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1.  Sleep in ring chromosome 20 syndrome: a peculiar electroencephalographic pattern  
Functional Neurology  2013;28(1): 47 - 53 .
Ring chromosome 20 [r(20)] syndrome is a chromosomal disorder characterized by epilepsy and intellectual disability. Distinctive electroclinical features and wakefulness EEG patterns have been described. The EEG features of sleep have not yet been evaluated.
We studied the pattern of sleep in six patients aged 2–59 years who underwent at least one polysomnographic recording.
Their sleep pattern evolution is described as deterioration ranging from normal to destructured NREM/REM sleep. NREM sleep alterations were observed from childhood and were more evident in adulthood. EEG abnormalities detected during wakefulness persisted, with morphological changes, during sleep. During NREM sleep all the subjects presented high amplitude delta sequences with a sharply contoured or notched appearance, prevalent over frontal regions. The theta rhythm of wakefulness was seen to persist during REM sleep.
Ring chromosome 20 syndrome shows sleep alterations that seem to be age-related. A potential role of cortical and thalamocortical dysfunction is discussed.
PMCID: PMC3812720  PMID: 23731915
electroencephalography ;  epilepsy ;  ring chromosome 20 syndrome ;  sleep
2.  Influenza and RSV make a modest contribution to invasive pneumococcal disease incidence in the UK 
The Journal of Infection  2013;66(6):512-520.
The common seasonality of incidence of invasive pneumococcal disease (IPD) and viral respiratory infections has long been recognized, however, the extent to which this affects the association between the pathogens is unknown. We have analysed weekly surveillance data of IPD, influenza and respiratory syncytial virus (RSV), using ambient temperature and hours of sunshine as measures of seasonality.
Reported cases of influenza, IPD and RSV, were collected in England and Wales, from week 1 (January) 1996 to week 23 (June) 2009. The associations between IPD and respiratory viral infections were analysed using several statistical methods, including correlation coefficients and both additive and multiplicative regression models.
6–7.5% of cases of IPD are attributable to influenza and 3–4% attributable to RSV. Correlation coefficients reported considerably stronger associations between IPD and the viral infections compared to regression models.
A small but potentially important percentage of IPD may be attributable to influenza and RSV when adjusted for seasonality by temperature. Jointly these viral infections may lead to over 10% of IPD cases. Therefore, prevention of viral respiratory infections may offer some additional benefit in reducing invasive pneumococcal infections.
PMCID: PMC3650581  PMID: 23473714
Invasive pneumococcal disease; Influenza; Respiratory syncytial virus; Seasonality
3.  Transmission of Chlamydia trachomatis through sexual partnerships: a comparison between three individual-based models and empirical data 
Chlamydia trachomatis is the most common bacterial sexually transmitted infection (STI) in many developed countries. The highest prevalence rates are found among young adults who have frequent partner change rates. Three published individual-based models have incorporated a detailed description of age-specific sexual behaviour in order to quantify the transmission of C. trachomatis in the population and to assess the impact of screening interventions. Owing to varying assumptions about sexual partnership formation and dissolution and the great uncertainty about critical parameters, such models show conflicting results about the impact of preventive interventions. Here, we perform a detailed evaluation of these models by comparing the partnership formation and dissolution dynamics with data from Natsal 2000, a population-based probability sample survey of sexual attitudes and lifestyles in Britain. The data also allow us to describe the dispersion of C. trachomatis infections as a function of sexual behaviour, using the Gini coefficient. We suggest that the Gini coefficient is a useful measure for calibrating infectious disease models that include risk structure and highlight the need to estimate this measure for other STIs.
PMCID: PMC3223622  PMID: 21653569
Chlamydia trachomatis; sexual partnerships; individual-based model; Natsal 2000; Gini coefficient
4.  Safety and Immunogenicity of the MRKAd5 gag HIV Type 1 Vaccine in a Worldwide Phase 1 Study of Healthy Adults 
The safety and immunogenicity of the MRK adenovirus type 5 (Ad5) HIV-1 clade B gag vaccine was assessed in an international Phase I trial. Three-hundred and sixty healthy HIV-uninfected adults were enrolled on five continents. Subjects received placebo or 1 × 109 or 1 × 1010 viral particles (vp) per dose of the MRKAd5 HIV-1 gag vaccine at day 1, week 4, and week 26. Immunogenicity was evaluated using an IFN-γ ELISPOT gag 15-mer assay with positive responses defined as ≥55 SFC/106 PBMCs and ≥4-fold over mock control. The vaccine was well tolerated. The most common adverse events were injection site reactions, headache, pyrexia, diarrhea, fatigue, and myalgia. At week 30, geometric mean ELISPOT responses were 24, 114, and 226 SFC/106 PBMCs in the placebo, 1 × 109 vp/dose, and 1 × 1010 vp/dose groups, respectively. Overall, responses to 1 × 1010 vp were 85% and 68% in subjects with low (≤200) and high (>200) baseline Ad5 titers, respectively. The MRKAd5 HIV-1 gag vaccine was immunogenic in diverse geographic regions. Gag ELISPOT responses were greater in the 1 × 1010 vp/dose groups than in the 1 × 109 vp/dose groups. Data from this first international study indicate that adenovirus-vectored vaccines are well tolerated and may be immunogenic in subjects from regions with high prevalence of preexisting Ad5 immunity.
