The Phenotype-Fitness Map in Experimental Evolution of Phages

Evolutionary biologists commonly interpret adaptations of organisms by reference to a phenotype-fitness map, a model of how different states of a phenotype affect fitness. Notwithstanding the popularity of this approach, it remains difficult to directly test these mappings, both because the map often describes only a small subset of phenotypes contributing to total fitness and because direct measures of fitness are difficult to obtain and compare to the map. Both limitations can be overcome for bacterial viruses (phages) grown in the experimental condition of unlimited hosts. A complete accounting of fitness requires 3 easily measured phenotypes, and total fitness is also directly measurable for arbitrary genotypes. Yet despite the presumed transparency of this system, directly estimated fitnesses often differ from fitnesses calculated from the phenotype-fitness map. This study attempts to resolve these discrepancies, both by developing a more exact analytical phenotype-fitness map and by exploring the empirical foundations of direct fitness estimates. We derive an equation (the phenotype-fitness map) for exponential phage growth that allows an arbitrary distribution of lysis times and burst sizes. We also show that direct estimates of fitness are, in many cases, plausibly in error because the population has not attained stable age distribution and thus violates the model underlying the phenotype-fitness map. In conjunction with data provided here, the new understanding appears to resolve a discrepancy between the reported fitness of phage T7 and the substantially lower value calculated from its phenotype-fitness map

Clinical Application of Liver MR Imaging in Wilson's Disease

Objective: To determine whether there is a correlation between liver MR findings and the clinical manifestations and severity of liver dysfunction in patients with Wilson`s disease. Materials and Methods: Two radiologists retrospectively evaluated MR images of the liver in 50 patients with Wilson`s disease. The Institutional Review Board approved this retrospective study and informed consent was waived. MR images were evaluated with a focus on hepatic contour abnormalities and the presence of intrahepatic nodules. By using Fisher`s exact test, MR findings were compared with clinical presentations (neurological and non-neurological) and hepatic dysfunction, which was categorized by the Child-Pugh classification system (A, B and C). Follow-up MR images were available for 17 patients. Results: Contour abnormalities of the liver and intrahepatic nodules were observed in 31 patients (62%) and 25 patients (50%), respectively. Each MR finding showed a statistically significant difference (p < 0.05) among the three groups of Child-Pugh classifications (A, n = 36; B, n = 5; C, n = 9), except for splenomegaly (p = 0.243). The mean age of the patients with positive MR findings was higher than that of patients with negative MR findings. For patients with Child-Pugh class A (n = 36) with neurological presentation, intrahepatic nodules, surface nodularity, and gallbladder fossa widening were more common. Intrahepatic nodules were improved (n = 8, 47%), stationary (n = 5, 29%), or aggravated (n = 4, 24%) on follow-up MR images. Conclusion: MR imaging demonstrates the contour abnormalities and parenchymal nodules of the liver in more than half of the patients with Wilson`s disease, which correlates with the severity of hepatic dysfunction and clinical manifestations.Cope-Yokoyama S, 2010, WORLD J GASTROENTERO, V16, P1487, DOI 10.3748/wjg.v16.i12.1487Akhan O, 2009, EUR J RADIOL, V69, P147, DOI 10.1016/j.ejrad.2007.09.029Taly AB, 2007, MEDICINE, V86, P112, DOI 10.1097/MD.0b013e318045a00eMerle U, 2007, GUT, V56, P115, DOI 10.1136/gut.2005.087262Akpinar E, 2007, EUR J RADIOL, V61, P25, DOI 10.1016/j.ejrad.2006.11.006Kozic D, 2006, ACTA RADIOL, V47, P624, DOI 10.1080/02841850600702176Kim TJ, 2006, AM J NEURORADIOL, V27, P1373SEO JK, 2006, KOREAN J HEPATOL, V12, P333Panagiotakaki E, 2004, AM J MED GENET A, V131A, P168, DOI 10.1002/ajmg.a.30345Chu WCW, 2004, AM J ROENTGENOL, V183, P1339ALA A, 2004, CLIN LIVER DIS, V8, P787Gitlin JD, 2003, GASTROENTEROLOGY, V125, P1868, DOI 10.1053/S0016-5085(03)01512-9Ferenci P, 2003, LIVER INT, V23, P139Akhan O, 2002, EUR RADIOL, V12, pS66, DOI 10.1007/s00330-002-1589-6Awaya H, 2002, RADIOLOGY, V224, P769, DOI 10.1148/radiol.2243011495Ito K, 1999, RADIOLOGY, V211, P723Ko SF, 1998, ABDOM IMAGING, V23, P56MERGO PJ, 1994, RADIOGRAPHICS, V14, P1291BULL PC, 1993, NAT GENET, V5, P327TANZI RE, 1993, NAT GENET, V5, P344DAVIES SE, 1989, HISTOPATHOLOGY, V15, P385CANCADO EL, 1987, ARQ NEURO-PSIQUIAT, V45, P131CHILD CG, 1964, LIVER PORTAL HYPERTE, P50

