Transcriptomic response and immunological responses to chimpanzee adenovirus- and MVA viral-vectored vaccines for RSV in healthy adults.

Cohorts of healthy younger adults (18-50yrs) and healthy older adults (60-75yrs) were immunized intramuscularly or intranasally with an adenovirus-vectored RSV vaccine (PanAd3-RSV) as a prime dose and boosted with PanAd3-RSV or a poxvirus-vectored vaccine (MVA-RSV) encoding the same insert. Whole blood gene expression was measured at baseline, 3- and 7-days post vaccination. Intramuscular prime vaccination with PanAd3-RSV induced differential expression of 643 genes (DEGs, FDR < 0.05). Intranasal prime vaccination with PanAd3-RSV did not induce any differentially expressed genes (DEGs) in blood samples at 3 days post vaccination. Intranasally primed participants showed greater numbers of DEGS on boosting than intramuscularly primed participants. The most highly enriched biological processes related to DEGs after both prime and boost vaccination were type-1 interferon related pathways, lymphocytic and humoral immune responses.

Batch adsorption of herbicides from aqueous solution onto diverse reusable materials and granulated activated carbon.

This study reports the kinetics and isotherms of the adsorption of five herbicides, MCPA, mecoprop-P, 2,4-D, fluroxypyr and triclopyr, from aqueous solutions onto a range of raw and pyrolysed waste materials originating from an industrial setting. The raw waste materials investigated demonstrated little capability for any herbicide adsorption. Granulated activated carbon (GAC) was capable of the best removal of the herbicides, with >95% removal observed. A first order kinetic model fitted the data best for GAC adsorption of 2,4-D, while a pseudo-first order model fitted the data best for GAC adsorption of fluroxypyr and triclopyr, indicating that adsorption was via physisorption. A pseudo-second order kinetic model fitted the GAC adsorption of MCPA and mecoprop-P, which is indicative of chemisorption. The adsorption of the herbicides in all cases was best described by the Freundlich model, indicating that adsorption occurred onto heterogeneous surfaces.

Testing a theoretical model of imminent fracture risk in elderly women: an observational cohort analysis of the Canadian Multicentre Osteoporosis Study.

We examined the underlying relationship between fracture risk factors and their imminent risk. Results suggested that having past year fracture, worse past year general health, worse past year physical functioning, and lower past year BMD T-score directly predicted higher imminent fracture risk. Past year falls indirectly predicted imminent risk through physical functioning and general health. INTRODUCTION: This study aimed to examine direct and indirect effects of several factors on imminent (1 year) fracture risk. METHODS: Data from women age 65 and older from population-based Canadian Multicentre Osteoporosis Study were used. Predictors were identified from study years 5 and 10, and imminent fracture data (1-year fracture) came from years 6 and 11 (year 5 predicts year 6, year 10 predicts year 11). A structural equation model (SEM) was used to test the theoretical construct. General health and physical functioning were measured as latent variables using items from the 36-Item Short Form Health Survey (SF-36) and bone mineral density (BMD) T-score was a latent variable based on observed site-specific BMD data (spine L1-L4, femoral neck, total hip). Observed variables were fractures and falls. Model fit was evaluated using root mean square error of approximation (RMSEA), Tucker Lewis index (TLI), and comparative fit index (CFI). RESULTS: The analysis included 3298 women. Model fit tests showed that the SEM fit the data well; χ2(172) = 1122.10 < .001, RMSEA = .03, TLI = .99, CFI = .99. Results suggested that having past year fracture, worse past year general health, worse past year physical functioning, and lower past year BMD T-score directly predicted higher risk of fracture in the subsequent year (p < .001). Past year falls had a statistically significant but indirect effect on imminent fracture risk through physical functioning and general health (p < .001). CONCLUSIONS: We found several direct and indirect pathways that predicted imminent fracture risk in elderly women. Future studies should extend this work by developing risk scoring methods and defining imminent risk thresholds.

Netmums: a phase II randomized controlled trial of a guided Internet behavioural activation treatment for postpartum depression.

