Understanding the role of patient and public involvement in renal dietetic research

The objective was to consult patients on a proposed recruitment strategy to a patient and public involvement exercise. We wanted to explore the reasoning and willingness of patients to become co-researchers within a grant application. Eighteen people using the renal health service informed the consultation by action research so that their experiences could be used to guide the overall methodology. Twelve people took part in semi-structured interviews. NVIVO 10 and Framework Analysis were used to interpret emerging themes from the data. The recruitment strategy, informed by research expertise, became an experience-based expert design. The design took into account the limitations of attendance, the informational and physical needs of these service users. Service users wanted to share their experiences with people who would listen and were in a position to help make the changes. This gave them a sense of purpose and autonomy in their treatment and helped them cope with living with renal disease in society. However, feelings of doubt as to whether they could personally ‘make a difference’ as a co-researcher, were common. Consulting service users enabled the research team to recruit more people to interviews to explore motivation considering the unique personal and social needs of this service user group. Service users may need additional and continued support if they are to successfully take part in a clinical study research advisory group

Estimating the rate of intersubtype recombination in early HIV-1 group M strains

West Central Africa has been implicated as the epicenter of the HIV-1 epidemic, and almost all group M subtypes can be found there. Previous analysis of early HIV-1 group M sequences from Kinshasa in the Democratic Republic of Congo, formerly Zaire, revealed that isolates from a number of individuals fall in different positions in phylogenetic trees constructed from sequences from opposite ends of the genome as a result of recombination between viruses of different subtypes. Here, we use discrete ancestral trait mapping to develop a procedure for quantifying HIV-1 group M intersubtype recombination across phylogenies, using individuals' gag (p17) and env (gp41) subtypes. The method was applied to previously described HIV-1 group M sequences from samples obtained in Kinshasa early in the global radiation of HIV. Nine different p17 and gp41 intersubtype recombinant combinations were present in the data set. The mean number of excess ancestral subtype transitions (NEST) required to map individuals' p17 subtypes onto the gp14 phylogeny samples, compared to the number required to map them onto the p17 phylogenies, and vice versa, indicated that excess subtype transitions occurred at a rate of approximately 7 × 10(−3) to 8 × 10(−3) per lineage per year as a result of intersubtype recombination. Our results imply that intersubtype recombination may have occurred in approximately 20% of lineages evolving over a period of 30 years and confirm intersubtype recombination as a substantial force in generating HIV-1 group M diversity

Reassortment between Influenza B Lineages and the Emergence of a Coadapted PB1-PB2-HA Gene Complex

Influenza B viruses make a considerable contribution to morbidity attributed to seasonal influenza. Currently circulating influenza B isolates are known to belong to two antigenically distinct lineages referred to as B/Victoria and B/Yamagata. Frequent exchange of genomic segments of these two lineages has been noted in the past, but the observed patterns of reassortment have not been formalized in detail. We investigate interlineage reassortments by comparing phylogenetic trees across genomic segments. Our analyses indicate that of the eight segments of influenza B viruses only segments coding for polymerase basic 1 and 2 (PB1 and PB2) and hemagglutinin (HA) proteins have maintained separate Victoria and Yamagata lineages and that currently circulating strains possess PB1, PB2, and HA segments derived entirely from one or the other lineage; other segments have repeatedly reassorted between lineages thereby reducing genetic diversity. We argue that this difference between segments is due to selection against reassortant viruses with mixed-lineage PB1, PB2, and HA segments. Given sufficient time and continued recruitment to the reassortment-isolated PB1–PB2–HA gene complex, we expect influenza B viruses to eventually undergo sympatric speciation

Transmission dynamics of Avian Influenza A virus

Influenza A virus (AIV) has an extremely high rate of mutation. Frequent exchanges of gene segments between different AIV (reassortment) have been responsible for major pandemics in recent human history. The presence of a wild bird reservoir maintains the threat of incursion of AIV into domestic birds, humans and other animals. In this thesis, I addressed unanswered questions of how diverse AIV subtypes (classified according to antigenicity of the two surface proteins, haemagglutinin and neuraminidase) evolve and interact among different bird populations in different parts of the world, using Bayesian phylogenetic methods with large datasets of full genome sequences. Firstly, I explored the reassortment patterns of AIV internal segments among different subtypes by quantifying evolutionary parameters including reassortment rate, evolutionary rate and selective constraint in time-resolved Bayesian tree phylogenies. A major conclusion was that reassortment rate is negatively associated with selective constraint and that infection of wild rather than domestic birds was associated with a higher reassortment rate. Secondly, I described the spatial transmission pattern of AIV in China. Clustering of related viruses in particular geographic areas and economic zones was identified from the viral phylogeographic diffusion networks. The results indicated that Central China and the Pearl River Delta are two main sources of viral out flow; while the East Coast, especially the Yangtze River delta, is the major recipient area. Simultaneously, by applying a general linear model, the predictors that have the strongest impact on viral spatial diffusion were identified, including economic (agricultural) activity, climate, and ecology. Thirdly, I determined the genetic and phylogeographic origin of a recent H7N3 highly pathogenic avian influenza outbreak in Mexico. Location, subtype, avian host species and pathogenicity were modelled as discrete traits and jointly analysed using all eight viral gene segments. The results indicated that the outbreak AIV is a novel reassortant carried by wild waterfowl from different migration flyways in North America during the time period studied. Importantly, I concluded that Mexico, and Central America in general, might be a potential hotspot for AIV reassortment events, a possibility which to date has not attracted widespread attention. Overall, the work carried out in this thesis described the evolutionary dynamics of AIV from which important conclusions regarding its epidemiological impact in both Eurasia and North America can be drawn

