Municipal water use in Northern Colorado: development of efficiency-of-use criterion

Includes bibliographical references.OWRT project no. A-042-COLO

Single-Cell RNA-Seq Analysis of Olfactory Mucosal Cells of Alzheimer's Disease Patients

Olfaction is orchestrated by olfactory mucosal cells located in the upper nasal cavity. Olfactory dysfunction manifests early in several neurodegenerative disorders including Alzheimer's disease, however, disease-related alterations to the olfactory mucosal cells remain poorly described. The aim of this study was to evaluate the olfactory mucosa differences between cognitively healthy individuals and Alzheimer's disease patients. We report increased amyloid-beta secretion in Alzheimer's disease olfactory mucosal cells and detail cell-type-specific gene expression patterns, unveiling 240 differentially expressed disease-associated genes compared to the cognitively healthy controls, and five distinct cell populations. Overall, alterations of RNA and protein metabolism, inflammatory processes, and signal transduction were observed in multiple cell populations, suggesting their role in Alzheimer's disease-related olfactory mucosa pathophysiology. Furthermore, the single-cell RNA-sequencing proposed alterations in gene expression of mitochondrially located genes in AD OM cells, which were verified by functional assays, demonstrating altered mitochondrial respiration and a reduction of ATP production. Our results reveal disease-related changes of olfactory mucosal cells in Alzheimer's disease and demonstrate the utility of single-cell RNA sequencing data for investigating molecular and cellular mechanisms associated with the disease.Peer reviewe

Developing cartoons for long-term condition self-management information

Background: Advocating the need to adopt more self-management policies has brought with it an increasing demand for information about living with and making decisions about long-term conditions, with a significant potential for using cartoons. However, the purposeful use of cartoons is notably absent in many areas of health care as is evidence of their acceptability to patients and lay others. This paper outlines the process used to develop and evaluate cartoons and their acceptability for a series of self-management guidebooks for people with inflammatory bowel disease, irritable bowel syndrome, diabetes, chronic obstructive pulmonary disease and chronic kidney disease (CKD). Methods: Principles for a process to develop information and cartoons were developed. Cartoon topics were created using qualitative research methods to obtain lay views and experiences. The CKD guidebook was used to provide a detailed exemplar of the process. Focus group and trial participants were recruited from primary care CKD registers. The book was part of a trial intervention; selected participants evaluated the cartoons during in-depth interviews which incorporated think-aloud methods. Results: In general, the cartoons developed by this process depict patient experiences, common situations, daily management dilemmas, making decisions and choices and the uncertainties associated with conditions. CKD cartoons were developed following two focus groups around the themes of getting a diagnosis; understanding the problem; feeling that facts were being withheld; and setting priorities. Think-aloud interviews with 27 trial participants found the CKD cartoons invoked amusement, recognition and reflection but were sometimes difficult to interpret. Conclusion: Humour is frequently utilised by people with long-term conditions to help adjustment and coping. Cartoons can help provide clarity and understanding and could address concerns related to health literacy. Using cartoons to engage and motivate people is a consideration untapped by conventional theories with the potential to improve information to support self-management

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Women's knowledge and attitudes regarding alcohol consumption in pregnancy: a national survey

Background. Alcohol exposure in pregnancy is a common and modifiable risk factor for poor pregnancy and child outcomes. Alcohol exposure in pregnancy can cause a range of physical and neurodevelopmental problems in the child including the Fetal Alcohol Spectrum Disorders (FASD). In order to improve prevention strategies, we sought to describe the knowledge and attitudes of women of childbearing age regarding alcohol consumption during pregnancy and its effects on the fetus.Methods. We conducted a national cross-sectional survey via computer assisted telephone interview of 1103 Australian women aged 18 to 45 years. Participants were randomly selected from the Electronic White Pages. Pregnant women were not eligible to participate. Quotas were set for age groups and a minimum of 100 participants per state to ensure a national sample reflecting the population. The questionnaire was based on a Health Canada survey with additional questions constructed by the investigators. Descriptive statistics were calculated and logistic regression analyses were used to assess associations with participants' knowledge and attitudes.Results. Of women surveyed, 61.5% had heard about effects of alcohol on the fetus and 55.3% had heard of Fetal Alcohol Syndrome. Although 92.7% agreed alcohol can affect the unborn child, 16.2% did not agree that the disabilities could be lifelong. Most women agreed that pregnant women should not drink alcohol (80.2%) and 79.2% reported having negative feelings towards pregnant women drinking alcohol. Women with higher education levels were more likely to know the effects of alcohol consumption in pregnancy (adjusted OR 5.62; 95% CI 3.20 to 9.87) but education level and knowledge were not associated with attitude.Conclusions. There was a disjunction between knowledge and attitudes towards alcohol consumption in pregnancy. These findings will assist in developing effective health promotion campaigns to reduce fetal alcohol exposure and subsequent fetal damage

Dbx1-Expressing Cells Are Necessary for the Survival of the Mammalian Anterior Neural and Craniofacial Structures