The Genetics of Adaptation for Eight Microvirid Bacteriophages

Theories of adaptive molecular evolution have recently experienced significant expansion, and their predictions and assumptions have begun to be subjected to rigorous empirical testing. However, these theories focus largely on predicting the first event in adaptive evolution, the fixation of a single beneficial mutation. To address long-term adaptation it is necessary to include new assumptions, but empirical data are needed for guidance. To empirically characterize the general properties of adaptive walks, eight recently isolated relatives of the single-stranded DNA (ssDNA) bacteriophage φX174 (family Microviridae) were adapted to identical selective conditions. Three of the eight genotypes were adapted in replicate, for a total of 11 adaptive walks. We measured fitness improvement and identified the genetic changes underlying the observed adaptation. Nearly all phages were evolvable; nine of the 11 lineages showed a significant increase in fitness. However, fitness plateaued quickly, and adaptation was achieved through only three substitutions on average. Parallel evolution was rampant, both across replicates of the same genotype as well as across different genotypes, yet adaptation of replicates never proceeded through the exact same set of mutations. Despite this, final fitnesses did not vary significantly among replicates. Final fitnesses did vary significantly across genotypes but not across phylogenetic groupings of genotypes. A positive correlation was found between the number of substitutions in an adaptive walk and the magnitude of fitness improvement, but no correlation was found between starting and ending fitness. These results provide an empirical framework for future adaptation theory

Exploring informed consent in HIV clinical trials: A case study in Uganda

Introduction: In settings with low literacy levels ensuring that participants are fully-informed before they consent to participate in clinical trials is a challenge. We explored the experiences and concerns of key actors in the informed consent process in two HIV clinical trials. Method: Semi-structured interviews were conducted with 46 respondents including trial participants, research study team and research ethics committee members about their experiences during the informed consent process. Three focus group discussions were conducted with 14 Community Advisory Board (CAB) members and 17 trial participants. Data were analysed to identify key themes. Findings: The consent process was highlighted as an important procedure by all the key actors however each group had a particular area of emphasis. Signing a consent form was given importance by research team and ethics committee members, because it provided documented evidence of a participant’s willingness to join a clinical trial. Participants did not welcome the presence of a witness for a non-literate participant because understanding study information was not closely related to an ability to read and write. Conclusion: This study’s findings indicated that obtaining a volunteer’s signature or thumbprint on a consent form did not necessarily mean that the participant was fully-informed about the information relevant to their taking part nor that they understood all the information shared with them. Informed consent requires sufficient time in the research process to have staff trained well enough before research begins. Ensuring and gaining informed consent should be understood and treated as a relation-centred, dynamic supportive process throughout the duration of a research study

Going home after infant cardiac surgery: a UK qualitative study

National Institute for Health Research Health Services and Delivery Research programme (Project No: 10/2002/29)

Phylodynamic Reconstruction Reveals Norovirus GII.4 Epidemic Expansions and their Molecular Determinants

Noroviruses are the most common cause of viral gastroenteritis. An increase in the number of globally reported norovirus outbreaks was seen the past decade, especially for outbreaks caused by successive genogroup II genotype 4 (GII.4) variants. Whether this observed increase was due to an upswing in the number of infections, or to a surveillance artifact caused by heightened awareness and concomitant improved reporting, remained unclear. Therefore, we set out to study the population structure and changes thereof of GII.4 strains detected through systematic outbreak surveillance since the early 1990s. We collected 1383 partial polymerase and 194 full capsid GII.4 sequences. A Bayesian MCMC coalescent analysis revealed an increase in the number of GII.4 infections during the last decade. The GII.4 strains included in our analyses evolved at a rate of 4.3–9.0×10−3 mutations per site per year, and share a most recent common ancestor in the early 1980s. Determinants of adaptation in the capsid protein were studied using different maximum likelihood approaches to identify sites subject to diversifying or directional selection and sites that co-evolved. While a number of the computationally determined adaptively evolving sites were on the surface of the capsid and possible subject to immune selection, we also detected sites that were subject to constrained or compensatory evolution due to secondary RNA structures, relevant in virus-replication. We highlight codons that may prove useful in identifying emerging novel variants, and, using these, indicate that the novel 2008 variant is more likely to cause a future epidemic than the 2007 variant. While norovirus infections are generally mild and self-limiting, more severe outcomes of infection frequently occur in elderly and immunocompromized people, and no treatment is available. The observed pattern of continually emerging novel variants of GII.4, causing elevated numbers of infections, is therefore a cause for concern

Detection of the pandemic norovirus variant GII.4 Sydney 2012 in Rio Branco, state of Acre, northern Brazil

Noroviruses (NoVs) are important cause of gastroenteritis in humans worldwide. Genotype GII.4 is responsible for the majority of outbreaks reported to date. This study describes, for the first time in Brazil, the circulation of NoV GII.4 variant Sydney 2012 in faecal samples collected from children aged less than or equal to eight years in Rio Branco, state of Acre, northern Brazil, during July-September 2012

Views on and experiences of electronic cigarettes: a qualitative study of women who are pregnant or have recently given birth.

