Pseudorehearsal in value function approximation

Catastrophic forgetting is of special importance in reinforcement learning, as the data distribution is generally non-stationary over time. We study and compare several pseudorehearsal approaches for Q-learning with function approximation in a pole balancing task. We have found that pseudorehearsal seems to assist learning even in such very simple problems, given proper initialization of the rehearsal parameters

Under one roof? A population-based survey of patient use and preference for sexual health services

To compare patterns of population service use and preference in areas with and without one-stop shop services. A number of strategy documents have recommended adopting a more integrated approach to sexual health service provision. One proposed model of integration is one-stop shops, where services for contraception and sexually transmitted infections are provided under the same roof. Currently, the potential impact of one-stop shop services on patient service use and preference is unclear, particularly at a population level. Three different models of one-stop shop were studied: a dedicated young persons’ service, a specialist mainstream service, and an enhanced general practice. In each model, the one-stop shop site was matched to two control sites with traditional service provision. Random samples of male and female patients were selected from general practices close to either the one-stop shop or control sites. These patients received a postal survey asking about their use or preference for services for six sexual health needs. One-stop shop and control samples were compared using multivariate logistic regression. Of the 14 387 patients surveyed, 3101 (21.6%) responded. In the young persons’ model, few significant differences were found in service use or preference between those living in one-stop shop and control site areas. In the specialist services model, women in the one-stop shop area were significantly more likely to cite specialist services for emergency contraception and abortion advice, when compared to those served by non-integrated control services. In the general practice model, respondents in the one-stop shop area were significantly more likely to cite general practice for all six sexual health needs. Overall, general practice was the preferred service provider cited for all sexual health needs, except condoms and pregnancy tests. These findings are discussed in terms of their implications for the provision of integrated sexual health services. In addition, key methodological issues and future research possibilities are identified. © 2009, Cambridge University Press. All rights reserved

Methodological challenges in measuring vaccine effectiveness using population cohorts in low resource settings.

Post-licensure real world evaluation of vaccine implementation is important for establishing evidence of vaccine effectiveness (VE) and programme impact, including indirect effects. Large cohort studies offer an important epidemiological approach for evaluating VE, but have inherent methodological challenges. Since March 2012, we have conducted an open prospective cohort study in two sites in rural Malawi to evaluate the post-introduction effectiveness of 13-valent pneumococcal conjugate vaccine (PCV13) against all-cause post-neonatal infant mortality and monovalent rotavirus vaccine (RV1) against diarrhoea-related post-neonatal infant mortality. Our study sites cover a population of 500,000, with a baseline post-neonatal infant mortality of 25 per 1000 live births. We conducted a methodological review of cohort studies for vaccine effectiveness in a developing country setting, applied to our study context. Based on published literature, we outline key considerations when defining the denominator (study population), exposure (vaccination status) and outcome ascertainment (mortality and cause of death) of such studies. We assess various definitions in these three domains, in terms of their impact on power, effect size and potential biases and their direction, using our cohort study for illustration. Based on this iterative process, we discuss the pros and cons of our final per-protocol analysis plan. Since no single set of definitions or analytical approach accounts for all possible biases, we propose sensitivity analyses to interrogate our assumptions and methodological decisions. In the poorest regions of the world where routine vital birth and death surveillance are frequently unavailable and the burden of disease and death is greatest We conclude that provided the balance between definitions and their overall assumed impact on estimated VE are acknowledged, such large scale real-world cohort studies can provide crucial information to policymakers by providing robust and compelling evidence of total benefits of newly introduced vaccines on reducing child mortality

(Not) talking about fertility: the role of digital technologies and health services in helping plan pregnancy. A qualitative study