BACKGROUND: Despite the high prevalence of postnatal depression (PND), few women seek help. Internet interventions may overcome many of the barriers to PND treatment use. We report a phase II evaluation of a 12-session, modular, guided Internet behavioural activation (BA) treatment modified to address postnatal-specific concerns [Netmums Helping With Depression (NetmumsHWD)]. METHOD: To assess feasibility, we measured recruitment and attrition to the trial and examined telephone session support and treatment adherence. We investigated sociodemographic and psychological predictors of treatment adherence. Effectiveness outcomes were estimated with the Edinburgh Postnatal Depression Scale (EPDS), Generalized Anxiety Disorder-7, Work and Social Adjustment Scale, Postnatal Bonding Questionnaire, and Social Provisions Scale. RESULTS: A total of 249 women were recruited via a UK parenting site, Netmums.com. A total of 83 women meeting DSM-IV criteria for major depressive disorder were randomized to NetmumsHWD (n = 41) or treatment-as-usual (TAU; n = 42). Of the 83 women, 71 (86%) completed the EPDS at post-treatment, and 71% (59/83) at the 6-month follow-up. Women completed an average of eight out of 12 telephone support sessions and five out of 12 modules. Working women and those with less support completed fewer modules. There was a large effect size favouring women who received NetmumsHWD on depression, work and social impairment, and anxiety scores at post-treatment compared with women in the TAU group, and a large effect size on depression at 6 months post-treatment. There were small effect sizes for postnatal bonding and perceived social support. CONCLUSIONS: A supported, modular, Internet BA programme can be feasibly delivered to postpartum women, offering promise to improve depression, anxiety and functioning.

Stochastic modelling of pesticide transport to drinking water sources via runoff and resulting human health risk assessment.

A modelling framework was developed to facilitate a probabilistic assessment of health risks posed by pesticide exposure via drinking water due to runoff, with the inclusion of influential site conditions and in-stream processes. A Monte-Carlo based approach was utilised to account for the inherent variability in pesticide and population properties, as well as site and climatic conditions. The framework presented in this study was developed with an ability to integrate different data sources and adapt the model for various scenarios and locations to meet the users' needs. The results from this model can be used by farm advisors and catchment managers to identify lower risk pesticides for use for given soil and site conditions and implement risk mitigation measures to protect water resources. Pesticide concentrations in surface water, and their risk of regulatory threshold exceedances, were simulated for fifteen pesticides in an Irish case study. The predicted concentrations in surface water were then used to quantify the level of health risk posed to Irish adults and children. The analysis indicated that herbicides triclopyr and MCPA occur in the greatest concentrations in surface water, while mecoprop was associated with the highest potential for health risks. The study found that the modelled pesticides posed little risk to human health under current application patterns and climatic conditions in Ireland using international acceptable intake values. A sensitivity study conducted examined the impact seasonal conditions, timing of application, and instream processes, have on the transport of pesticides to drinking water.

Impact of historical legacy pesticides on achieving legislative goals in Europe.

Pesticides are widely used in agriculture to optimise food production. However, the movement of pesticides into water bodies negatively impacts aquatic environments. The European Union (EU) aims to make food systems fair, healthy and environmentally friendly through its current Farm to Fork strategy. As part of this strategy, the EU plans to reduce the overall use and risk of chemical pesticides by 50 % by 2030. The attainment of this target may be compromised by the prevalence of legacy pesticides arising from historical applications to land, which can persist in the environment for several decades. The current EU Farm to Fork policy overlooks the potential challenges of legacy pesticides and requirements for their remediation. In this review, the current knowledge regarding pesticide use in Europe, as well as pathways of pesticide movement to waterways, are investigated. The issues of legacy pesticides, including exceedances, are examined, and existing and emerging methods of pesticide remediation, particularly of legacy pesticides, are discussed. The fact that some legacy pesticides can be detected in water samples, more than twenty-five years after they were prohibited, highlights the need for improved EU strategies and policies aimed at targeting legacy pesticides in order to meet future targets.

Rural living and health-related quality of life in Australians with Parkinson's disease.

INTRODUCTION: The motor and non-motor symptoms associated with idiopathic Parkinson's disease (PD) may compromise the health-related quality of life (HRQOL) of some individuals living with this debilitating condition. Although growing evidence suggests that PD may be more prevalent in rural communities, there is little information about the life quality of these individuals. This study examines whether HRQOL ratings vary in relation to rural and metropolitan life settings. METHODS: An analytic cross-sectional study was conducted to compare the HRQOL of two separate samples of people with PD living in metropolitan Melbourne and rural Victoria. The metropolitan sample consisted of 210 individuals who had participated in the baseline assessment for an existing clinical trial. The rural sample comprised 24 participants who attended community-based rehabilitation programs and support groups in rural Victoria. Health-related quality of life was quantified using the Parkinson's Disease Questionnaire-39 (PDQ-39). RESULTS: The HRQOL of participants in rural Australia differed from individuals living in a large metropolitan city (p=0.025). Participants in rural Australia reported worse overall HRQOL, after controlling for differences in disease duration. Their overall HRQOL was lower than for city dwellers. Rural living was also found to be a significant negative predictor of HRQOL (ß=0.14; 95% CI -1.27 to -0.08; p=0.027). CONCLUSION: The findings of this study suggest that some people with PD living in rural Victoria perceive their HRQOL to be relatively poor. In order to minimise the debilitating consequences of this disease, further studies examining the factors that may contribute to the HRQOL of individuals living in rural and remote areas are required.

