were more likely to attain LDA [odds ratio (OR) 3.82 (95% CI: 1.44, 10.15), P = 0.007], LLDAS [OR 5.03 (95% CI: 1.32, 19.06), P = 0.018] or remission [OR 3.98 (95% CI: 0.78, 20.15), P = 0.095]. CONCLUSION At week 24, LDA, LLDAS and remission were more stringent than SRI-4 and SRI-6 response, were attainable in the HDA population and discriminated between treatment with atacicept 150 mg and placebo. These results suggest that T2T endpoints are robust outcome measures in SLE clinical trials and support further evaluation of atacicept in SLE. TRAIL REGISTRATION ClinicalTrials.gov, http://clinicaltrials.gov, NCT01972568