AimTo explore how women and their partners navigate (pre)conception healthcare and the role of Natural Cycles fertility awareness technology in this process.MethodsIn-depth interviews with 24 cisgender women aged 24–43 years who had used Natural Cycles’ ‘Plan a Pregnancy’ mode, and six partners of Natural Cycles users, all cisgender men aged 30–39 years. Participants were recruited via direct messaging in the Natural Cycles app, social media and, for partners, snowball sampling. Purposive sampling was conducted to ensure diversity among participants. Interviews were audio-recorded and transcribed verbatim. An iterative, inductive approach was adopted for thematic data analysis.ResultsNatural Cycles helped most users better understand their menstrual cycles and fertility. Fertility awareness and preconception counselling with healthcare providers were uncommon. Women felt discussions about planning pregnancy in healthcare settings were often fraught with difficulties. They described not wanting to be an extra burden to overworked staff, being concerned that their worries about trying for pregnancy would be dismissed, or feeling staff did not have expertise in fertility awareness. Some women had shared their Natural Cycles data with healthcare professionals to demonstrate their menstrual cycle data or time of conception. However, it was not always clear to those not accessing services when they should seek further advice, for example, those using the app for longer time periods who had not yet conceived.ConclusionsDigital technologies can provide information and support for those wanting to conceive. They should, however, complement care in statutory services, and be accompanied by greater investment in fertility awareness and preconception support.</jats:sec

Pan-GWAS of Streptococcus agalactiae Highlights Lineage-Specific Genes Associated with Virulence and Niche Adaptation

Streptococcus agalactiae (group B streptococcus; GBS) is a colonizer of the gastrointestinal and urogenital tracts, and an opportunistic pathogen of infants and adults. The worldwide population of GBS is characterized by clonal complexes (CCs) with different invasive potentials. CC17, for example, is a hypervirulent lineage commonly associated with neonatal sepsis and meningitis, while CC1 is less invasive in neonates and more commonly causes invasive disease in adults with comorbidities. The genetic basis of GBS virulence and the extent to which different CCs have adapted to different host environments remain uncertain. We have therefore applied a pan-genome-wide association study (GWAS) approach to 1,988 GBS strains isolated from different hosts and countries. Our analysis identified 279 CC-specific genes associated with virulence, disease, metabolism, and regulation of cellular mechanisms that may explain the differential virulence potential of particular CCs. In CC17 and CC23, for example, we have identified genes encoding pilus, quorum-sensing proteins, and proteins for the uptake of ions and micronutrients which are absent in less invasive lineages. Moreover, in CC17, carriage and disease strains were distinguished by the allelic variants of 21 of these CC-specific genes. Together our data highlight the lineage-specific basis of GBS niche adaptation and virulence.IMPORTANCE GBS is a leading cause of mortality in newborn babies in high- and low-income countries worldwide. Different strains of GBS are characterized by different degrees of virulence, where some are harmlessly carried by humans or animals and others are much more likely to cause disease.The genome sequences of almost 2,000 GBS samples isolated from both animals and humans in high- and low- income countries were analyzed using a pan-genome-wide association study approach. This allowed us to identify 279 genes which are associated with different lineages of GBS, characterized by a different virulence and preferred host. Additionally, we propose that the GBS now carried in humans may have first evolved in animals before expanding clonally once adapted to the human host.These findings are essential to help understand what is causing GBS disease and how the bacteria have evolved and are transmitted

Recombination in Streptococcus pneumoniae Lineages Increase with Carriage Duration and Size of the Polysaccharide Capsule.

Streptococcus pneumoniae causes a high burden of invasive pneumococcal disease (IPD) globally, especially in children from resource-poor settings. Like many bacteria, the pneumococcus can import DNA from other strains or even species by transformation and homologous recombination, which has allowed the pneumococcus to evade clinical interventions such as antibiotics and pneumococcal conjugate vaccines (PCVs). Pneumococci are enclosed in a complex polysaccharide capsule that determines the serotype; the capsule varies in size and is associated with properties including carriage prevalence and virulence. We determined and quantified the association between capsule and recombination events using genomic data from a diverse collection of serotypes sampled in Malawi. We determined both the amount of variation introduced by recombination relative to mutation (the relative rate) and how many individual recombination events occur per isolate (the frequency). Using univariate analyses, we found an association between both recombination measures and multiple factors associated with the capsule, including duration and prevalence of carriage. Because many capsular factors are correlated, we used multivariate analysis to correct for collinearity. Capsule size and carriage duration remained positively associated with recombination, although with a reduced P value, and this effect may be mediated through some unassayed additional property associated with larger capsules. This work describes an important impact of serotype on recombination that has been previously overlooked. While the details of how this effect is achieved remain to be determined, it may have important consequences for the serotype-specific response to vaccines and other interventions. IMPORTANCE: The capsule determines >90 different pneumococcal serotypes, which vary in capsule size, virulence, duration, and prevalence of carriage. Current serotype-specific vaccines elicit anticapsule antibodies. Pneumococcus can take up exogenous DNA by transformation and insert it into its chromosome by homologous recombination. This mechanism has disseminated drug resistance and generated vaccine escape variants. It is hence crucial to pneumococcal evolutionary response to interventions, but there has been no systematic study quantifying whether serotypes vary in recombination and whether this is associated with serotype-specific properties such as capsule size or carriage duration. Larger capsules could physically inhibit DNA uptake, or given the longer carriage duration for larger capsules, this may promote recombination. We find that recombination varies among capsules and is associated with capsule size, carriage duration, and carriage prevalence and negatively associated with invasiveness. The consequence of this work is that serotypes with different capsules may respond differently to selective pressures like vaccines