Background Electronic cigarettes (ECs) are increasingly used for reducing or stopping smoking, with some studies showing positive outcomes. However, little is known about views on ECs during pregnancy or postpartum and previous studies have nearly all been conducted in the US and have methodological limitations, such as not distinguishing between smokers and ex/non-smokers. A greater understanding of this topic will help to inform both clinicians and EC interventions. We elicited views and experiences of ECs among UK pregnant or recently pregnant women. Methods We conducted semi-structured telephone interviews, using topic guides, with pregnant or recently pregnant women, who were current or recent ex-smokers. To ensure broad views of ECs were obtained, recruitment was from several geographical locations and via various avenues of recruitment. This included stop smoking services, antenatal and health visitor clinics, a pregnancy website and an informal network. Participants were 15 pregnant and 15 postpartum women, including nine current EC users, 11 ex-users, and 10 never-users. Five women who were interviewed in pregnancy were later interviewed in postpartum to explore if their views had changed. Audio data was transcribed verbatim and framework analysis was applied. Results Five main themes emerged: motivations for use (e.g., for stopping or reducing smoking), social stigma (e.g., avoiding use in public, preferring ‘discrete’ NRT), using the EC (e.g., mostly used at home); consumer aspects (e.g., limited advice available), and harm perceptions (e.g., viewed as less harmful than smoking; concerns about safety and addiction). Conclusions ECs were viewed positively by some pregnant and postpartum women and seen as less harmful than smoking and useful as aids for reducing and stopping smoking. However, due to perceived social stigma, some women feel uncomfortable using ECs in public, especially during pregnancy, and had concerns about safety and nicotine dependence. Health professionals and designers of EC interventions need to provide women with up-to-date and consistent information and advice about safety and dependence, as well as considering the influence of social stigma

Barriers and facilitators to smoking cessation in pregnancy and following childbirth: literature review and qualitative study

Background: Although many women stop smoking in pregnancy, others continue, causing harm to maternal and child health. Smoking behaviour is influenced by many factors, including the role of women’s significant others (SOs) and support from health-care professionals (HPs). Objectives: To enhance understanding of the barriers to, and facilitators of, smoking cessation and the feasibility and acceptability of interventions to reach and support pregnant women to stop smoking. Design: Four parts: (1) a description of interventions in the UK for smoking cessation in pregnancy; (2) three systematic reviews (syntheses) of qualitative research of women’s, SOs’ and HPs’ views of smoking in pregnancy using meta-ethnography (interpretative approach for combining findings); (3) semistructured interviews with pregnant women, SOs and HPs, guided by the social–ecological framework (conceptualises behaviour as an outcome of individuals’ interactions with environment); and (4) identification of new/improved interventions for future testing. Setting: Studies in reviews conducted in high-income countries. Qualitative research was conducted from October 2013 to December 2014 in two mixed urban/rural study sites: area A (Scotland) and area B (England). Participants: Thirty-eight studies (1100 pregnant women) in 42 papers, nine studies (150 partners) in 14 papers and eight studies described in nine papers (190 HPs) included in reviews. Forty-one interviews with pregnant women, 32 interviews with pregnant women’s SOs and 28 individual/group interviews with 48 HPs were conducted. Main outcome measures: The perceived barriers to, and facilitators of, smoking cessation in pregnancy and the identification of potential new/modified interventions. Results: Syntheses identified smoking-related perceptions and experiences for pregnant women and SOs that were fluid and context dependent with the capacity to help or hinder smoking cessation. Themes were analysed in accordance with the social–ecological framework levels. From the analysis of the interviews, the themes that were central to cessation in pregnancy at an individual level, and that reflected the findings from the reviews, were perception of risk to baby, self-efficacy, influence of close relationships and smoking as a way of coping with stress. Overall, pregnant smokers were faced with more barriers than facilitators. At an interpersonal level, partners’ emotional and practical support, willingness to change smoking behaviour and role of smoking within relationships were important. Across the review and interviews of HPs, education to enhance knowledge and confidence in delivering information about smoking in pregnancy and the centrality of the client relationship, protection of which could be a factor in downplaying risks, were important. HPs acknowledged that they could best assist by providing support and understanding, and access to effective interventions, including an opt-out referral pathway to Stop Smoking Services, routine carbon monoxide screening, behavioural support and access to pharmacotherapy. Additional themes at community, organisational and societal levels were also identified. Limitations: Limitations include a design grounded in qualitative studies, difficulties recruiting SOs, and local service configurations and recruitment processes that potentially skewed the sample. Conclusions: Perceptions and experiences of barriers to and facilitators of smoking cessation in pregnancy are fluid and context dependent. Effective interventions for smoking cessation in pregnancy should take account of the interplay between the individual, interpersonal and environmental aspects of women’s lives. Future work: Research focus: removing barriers to support, improving HPs’ capacity to offer accurate advice, and exploration of weight concerns and relapse prevention. Interventions focus: financial incentives, self-help and social network interventions