PMCID: PMC3422055  PMID: 20854108
5.  Impact of Silver-Containing Wound Dressings on Bacterial Biofilm Viability and Susceptibility to Antibiotics during Prolonged Treatment ▿  
Antimicrobial Agents and Chemotherapy  2010;54(12):5120-5131.
The long-term antimicrobial efficacy of silver dressings against bacterial biofilms was investigated in a 7-day treatment in vitro model where the protein-rich medium was refreshed daily in order to mimic the conditions found in a wound bed. The use of plate-to-plate transfer assays demonstrated measurable differences in the effectivenesses of several silver dressings on the viability of biofilm bacteria and their susceptibility to antibiotics. Whereas after the first day of treatment, all dressings used resulted in a significant reduction in the number of viable cells in the biofilms and disruption of the biofilm colonies, during prolonged treatment, the efficacy of dressings with hydrophilic base materials diminished with daily transfers, and bacterial populations recovered. For dressings with hydrophobic base materials, the level of efficacy correlated with the silver species loaded. Biofilm bacteria, which survived the initial silver treatment, were susceptible to tobramycin, ciprofloxacin, and trimethoprim-sulfamethoxazole, in contrast to untreated biofilms, which were highly tolerant to the same antibiotics. This acquired susceptibility was unaffected by the longevity of pretreatment with the silver dressings but depended on the dressing used. The antimicrobial efficacy of the dressings correlated with the type of the dressing base material and silver species loaded.
PMCID: PMC2981228  PMID: 20855737
6.  Health-related quality of life in adults with epilepsy: the effect of age, age at onset and duration of epilepsy in a multicentre Italian study 
BMC Neurology  2011;11:33.
The potential effect of age-related factors on health-related quality of life (HRQOL) of patients with epilepsy has rarely been analyzed in the literature.
We examined this association in a selected population of 815 adults with epilepsy recruited in the context of a multicentre study for the evaluation of Epi-QoL, one of the first Italian epilepsy-specific measures of HRQOL for adults with epilepsy. The Epi-QoL is a 46-item self-administered questionnaire focusing on six domains, which was successfully tested for reproducibility and validity. Ordinary least-squares regression models were used to assess the relationships between age-related factors (patient's age, age at seizure onset, and duration of epilepsy) and overall Epi-QoL score, controlling for the effect of potential confounders. We fitted simple regression models including each age-related factor alone to assess the independent role of each factor on the overall Epi-QoL score. We also fitted multiple regression models including pairs of age-related factors solely, as well as one or two age-related factors together with the same set of confounders.
Simple regression models showed that age and duration of epilepsy were significant negative predictors of the overall Epi-QoL score: the higher was each age-related factor, the lower was the overall Epi-QoL score; age at onset alone was a nonsignificant predictor of the overall Epi-QoL score. Multiple regression models including two age-related factors solely showed that duration of epilepsy was still a significant negative predictor of the overall Epi-QoL score in both pairwise models, whereas age was a significant negative predictor only in the model including age at onset. Age at onset emerged as a significant positive predictor of the overall Epi-QoL score only in the model including age: the higher was age at onset, the higher was the overall Epi-QoL score. Adjusted regression models including either one or two age-related factors and controlling for the selected confounding variables showed that the age-related factors had no significant effect on the overall Epi-QoL score anymore.
If no other known correlates of the overall Epi-QoL score are considered, age and duration of epilepsy can be expected to have a significant negative association with HRQOL in epilepsy (with the effect of duration being stronger and more consistent across models than the one of age), whereas age at onset is a positive predictor of the overall HRQOL of limited significance. However, demographic and clinical factors, such as seizure frequency in the preceding 12 months, may provide a better explanation of HRQOL in epilepsy.
