Summary
Background
The human virome consists of animal‐cell viruses causing transient infections, bacteriophage (phage) predators of bacteria and archaea, endogenous retroviruses and viruses causing ...persistent and latent infections. High‐throughput, inexpensive, sensitive sequencing methods and metagenomics now make it possible to study the contribution dsDNA, ssDNA and RNA virus‐like particles make to the human virome, and in particular the intestinal virome.
Aim
To review and evaluate the pioneering studies that have attempted to characterise the human virome and generated an increased interest in understanding how the intestinal virome might contribute to maintaining health, and the pathogenesis of chronic diseases.
Methods
Relevant virome‐related articles were selected for review following extensive language‐ and date‐unrestricted, electronic searches of the literature.
Results
The human intestinal virome is personalised and stable, and dominated by phages. It develops soon after birth in parallel with prokaryotic communities of the microbiota, becoming established during the first few years of life. By infecting specific populations of bacteria, phages can alter microbiota structure by killing host cells or altering their phenotype, enabling phages to contribute to maintaining intestinal homeostasis or microbial imbalance (dysbiosis), and the development of chronic infectious and autoimmune diseases including HIV infection and Crohn's disease, respectively.
Conclusions
Our understanding of the intestinal virome is fragmented and requires standardised methods for virus isolation and sequencing to provide a more complete picture of the virome, which is key to explaining the basis of virome‐disease associations, and how enteric viruses can contribute to disease aetiologies and be rationalised as targets for interventions.
Airway management complications causing temporary patient harm are common, but serious injury is rare. Because most airways are easy, most complications occur in easy airways: these complications can ...and do lead to harm and death. Because these events are rare, most of our learning comes from large litigation and critical incident databases that help identify patterns and areas where care can be improved: but both have limitations. The recent 4th National Audit Project of the Royal College of Anaesthetists and Difficult Airway Society provides important detailed information and our best estimates of the incidence of major airway complications. A significant proportion of airway complications occur in Intensive Care Units and Emergency Departments, and these more frequently cause patient harm/death and are associated with suboptimal care. Hypoxia is the commonest cause of airway-related deaths. Obesity markedly increases risk of airway complications. Pulmonary aspiration remains the leading cause of airway-related anaesthetic deaths, most cases having identifiable risk factors. Unrecognized oesophageal intubation is not of only historical interest and is entirely avoidable. All airway management techniques fail and prediction scores are rather poor, so many failures are unanticipated. Avoidance of airway complications requires institutional and individual preparedness, careful assessment, good planning and judgement, good communication and teamwork, knowledge and use of a range of techniques and devices, and a willingness to stop performing techniques when they are failing. Analysis of major airway complications identifies areas where practice is suboptimal; research to improve understanding, prevention, and management of such complications remains an anaesthetic priority.
Cardiovascular disease (CVD) is the leading cause of death in women aged 65 years and older. Sex hormones have been implicated as having a critical role in the evolution of CVD, with the focus mainly ...on estrogens in women. Available data also indicate that low testosterone blood levels may be detrimental to cardiovascular function in women. At blood concentrations considered normal for premenopausal women, testosterone has favorable effects on blood vessel function (relaxation and contraction), much of which is determined by the endothelial cells that line the inside of blood vessels. Testosterone enhances endothelium-dependent and independent brachial artery vasodilation and has an acute systolic blood pressure-lowering effect in postmenopausal women. Advantageous effects of testosterone in animal models have been seen for myocardial function and cardiac electrical signaling. Human data are mainly limited to observational and mechanistic studies, which mostly demonstrate beneficial effects of testosterone on cardiovascular health. Few studies of testosterone use in women, with cardiovascular endpoints as primary outcomes, have been published.