A risk ranking of pesticides in Irish drinking water considering chronic health effects.

This paper presents a novel scoring system which facilitates a relative ranking of pesticide risk to human health arising from contaminated drinking water. This method was developed to identify risky pesticides to better inform monitoring programmes and risk assessments. Potential risk was assessed considering pesticide use, chronic human health effects and environmental fate. Site-specific soil conditions, such as soil erodibility, hydrologic group, soil depth, clay, sand, silt, and organic carbon content of soil, were incorporated to demonstrate how pesticide fate can be influenced by the areas in which they are used. The indices of quantity of use, consequence and likelihood of exposure, hazard score and quantity-weighted hazard score were used to describe the level of concern that should be attributed to a pesticide. Metabolite toxicity and persistence were also considered in a separate scoring to highlight the contribution metabolites make to overall pesticide risk. This study presents two sets of results for 63 pesticides in an Irish case study, (1) risk scores calculated for the parent compounds only and (2) a combined pesticide-metabolite risk score. In both cases the results are assessed for two locations with differing soil and hydrological properties. The method developed in this paper can be adapted by pesticide users to assess and compare pesticide risk at site level using pesticide hazard scores. Farm advisors, water quality monitors, and catchment managers can apply this method to screen pesticides for human health risk at a regional or national level.

Reliability and validity of the FSHD-composite outcome measure in childhood facioscapulohumeral dystrophy.

This study aims to investigate intra-rater reliability and construct validity of the Facioscapulohumeral Dystrophy Composite Outcome Measure (FSHD-COM), in childhood FSHD. Participants included eighteen children with FSHD, and matched healthy controls. Reliability data were collected from 15 participants with FSHD over two testing sessions. Validity data were collected from all participants. Participants with FSHD completed; the FSHD-COM (and modified pediatric version), Motor Function Measure-32 (MFM-32), FSHD Severity Scales, Performance of the Upper Limb 2.0, Pediatric Quality of Life™ Neuromuscular Module and pediatric FSHD Health-Index Questionnaire. Both versions of the FSHD-COM showed excellent intra-rater reliability (ICC1,2 > 0.99, lower 95%CI > 0.98) with a Minimal Detectable Change (MDC95%) of ≤14.5%. The FSHD-COM had robust and widespread correlations with other related outcome measures. The FSHD-COM versions and 6 min walk test effectively discriminated between children with and without FSHD; the MFM-32 and 10 m walk/run test did not. Ceiling effects were not observed on either version of the FSHD-COM. Reliability and validity findings in this childhood FSHD study concord with estimates in adults. Both versions of the FSHD-COM were effective in discriminating disease in children with mild FSHD symptoms. The FSHD-COM has the potential to be a useful measure of function across the life span.

Steroid 5alpha-reductase deficiency in man: an inherited form of male pseudohermaphroditism.

In male pseudohermaphrodites born with ambiguity of the external genitalia but with marked virilization at puberty, biochemical evaluation reveals a marked decrease in plasma dihydrotestosterone secondary to a decrease in steroid 5alpha-reductase activity. In utero the decrease in dihydrotestosterone results in incomplete masculinization of the external genitalia. Inheritance is autosomal recessive.

Measurement properties and utility of performance-based outcome measures of physical functioning in individuals with facioscapulohumeral dystrophy - A systematic review and evidence synthesis.