Rings in the Solar System: a short review

Rings are ubiquitous around giant planets in our Solar System. They evolve jointly with the nearby satellite system. They could form either during the giant planet formation process or much later, as a result of large scale dynamical instabilities either in the local satellite system, or at the planetary scale. We review here the main characteristics of rings in our solar system, and discuss their main evolution processes and possible origin. We also discuss the recent discovery of rings around small bodies.Comment: Accepted for the Handbook of Exoplanet

Emergence of Double- and Triple-Gene Reassortant G1P[8]Rotaviruses Possessing a DS-1-Like Backbone after RotavirusVaccine Introduction in Malawi

To combat the high burden of rotavirus gastroenteritis, multiple African countries have introduced rotavirus vaccines into their childhood immunisation programmes. Malawi incorporated a G1P[8] rotavirus vaccine (Rotarix™) into its immunisation schedule in 2012. Utilising a surveillance platform of hospitalised rotavirus gastroenteritis cases, we examined the phylodynamics of G1P[8] rotavirus strains that circulated in Malawi before (1998 - 2012) and after (2013 - 2014) vaccine introduction. Analysis of whole genomes obtained through next generation sequencing revealed that all randomly-selected pre-vaccine G1P[8] strains sequenced (n=32) possessed a Wa-like genetic constellation, whereas post-vaccine G1P[8] strains (n=18) had a DS-1-like constellation. Phylodynamic analyses indicated that post-vaccine G1P[8] strains emerged through reassortment events between human Wa- and DS-1-like rotaviruses that circulated in Malawi from the 1990's, hence classified as atypical DS-1-like reassortants. The time to the most recent common ancestor for G1P[8] strains was from 1981-1994; their evolutionary rates ranged from 9.7 x 10(-4)-4.1 x 10(-3) nucleotide/substitutions/site/year. Three distinct G1P[8] lineages chronologically replaced each other between 1998 and 2014. Genetic drift was the likely driver for lineage turnover in 2005, whereas replacement in 2013 was due to reassortment. Amino acid substitution within the outer glycoprotein VP7 of G1P[8] strains had no impact on the structural conformation of the antigenic regions, suggesting that it is unlikely that they would affect recognition by vaccine-induced neutralizing antibodies. While the emergence of DS-1-like G1P[8] rotavirus reassortants in Malawi was therefore likely due to natural genotype variation, vaccine effectiveness against such strains needs careful evaluation.ImportanceThe error-prone RNA-dependent RNA polymerase and the segmented RNA genome predispose rotaviruses to genetic mutation and genome reassortment, respectively. These evolutionary mechanisms generate novel strains and have the potential to lead to the emergence of vaccine-escape mutants. While multiple African countries have introduced rotavirus vaccine, there are few data describing the evolution of rotaviruses that circulated before and after vaccine introduction. We report the emergence of atypical DS-1-like G1P[8] strains during the post-vaccine era in Malawi. Three distinct G1P[8] lineages circulated chronologically from 1998-2014; mutation and reassortment drove lineage turnover in 2005 and 2013, respectively. Amino acid substitutions within the outer capsid VP7 glycoprotein did not affect the structural conformation of mapped antigenic sites, suggesting limited effect in recognition of G1 specific vaccine-derived antibodies. The genes that constitute the remaining genetic backbone may play important roles in immune evasion, and vaccine effectiveness against such atypical strains needs careful evaluation