The extragalactic background light (EBL) is of fundamental importance both for understanding the entire process of galaxy evolution and for γ-ray astronomy, but the overall spectrum of the EBL ...between 0.1 and 1000 μm has never been determined directly from galaxy spectral energy distribution (SED) observations over a wide redshift range. The evolving, overall spectrum of the EBL is derived here utilizing a novel method based on observations only. This is achieved from the observed evolution of the rest-frame K-band galaxy luminosity function up to redshift 4, combined with a determination of galaxy-SED-type fractions. These are based on fitting Spitzer Wide-Area Infrared Extragalactic Survey (SWIRE) templates to a multiwavelength sample of about 6000 galaxies in the redshift range from 0.2 to 1 from the All-wavelength Extended Groth Strip International Survey (AEGIS). The changing fractions of quiescent galaxies, star-forming galaxies, starburst galaxies and active galactic nucleus (AGN) galaxies in that redshift range are estimated, and two alternative extrapolations of SED types to higher redshifts are considered. This allows calculation of the evolution of the luminosity densities from the ultraviolet (UV) to the infrared (IR), the evolving star formation rate density of the Universe, the evolving contribution to the bolometric EBL from the different galaxy populations including AGN galaxies and the buildup of the EBL. Our EBL calculations are compared with those from a semi-analytic model, another observationally based model and observational data. The EBL uncertainties in our modelling based directly on the data are quantified, and their consequences for attenuation of very-high-energy γ-rays due to pair production on the EBL are discussed. It is concluded that the EBL is well constrained from the UV to the mid-IR, but independent efforts from IR and γ-ray astronomy are needed in order to reduce the uncertainties in the far-IR.
The clinical effects of testosterone in women have expanded from the field of androgen excess to consideration of testosterone action and the consequences of depletion and replacement. This article ...is not a comprehensive review of the vast and increasing literature in this field. Rather, it summarizes some of what is known of testosterone in women that the author elected to highlight in a plenary lecture and is hopefully informative, but not to be considered conclusive.
Highlights • Lifetime depression and anxiety increase risk of current mood problems in diabetes. • Health behaviour and glycemic control are poorer for these individuals. • Current mood accounts for ...some of the effect of lifetime history on diabetes control. • Early identification and treatment of lifetime depression and anxiety is warranted.
The number of secretory cells in the mammary gland is often cited as a major determinant of milk production. However, literature data for proxy measures of secretory cell number do not fully support ...such a claim. In particular, measurements of total mammary DNA in livestock explain only <25% of variation in milk yield, probably because of tissue heterogeneity for DNA concentration. Relative to BW, measurements of udder size in dairy cattle, as total DNA or udder weight, are approximately double those seen in most other livestock classes. Therefore, selection for dairy production, not surprisingly, has resulted in cows with greater secretory capacity. There is limited evidence that genetic selection is still increasing udder size in some cattle populations, but more recent data are needed. It is contended that the most important period of mammary growth for determination of milk yield is that occurring in pregnancy and early lactation. Mammary development is largely complete, at term, in sheep, goats, and cattle, but in pigs, the udder continues to grow during the first 3 wk of lactation, depending, in part, on litter size. Increased litter size in sheep and goats will enhance the extent of mammary development at the end of gestation (and milk yield) by 20 to 25%. However, twinning in dairy cattle does not affect milk production and, by inference only, is not likely to affect numbers of secretory cells at term. Milking frequency and suckling intensity in very early lactation will increase milk yield in cows and increase mammogenesis and milk yield in sheep, indicating that even at term, the ruminant gland retains some capacity for further development, if demand requires it. There is limited understanding of the hormonal signals in pregnancy that regulate mammary development relative to the number of young carried. Furthermore, the genetic differences between dairy and beef cattle that lead to substantially greater udder size in the dairy breeds have not been identified. During lactation, the drivers for secretory cell loss in relation to milking frequency and nutritional status are still not known. Measurement of mammary development and using this phenotype in genomewide association studies to identify key genetic variants for mammogenesis will provide knowledge that is fundamental to understanding the quantitative regulation of milk production.
