The unrooted set covering connected subgraph problem differentiating between HIV envelope sequences

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordThis paper presents a novel application of operations research techniques to the analysis of HIV Env gene sequences, aiming to identify key features that are possible vaccine targets. These targets are identified as being critical to the transmission of HIV by being present in early transmitted (founder) sequences and absent in later chronic sequences. Identifying the key features of Env involves two steps: first, calculating the covariance of amino acid combinations and positions to form a network of related and compensatory mutations; and second, developing an integer program to identify the smallest connected subgraph of the constructed covariance network that exhibits a set covering property. The integer program developed for this analysis, labelled the unrooted set covering connected subgraph problem (USCCSP), integrates a set covering problem and connectivity evaluation, the latter formulated as a network flow problem. The resulting integer program is very large and complex, requiring the use of Benders’ decomposition to develop an efficient solution approach. The results will demonstrate the necessity of applying acceleration techniques to the Benders’ decomposition solution approach and the effectiveness of these techniques and heuristic approaches for solving the USCCSP

Cluster randomised trials in the medical literature: two bibliometric surveys

Background: Several reviews of published cluster randomised trials have reported that about half did not take clustering into account in the analysis, which was thus incorrect and potentially misleading. In this paper I ask whether cluster randomised trials are increasing in both number and quality of reporting. Methods: Computer search for papers on cluster randomised trials since 1980, hand search of trial reports published in selected volumes of the British Medical Journal over 20 years. Results: There has been a large increase in the numbers of methodological papers and of trial reports using the term 'cluster random' in recent years, with about equal numbers of each type of paper. The British Medical Journal contained more such reports than any other journal. In this journal there was a corresponding increase over time in the number of trials where subjects were randomised in clusters. In 2003 all reports showed awareness of the need to allow for clustering in the analysis. In 1993 and before clustering was ignored in most such trials. Conclusion: Cluster trials are becoming more frequent and reporting is of higher quality. Perhaps statistician pressure works

Modelling Oscillator synchronisation during vertebrate axis segmentation

he somitogenesis clock regulates the periodicity with which somites form in the posterior pre-somitic mesoderm. Whilst cell heterogeneity results in noisy oscillation rates amongst constituent cells, synchrony within the population is maintained as oscillators are entrained via juxtracine signalling mechanisms. Here we consider a population of phase-coupled oscillators and investigate how biologically motivated perturbations to the entrained state can perturb synchrony within the population. We find that the ratio of mitosis length to clock period can influence levels of desynchronisation. Moreover, we observe that random cell movement, and hence change of local neighbourhoods, increases synchronisation

A systematic review of naturalistic interventions in refugee populations

Naturalistic interventions with refugee populations examine outcomes following mental health interventions in existing refugee service organisations. The current review aimed to examine outcomes of naturalistic interventions and quality of the naturalistic intervention literature in refugee populations with the view to highlight the strengths and limitations of naturalistic intervention studies. Database search was conducted using the search terms ‘refugee’, ‘asylum seeker’, ‘treatment’, ‘therapy’ and ‘intervention. No date limitations were applied, but searches were limited to articles written in English. Seven studies were identified that assessed the outcome of naturalistic interventions on adult refugees or asylum seekers in a country of resettlement using quantitative outcome measures. Results showed significant variation in the outcomes of naturalistic intervention studies, with a trend towards showing decreased symptomatology at post-intervention. However, conclusions are limited by methodological problems of the studies reviewed, particularly poor documentation of intervention methods and lack of control in the design of naturalistic intervention studies. Further examination of outcomes following naturalistic interventions is needed with studies which focus on increasing the rigour of the outcome assessment process

Differentiating founder and chronic HIV envelope sequences

This is the final version. Available from Public Library of Science via the DOI in this record.The sequence data are available in the Dryad Data Depository. Data package title: Data from: Differentiating founder and chronic HIV envelope sequences Provisional DOI: doi:10.5061/dryad.r19c2 Data files: HIV envelope sequences Seroconverter HIV subtype B envelope sequences.Significant progress has been made in characterizing broadly neutralizing antibodies against the HIV envelope glycoprotein Env, but an effective vaccine has proven elusive. Vaccine development would be facilitated if common features of early founder virus required for transmission could be identified. Here we employ a combination of bioinformatic and operations research methods to determine the most prevalent features that distinguish 78 subtype B and 55 subtype C founder Env sequences from an equal number of chronic sequences. There were a number of equivalent optimal networks (based on the fewest covarying amino acid (AA) pairs or a measure of maximal covariance) that separated founders from chronics: 13 pairs for subtype B and 75 for subtype C. Every subtype B optimal solution contained the founder pairs 178–346 Asn-Val, 232–236 Thr-Ser, 240–340 Lys-Lys, 279–315 Asp-Lys, 291–792 Ala-Ile, 322–347 Asp-Thr, 535–620 Leu-Asp, 742–837 Arg-Phe, and 750–836 Asp-Ile; the most common optimal pairs for subtype C were 644–781 Lys-Ala (74 of 75 networks), 133–287 Ala-Gln (73/75) and 307–337 Ile-Gln (73/75). No pair was present in all optimal subtype C solutions highlighting the difficulty in targeting transmission with a single vaccine strain. Relative to the size of its domain (0.35% of Env), the α4β7 binding site occurred most frequently among optimal pairs, especially for subtype C: 4.2% of optimal pairs (1.2% for subtype B). Early sequences from 5 subtype B pre-seroconverters each exhibited at least one clone containing an optimal feature 553–624 (Ser-Asn), 724–747 (Arg-Arg), or 46–293 (Arg-Glu).University of New South Wales (UNSW) Goldstar Gran