Effect of dietary potassium restriction on serum potassium, disease progression, and mortality in chronic kidney disease : a systematic review and meta-analysis

Low-potassium diets are recommended to reduce serum potassium (Sk) and prevent complications of chronic kidney disease (CKD), but evidence underpinning this recommendation has not been systematically reviewed and synthesized. We conducted a systematic review comparing change in Sk, CKD progression, and mortality between those on a low-potassium versus unrestricted potassium diet. We searched Medline, AMED, PsycINFO, CINAHL, Cochrane Central Register of Controlled Trials, and Clinicaltrials.org from inception to 3 April 2018. We included randomized and observational studies that compared these outcomes in adults with CKD who ate a restricted versus unrestricted amount of dietary potassium. We pooled mean change in Sk and adjusted hazard ratios of disease progression and mortality using random-effects meta-analyses. We identified 5,563 articles, of which seven studies (3,489 participants) met our inclusion criteria. We found very low-quality evidence that restricted (1,295 mg/d) versus unrestricted (1,570 mg/d) dietary potassium lowered Sk by -0.22 mEq/L (95% confidence interval [CI]: -0.33, -0.10; I  = 0%). Lower (1,725 mg/d) versus higher (4,558 mg/d) dietary potassium was not significantly associated with disease progression (hazard ratio [HR]: 1.14; 95% CI: 0.77, 1.70; I  = 57%). Lower (1,670 mg/d), compared with higher (4,414 mg/d) dietary potassium intake was associated with a 40% reduction in mortality hazard (HR: 0.60; 95% CI: 0.40, 0.89; I  = 56%). Very-low-quality evidence supports consensus that dietary potassium restriction reduces Sk in normokalemia and is associated with a reduced risk of death in those with CKD. High-quality randomized controlled trials are needed. [Abstract copyright: Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Evolutionary interactions between haemagglutinin and neuraminidase in avian influenza

Background: Reassortment between the RNA segments encoding haemagglutinin (HA) and neuraminidase (NA), the major antigenic influenza proteins, produces viruses with novel HA and NA subtype combinations and has preceded the emergence of pandemic strains. It has been suggested that productive viral infection requires a balance in the level of functional activity of HA and NA, arising from their closely interacting roles in the viral life cycle, and that this functional balance could be mediated by genetic changes in the HA and NA. Here, we investigate how the selective pressure varies for H7 avian influenza HA on different NA subtype backgrounds. Results: By extending Bayesian stochastic mutational mapping methods to calculate the ratio of the rate of non-synonymous change to the rate of synonymous change (d N/d S), we found the average d N/d S across the avian influenza H7 HA1 region to be significantly greater on an N2 NA subtype background than on an N1, N3 or N7 background. Observed differences in evolutionary rates of H7 HA on different NA subtype backgrounds could not be attributed to underlying differences between avian host species or virus pathogenicity. Examination of d N/d S values for each subtype on a site-by-site basis indicated that the elevated d N/d S on the N2 NA background was a result of increased selection, rather than a relaxation of selective constraint. Conclusions: Our results are consistent with the hypothesis that reassortment exposes influenza HA to significant changes in selective pressure through genetic interactions with NA. Such epistatic effects might be explicitly accounted for in future models of influenza evolution

Transmission of non-B HIV subtypes in the UK is increasingly driven by large non-heterosexual clusters

BACKGROUND: The United Kingdom human immunodeficiency virus (HIV) epidemic was historically dominated by HIV subtype B transmission among men who have sex with men (MSM). Now 50% of diagnoses and prevalent infections are among heterosexual individuals and mainly involve non-B subtypes. Between 2002 and 2010, the prevalence of non-B diagnoses among MSM increased from 5.4% to 17%, and this study focused on the drivers of this change. METHODS: Growth between 2007 and 2009 in transmission clusters among 14 000 subtype A1, C, D, and G sequences from the United Kingdom HIV Drug Resistance Database was analysed by risk group. RESULTS: Of 1148 clusters containing at least 2 sequences in 2007, >75% were pairs and >90% were heterosexual. Most clusters (71.4%) did not grow during the study period. Growth was significantly lower for small clusters and higher for clusters of ≥7 sequences, with the highest growth observed for clusters comprising sequences from MSM and people who inject drugs (PWID). Risk group (P< .0001), cluster size (P< .0001), and subtype (P< .01) were predictive of growth in a generalized linear model. DISCUSSION: Despite the increase in non-B subtypes associated with heterosexual transmission, MSM and PWID are at risk for non-B infections. Crossover of subtype C from heterosexuals to MSM has led to the expansion of this subtype within the United Kingdom

Modelling the impact of co-circulating low pathogenic avian influenza viruses on epidemics of highly pathogenic avian influenza in poultry

It is well known that highly pathogenic avian influenza (HPAI) viruses emerge through mutation of precursor low pathogenic avian influenza (LPAI) viruses in domestic poultry populations. The potential for immunological cross-protection between these pathogenic variants is recognised but the epidemiological impact during co-circulation is not well understood. Here we use mathematical models to investigate whether altered flock infection parameters consequent to primary LPAI infections can impact on the spread of HPAI at the population level. First we used mechanistic models reflecting the co-circulatory dynamics of LPAI and HPAI within a single commercial poultry flock. We found that primary infections with LPAI led to HPAI prevalence being maximised under a scenario of high but partial cross-protection. We then tested the population impact in spatially-explicit simulations motivated by a major avian influenza A(H7N1) epidemic that afflicted the Italian poultry industry in 1999-2001. We found that partial cross-protection can lead to a prolongation of HPAI epidemic duration. Our findings have implications for the control of HPAI in poultry particularly for settings in which LPAI and HPAI frequently co-circulate