Aims/hypothesis Fenofibrate caused an acute, sustained plasma creatinine increase in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in ...Diabetes (ACCORD) studies. We assessed fenofibrate's renal effects overall and in a FIELD washout sub-study. Methods Type 2 diabetic patients (n = 9,795) aged 50 to 75 years were randomly assigned to fenofibrate (n = 4,895) or placebo (n = 4,900) for 5 years, after 6 weeks fenofibrate run-in. Albuminuria (urinary albumin/creatinine ratio measured at baseline, year 2 and close-out) and estimated GFR, measured four to six monthly according to the Modification of Diet in Renal Disease Study, were pre-specified endpoints. Plasma creatinine was re-measured 8 weeks after treatment cessation at close-out (washout sub-study, n = 661). Analysis was by intention-to-treat. Results During fenofibrate run-in, plasma creatinine increased by 10.0 μmol/l (p < 0.001), but quickly reversed on placebo assignment. It remained higher on fenofibrate than on placebo, but the chronic rise was slower (1.62 vs 1.89 μmol/l annually, p = 0.01), with less estimated GFR loss (1.19 vs 2.03 ml min⁻¹ 1.73 m⁻² annually, p < 0.001). After washout, estimated GFR had fallen less from baseline on fenofibrate (1.9 ml min⁻¹ 1.73 m⁻², p = 0.065) than on placebo (6.9 ml min⁻¹ 1.73 m⁻², p < 0.001), sparing 5.0 ml min⁻¹ 1.73 m⁻² (95% CI 2.3-7.7, p < 0.001). Greater preservation of estimated GFR with fenofibrate was observed with baseline hypertriacylglycerolaemia (n = 169 vs 491 without) alone, or combined with low HDL-cholesterol (n = 140 vs 520 without) and reductions of ≥0.48 mmol/l in triacylglycerol over the active run-in period (pre-randomisation) (n = 356 vs 303 without). Fenofibrate reduced urine albumin concentrations and hence albumin/creatinine ratio by 24% vs 11% (p < 0.001; mean difference 14% 95% CI 9-18; p < 0.001), with 14% less progression and 18% more albuminuria regression (p < 0.001) than in participants on placebo. End-stage renal event frequency was similar (n = 21 vs 26, p = 0.48). Conclusions/interpretation Fenofibrate reduced albuminuria and slowed estimated GFR loss over 5 years, despite initially and reversibly increasing plasma creatinine. Fenofibrate may delay albuminuria and GFR impairment in type 2 diabetes patients. Confirmatory studies are merited. Trial registration ISRCTN64783481 Funding The study was funded by grants from Laboratoires Fournier SA (Dijon, France; now part of Abbott Pharmaceuticals) and the National Health and Medical Research Council, Australia
Mucin-related carbohydrates are overexpressed on the surface of cancer cells, providing a disease-specific target for cancer immunotherapy. Here, we describe the design and construction of ...peptide-free multivalent glycosylated nanoscale constructs as potential synthetic cancer vaccines that generate significant titers of antibodies selective for aberrant mucin glycans. A polymerizable version of the Tn-antigen glycan was prepared and converted into well-defined glycopolymers by Reversible Addition–Fragmentation chain Transfer (RAFT) polymerization. The polymers were then conjugated to gold nanoparticles, yielding ‘multicopy-multivalent’ nanoscale glycoconjugates. Immunological studies indicated that these nanomaterials generated strong and long-lasting production of antibodies that are selective to the Tn-antigen glycan and cross-reactive toward mucin proteins displaying Tn. The results demonstrate proof-of-concept of a simple and modular approach toward synthetic anticancer vaccines based on multivalent glycosylated nanomaterials without the need for a typical vaccine protein component.
Background. The incidence and severity of Clostridium difficile–associated diarrhea (CDAD) has been increasing, and there have been recent reports of metronidazole treatment failure. Metronidazole is ...still commonly used as first-line treatment for CDAD but has never been compared with vancomycin in a prospective, randomized, double-blind, placebo-controlled trial. We conducted such a trial, stratifying patients according to disease severity, to investigate whether one agent was superior for treating either mild or severe disease. Methods. From October 1994 through June 2002, patients with CDAD were stratified according to whether they had mild or severe disease based on clinical criteria and were randomly assigned to receive oral metronidazole (250 mg 4 times per day) or oral vancomycin (125 mg 4 times per day) for 10 days. Both groups received an oral placebo in addition to the study drug. Patients were followed up for 21 days to assess cure, treatment failure, relapse, or intolerance. Results. One hundred seventy-two patients were enrolled, and 150 of these patients successfully completed the trial. Among the patients with mild CDAD, treatment with metronidazole or vancomycin resulted in clinical cure in 90% and 98% of the patients, respectively (P = .36). Among the patients with severe CDAD, treatment with metronidazole or vancomycin resulted in clinical cure in 76% and 97% of the patients, respectively (P = .02). Clinical symptoms recurred in 15% of the patients treated with metronidazole and 14% of those treated with vancomycin. Conclusions. Our findings suggest that metronidazole and vancomycin are equally effective for the treatment of mild CDAD, but vancomycin is superior for treating patients with severe CDAD.
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