A qualitative study of patients’ feedback about Outpatient Parenteral Antimicrobial Therapy (OPAT) services in Northern England: implications for service improvement

Objective Outpatient parenteral antimicrobial therapy (OPAT) provides opportunities for improved cost savings, but in the UK, implementation is patchy and a variety of service models are in use. The slow uptake in the UK and Europe is due to a number of clinical, financial and logistical issues, including concern about patient safety. The measurement of patient experience data is commonly used to inform commissioning decisions, but these focus on functional aspects of services and fail to examine the relational aspects of care. This qualitative study examines patients’ experiences of OPAT. Design In-depth, semistructured interviews. Setting Purposive sample of OPAT patients recruited from four acute National Health Service (NHS) Trusts in Northern England. These NHS Trusts between them represented both well-established and recently set-up services running nurse at home, hospital outpatient and/or selfadministration models. Participants We undertook 28 semistructured interviews and one focus group (n=4). Results Despite good patient outcomes, experiences were coloured by patients' personal situation and material circumstances. Many found looking after themselves at home more difficult than they expected, while others continued to work despite their infection. Expensive car parking, late running services and the inconvenience of waiting in for the nurse to arrive frustrated patients, while efficient services, staffed by nurses with the specialist skills needed to manage intravenous treatment had the opposite effect. Many patients felt a local, general practitioner or community health centre based service would resolve many of the practical difficulties that made OPAT inconvenient. Patients could find OPAT anxiety provoking but this could be ameliorated by staff taking the time to reassure patients and provide tailored information. Conclusion Services configurations must accommodate the diversity of the local population. Poor communication can leave patients lacking the confidence needed to be a competent collaborator in their own care and affect their perceptions of the service

Mutational networks of escape from transmitted HIV-1 infection

This is the final version. Available on open access from the Public Library of Science via the DOI in this recordData availability: The sequence data are available in the Dryad Data Depository, DOI: doi:10.5061/dryad.r19c2 Data files: HIV envelope sequences Seroconverter HIV subtype B envelope sequences.Human immunodeficiency virus (HIV) is subject to immune selective pressure soon after it establishes infection at the founder stage. As an individual progresses from the founder to chronic stage of infection, immune pressure forces a history of mutations that are embedded in envelope sequences. Determining this pathway of coevolving mutations can assist in understanding what is different with the founder virus and the essential pathways it takes to maintain infection. We have combined operations research and bioinformatics methods to extract key networks of mutations that differentiate founder and chronic stages for 156 subtype B and 107 subtype C envelope (gp160) sequences. The chronic networks for both subtypes revealed strikingly different hub-and-spoke topologies compared to the less structured transmission networks. This suggests that the hub nodes are impacted by the immune response and the resulting loss of fitness is compensated by mutations at the spoke positions. The major hubs in the chronic C network occur at positions 12, 137 (within the N136 glycan), and 822, and at position 306 for subtype B. While both founder networks had a more heterogeneous connected network structure, interestingly founder B subnetworks around positions 640 and 837 preferentially contained CD4 and coreceptor binding domains. Finally, we observed a differential effect of glycosylation between founder and chronic subtype B where the latter had mutational pathways significantly driven by N-glycosylation. Our study provides insights into the mutational pathways HIV takes to evade the immune response, and presents features more likely to establish founder infection, valuable for effective vaccine design.Australian Research Council (ARC

The splice site variant rs11078928 may be associated with a genotype-dependent alteration in expression of GSDMB transcripts.

Published onlineJournal ArticleResearch Support, Non-U.S. Gov'tBACKGROUND: Many genetic variants have been associated with susceptibility to complex traits by genome wide association studies (GWAS), but for most, causal genes and mechanisms of action have yet to be elucidated. Using bioinformatics, we identified index and proxy variants associated with autoimmune disease susceptibility, with the potential to affect splicing of candidate genes. PCR and sequence analysis of whole blood RNA samples from population controls was then carried out for the 8 most promising variants to determine the effect of genetic variation on splicing of target genes. RESULTS: We identified 31 splice site SNPs with the potential to affect splicing, and prioritised 8 to determine the effect of genotype on candidate gene splicing. We identified that variants rs11078928 and rs2014886 were associated with altered splicing of the GSDMB and TSFM genes respectively. rs11078928, present in the asthma and autoimmune disease susceptibility locus on chromosome 17q12-21, was associated with the production of a novel Δ exon5-8 transcript of the GSDMB gene, and a separate decrease in the percentage of transcripts with inclusion of exon 6, whereas the multiple sclerosis susceptibility variant rs2014886, was associated with an alternative TFSM transcript encompassing a short cryptic exon within intron 2. CONCLUSIONS: Our findings demonstrate the utility of a bioinformatic approach in identification and prioritisation of genetic variants effecting splicing of their host genes, and suggest that rs11078928 and rs2014886 may affect the splicing of the GSDMB and TSFM genes respectively.Mendip Golf ClubNIHR Exeter Clinical Research Facilit