Access to reliable, valid, accurate and responsive outcome measures is essential to ensure standards of care and clinical trial readiness in facioscapulohumeral dystrophy. Review aims: 1. identify and provide a descriptive summary of all outcome measures used to measure physical function. 2. systematically appraise the evidence on measurement properties (reliability, construct validity, measurement error and responsiveness) of performance-based outcome measures of physical function in individuals diagnosed with facioscapulohumeral dystrophy. Selected electronic health-related databases were searched from inception - Feb 2019. Two authors independently screened studies for eligibility and extracted data for psychometric evidence. The methodological quality of outcome measure studies was appraised using the consensus-based standards for the selection of health measurement instruments (COSMIN) checklist. Of 12 identified outcome measures, four required high-technology equipment. Only three were FSHD specific. The FSH-clinical score had 'moderate' quality positive evidence for reliability. The remaining measures had 'low' to 'very low' quality evidence supporting properties of reliability, validity, responsiveness and measurement error. Identified studies tended towards low recruitment in middle-aged, ambulant individuals making results hard to generalise across lifespan and levels of severity. There is a paucity of measurement evidence supporting the use of outcome measures in people with facioscapulohumeral dystrophy.

Genetic and pharmacological evidence for more than one human steroid 5 alpha-reductase.

The enzyme steroid 5 alpha-reductase catalyzes the conversion of testosterone into the more potent androgen, dihydrotestosterone, and impairment of this reaction causes a form of male pseudohermaphroditism in which genetic males differentiate predominantly as phenotypic females. We previously isolated cDNA clones that encode a human steroid 5 alpha-reductase enzyme. Here, we report molecular and genetic studies demonstrating that the gene encoding this cDNA is normal in subjects with the genetic disease steroid 5 alpha-reductase deficiency. We further show that in contrast to the major steroid 5 alpha-reductase in the prostate and cultured skin fibroblasts, the cDNA-encoded enzyme exhibits a neutral to basic pH optima and is much less sensitive to inhibition by the 4-aza steroid, finasteride (MK-906). The results provide genetic, biochemical, and pharmacological support for the existence of at least two steroid 5 alpha-reductase isozymes in man.

Molecular genetics of steroid 5 alpha-reductase 2 deficiency.

Two isozymes of steroid 5 alpha-reductase encoded by separate loci catalyze the conversion of testosterone to dihydrotestosterone. Inherited defects in the type 2 isozyme lead to male pseudohermaphroditism in which affected males have a normal internal urogenital tract but external genitalia resembling those of a female. The 5 alpha-reductase type 2 gene (gene symbol SRD5A2) was cloned and shown to contain five exons and four introns. The gene was localized to chromosome 2 band p23 by somatic cell hybrid mapping and chromosomal in situ hybridization. Molecular analysis of the SRD5A2 gene resulted in the identification of 18 mutations in 11 homozygotes, 6 compound heterozygotes, and 4 inferred compound heterozygotes from 23 families with 5 alpha-reductase deficiency. 6 apparent recurrent mutations were detected in 19 different ethnic backgrounds. In two patients, the catalytic efficiency of the mutant enzymes correlated with the severity of the disease. The high proportion of compound heterozygotes suggests that the carrier frequency of mutations in the 5 alpha-reductase type 2 gene may be higher than previously thought.

Gait characteristics, balance performance and falls in ambulant adults with cerebral palsy: An observational study.

The relationship between spatiotemporal gait parameters, balance performance and falls history was investigated in ambulant adults with cerebral palsy (CP). Participants completed a single assessment of gait using an instrumented walkway at preferred and fast speeds, balance testing (Balance Evaluation Systems Test; BESTest), and reported falls history. Seventeen ambulatory adults with CP, mean age 37 years, participated. Gait speed was typically slow at both preferred and fast speeds (mean 0.97 and 1.21m/s, respectively), with short stride length and high cadence relative to speed. There was a significant, large positive relationship between preferred gait speed and BESTest total score (ρ=0.573; p<0.05) and fast gait speed and BESTest total score (ρ=0.647, p<0.01). The stride lengths of fallers at both preferred and fast speeds differed significantly from non-fallers (p=0.032 and p=0.025, respectively), with those with a prior history of falls taking shorter strides. Faster gait speed was associated with better performance on tests of anticipatory and postural response components of the BESTest, suggesting potential therapeutic training targets to address either gait speed or balance performance. Future exploration of the implications of slow walking speed and reduced stride length on falls and community engagement, and the potential prognostic value of stride length on identifying falls risk is recommended.

Critique of the review of 'Water fluoridation for the prevention of dental caries' published by the Cochrane Collaboration in 2015.