Development of the vertebrate forebrain and craniofacial structures are intimately linked processes, the coordinated growth of these tissues being required to ensure normal head formation. In this study, we identify five small subsets of progenitors expressing the transcription factor dbx1 in the cephalic region of developing mouse embryos at E8.5. Using genetic tracing we show that dbx1-expressing cells and their progeny have a modest contribution to the forebrain and face tissues. However, their genetic ablation triggers extensive and non cell-autonomous apoptosis as well as a decrease in proliferation in surrounding tissues, resulting in the progressive loss of most of the forebrain and frontonasal structures. Targeted ablation of the different subsets reveals that the very first dbx1-expressing progenitors are critically required for the survival of anterior neural tissues, the production and/or migration of cephalic neural crest cells and, ultimately, forebrain formation. In addition, we find that the other subsets, generated at slightly later stages, each play a specific function during head development and that their coordinated activity is required for accurate craniofacial morphogenesis. Our results demonstrate that dbx1-expressing cells have a unique function during head development, notably by controlling cell survival in a non cell-autonomous manner

Immunogenicity and safety of concomitant administration of a measles, mumps and rubella vaccine (M-M-RvaxPro®) and a varicella vaccine (VARIVAX®) by intramuscular or subcutaneous routes at separate injection sites: a randomised clinical trial

<p>Abstract</p> <p>Background</p> <p>When this trial was initiated, the combined measles, mumps and rubella (MMR) vaccine was licensed for subcutaneous administration in all European countries and for intramuscular administration in some countries, whereas varicella vaccine was licensed only for subcutaneous administration. This study evaluated the intramuscular administration of an MMR vaccine (M-M-RvaxPro^®) and a varicella vaccine (VARIVAX^®) compared with the subcutaneous route.</p> <p>Methods</p> <p>An open-label randomised trial was performed in France and Germany. Healthy children, aged 12 to18 months, received single injections of M-M-RvaxPro and VARIVAX concomitantly at separate injection sites. Both vaccines were administered either intramuscularly (IM group, <it>n </it>= 374) or subcutaneously (SC group, <it>n </it>= 378). Immunogenicity was assessed before vaccination and 42 days after vaccination. Injection-site erythema, swelling and pain were recorded from days 0 to 4 after vaccination. Body temperature was monitored daily between 0 and 42 days after vaccination. Other adverse events were recorded up to 42 days after vaccination and serious adverse events until the second study visit.</p> <p>Results</p> <p>Antibody response rates at day 42 in the per-protocol set of children initially seronegative to measles, mumps, rubella or varicella were similar between the IM and SC groups for all four antigens. Response rates were 94 to 96% for measles, 98% for both mumps and rubella and 86 to 88% for varicella. For children initially seronegative to varicella, 99% achieved the seroconversion threshold (antibody concentrations of ≥ 1.25 gpELISA units/ml). Erythema and swelling were the most frequently reported injection-site reactions for both vaccines. Most injection-site reactions were of mild intensity or small size (≤ 2.5 cm). There was a trend for lower rates of injection-site erythema and swelling in the IM group. The incidence and nature of systemic adverse events were comparable for the two routes of administration, except varicella-like rashes, which were less frequent in the IM group.</p> <p>Conclusion</p> <p>The immunogenicities of M-M-RvaxPro and VARIVAX administered by the intramuscular route were comparable with those following subcutaneous administration, and the tolerability of the two vaccines was comparable regardless of administration route. Integration of both administration routes in the current European indications for the two vaccines will now allow physicians in Europe to choose their preferred administration route in routine clinical practice.</p> <p>Trial registration</p> <p>ClinicalTrials.gov NCT00432523</p

Identification of a PA-Binding Peptide with Inhibitory Activity against Influenza A and B Virus Replication

There is an urgent need for new drugs against influenza type A and B viruses due to incomplete protection by vaccines and the emergence of resistance to current antivirals. The influenza virus polymerase complex, consisting of the PB1, PB2 and PA subunits, represents a promising target for the development of new drugs. We have previously demonstrated the feasibility of targeting the protein-protein interaction domain between the PB1 and PA subunits of the polymerase complex of influenza A virus using a small peptide derived from the PA-binding domain of PB1. However, this influenza A virus-derived peptide did not affect influenza B virus polymerase activity. Here we report that the PA-binding domain of the polymerase subunit PB1 of influenza A and B viruses is highly conserved and that mutual amino acid exchange shows that they cannot be functionally exchanged with each other. Based on phylogenetic analysis and a novel biochemical ELISA-based screening approach, we were able to identify an influenza A-derived peptide with a single influenza B-specific amino acid substitution which efficiently binds to PA of both virus types. This dual-binding peptide blocked the viral polymerase activity and growth of both virus types. Our findings provide proof of principle that protein-protein interaction inhibitors can be generated against influenza A and B viruses. Furthermore, this dual-binding peptide, combined with our novel screening method, is a promising platform to identify new antiviral lead compounds

Virology—the path forward

In the United States (US), biosafety and biosecurity oversight of research on viruses is being reappraised. Safety in virology research is paramount and oversight frameworks should be reviewed periodically. Changes should be made with care, however, to avoid impeding science that is essential for rapidly reducing and responding to pandemic threats as well as addressing more common challenges caused by infectious diseases. Decades of research uniquely positioned the US to be able to respond to the COVID-19 crisis with astounding speed, delivering life-saving vaccines within a year of identifying the virus. We should embolden and empower this strength, which is a vital part of protecting the health, economy, and security of US citizens. Herein, we offer our perspectives on priorities for revised rules governing virology research in the US