The Cochrane Review on water fluoridation for the prevention of dental caries was published in 2015 and attracted considerable interest and comment, especially in countries with extensive water fluoridation programmes. The Review had two objectives: (i) to evaluate the effects of water fluoridation (artificial or natural) on the prevention of dental caries, and (ii) to evaluate the effects of water fluoridation (artificial or natural) on dental fluorosis. The authors concluded, inter alia, that there was very little contemporary evidence, meeting the Review's inclusion criteria, that evaluated the effectiveness of water fluoridation for the prevention of dental caries. The purpose of this critique is to examine the conduct of the above Review, and to put it into context in the wider body of evidence regarding the effectiveness of water fluoridation. While the overall conclusion that water fluoridation is effective in caries prevention agrees with previous reviews, many important public health questions could not be answered by the Review because of the restrictive criteria used to judge adequacy of study design and risk of bias. The potential benefits of using wider criteria in order to achieve a fuller understanding of the effectiveness of water fluoridation are discussed.

Complete androgen insensitivity Pathophysiology, diagnosis, and management.

The syndrome of complete androgen insensitivity is an X-linked inherited disorder resulting in marked inhibition of androgen action. The following case illustrates a subject with complete androgen insensitivity who, despite being a genetic and gonadal male, presents as a phenotypic female with primary amenorrhea, normal breast development, and lack of axillary and pubic hair. The diagnosis, pathophysiology, and management of the condition are discussed, as well as recently identified abnormalities in the androgen-receptor gene. The partial forms of androgen insensitivity are also included in the discussion.

Cyclotron production of Ac-225 for targeted alpha therapy.

The feasibility of producing Ac-225 by proton irradiation of Ra-226 in a cyclotron through the reaction Ra-226(p,2n)Ac-225 has been experimentally demonstrated for the first time. Proton energies were varied from 8.8 to 24.8 MeV and cross-sections were determined by radiochemical analysis of reaction yields. Maximum yields were reached at incident proton energies of 16.8 MeV. Radiochemical separation of Ac-225 from the irradiated target yielded a product suitable for targeted alpha therapy of cancer.

Nipple differentiation in fetal male rats treated with an inhibitor of the enzyme 5 alpha-reductase: definition of a selective role for dihydrotestosterone.

In the rat, androgens are responsible for sexually dimorphic nipple differentiation. Nipples are expressed in the female, while in the male, the nipple anlage regress prenatally. Mammary gland development is present in both sexes. Treatment of pregnant Sprague-Dawley rats from days 12-21 of gestation with the aza-steroid 17 beta-N,N-diisopropylcarbamoyl-4-aza-5 alpha-androstan-3-one, a competitive inhibitor of the enzyme 5 alpha-reductase, resulted in nipple development in male offspring. Additionally, there was feminization of the external genitalia, with urethral displacement to the base of the phallus. The role of androgens in suppression of nipple anlage in the male rat fetus is known. This study, however, suggests for the first time a selective role for 5 alpha-dihydrotestosterone in regression of the nipple anlage in utero. Thus, 5 alpha-dihydrotestosterone may be critical not only for masculinization of the external genitalia, but also for inhibition of nipple development in the male rat fetus.

The development of a male pseudohermaphroditic rat using an inhibitor of the enzyme 5 alpha-reductase.

Incomplete masculinization of the external genitalia occurred in male Sprague-Dawley rats treated with a potent inhibitor of enzyme 5 alpha-reductase at the critical period of sexual differentiation in utero. The studies were performed using the 5 alpha-reductase inhibitor, 4-methyl-4-aza-5-pregnan-3-one-20[s] carboxylate, one of a series of aza steroids known to competitively inhibit the enzyme 5 alpha-reductase. The degree of inhibition of male external genital development was dependent upon the dose of the inhibitor, and at a dose of 36 mg/kg X day, there was complete feminization of the external genitalia of the male animal with a urogenital sinus and a pseudovagina. These studies provide conclusive evidence for the hypothesis that 5 alpha-reductase activity and dihydrotestosterone (17 beta-hydroxy-5 alpha-androstan-3-one) formation are essential for normal differentiation of male external genitalia. Epididymidis, vasa deferentia, and seminal vesicles were present at all doses of the inhibitor, suggesting testosterone dependency. However, confirmation of the testosterone dependency of Wolffian ductal differentiation awaits further studies, particularly comparison studies with the rabbit and dog, since Wolffian ductal differentiation in the rat, unlike the rabbit and dog, is not abolished with the antiandrogen, cyproterone acetate. The presence of prostatic buds, despite complete external genital feminization, was unexpected and suggests that these structures may have different thresholds of response for dihydrotestosterone. Prostatic differentiation may have a much lower threshold, requiring less dihydrotestosterone for differentiation.