PMCID: PMC3062600  PMID: 21392391
7.  The cost effectiveness of opportunistic chlamydia screening in England 
Sexually Transmitted Infections  2007;83(4):267-275.
The National Chlamydia Screening Programme (NCSP) is being implemented in England. This study aims to estimate the cost effectiveness of (a) the NCSP strategy (annual screening offer to men and women aged under 25 years) and (b) alternative screening strategies.
A stochastic, individual based, dynamic sexual network model was combined with a cost effectiveness model to estimate the complications and associated costs of chlamydial infection. The model was constructed and parameterised from the perspective of the National Health Service (NHS) (England), including the direct costs of infection, complications and screening. Unit costs were derived from standard data sources and published studies. The average and incremental cost effectiveness ratio (cost per major outcome averted or quality adjusted life year (QALY) gained) of chlamydia screening strategies targeting women and/or men of different age groups was estimated. Sensitivity analyses were done to explore model uncertainty.
All screening strategies modelled are likely to cost the NHS money and improve health. If pelvic inflammatory disease (PID) progression is less than 10% then screening at any level is unlikely to be cost effective. However, if PID progression is 10% or higher the NCSP strategy compared to no screening appears to be cost effective. The incremental cost effectiveness analysis suggests that screening men and women aged under 20 years is the most beneficial strategy that falls below accepted thresholds. There is a high degree of uncertainty in the findings.
Offering an annual screening test to men and women aged under 20 years may be the most cost effective strategy (that is, under accepted thresholds) if PID progression is 10% or higher.
PMCID: PMC2598679  PMID: 17475686
Chlamydia trachomatis ; screening; cost effectiveness; mathematical model; health economics
PMCID: PMC2598692
9.  Housing, income support and mental health: Points of disconnection 
There exists a disconnection between evolving policies in the policy arenas of mental health, housing, and income support in Canada. One of the complexities associated with analysing the intersection of these policies is that federal, provincial, and municipal level policies are involved. Canada is one of the few developed countries without a national mental health policy and because of the federal policy reforms of the 1970s, the provincial governments now oversee the process of deinstitutionalization from the hospital to the community level. During this same period the availability of affordable housing has decreased as responsibility for social housing has been transfered from the federal government to the provincial and/or municipal levels of government. Canada also stands alone in terms of being a developed nation without national housing policy instead what is considered "affordable" housing is partially dependant upon individuals' personal economic resources. As well, over the past decade rates of income supports have also been reduced. Psychiatric survivors have long been identified as being at risk for homelessness, with the disconnection existing between housing, income and mental health policies and the lack of a national policy in any of these policies areas further contributing to this risk.
PMCID: PMC2238740  PMID: 18072980
10.  Modelling bacterial speciation 
A central problem in understanding bacterial speciation is how clusters of closely related strains emerge and persist in the face of recombination. We use a neutral Fisher–Wright model in which genotypes, defined by the alleles at 140 house-keeping loci, change in each generation by mutation or recombination, and examine conditions in which an initially uniform population gives rise to resolved clusters. Where recombination occurs at equal frequency between all members of the population, we observe a transition between clonal structure and sexual structure as the rate of recombination increases. In the clonal situation, clearly resolved clusters are regularly formed, break up or go extinct. In the sexual situation, the formation of distinct clusters is prevented by the cohesive force of recombination. Where the rate of recombination is a declining log-linear function of the genetic distance between the donor and recipient strain, distinct clusters emerge even with high rates of recombination. These clusters arise in the absence of selection, and have many of the properties of species, with high recombination rates and thus sexual cohesion within clusters and low rates between clusters. Distance-scaled recombination can thus lead to a population splitting into distinct genotypic clusters, a process that mimics sympatric speciation. However, empirical estimates of the relationship between sequence divergence and recombination rate indicate that the decline in recombination is an insufficiently steep function of genetic distance to generate species in nature under neutral drift, and thus that other mechanisms should be invoked to explain speciation in the presence of recombination.
PMCID: PMC1764933  PMID: 17062418
Fisher–Wright model; simulation; species; recombination; multilocus genotypes; genetic cartography
11.  Assessing the reliability of eBURST using simulated populations with known ancestry 
BMC Microbiology  2007;7:30.
The program eBURST uses multilocus sequence typing data to divide bacterial populations into groups of closely related strains (clonal complexes), predicts the founding genotype of each group, and displays the patterns of recent evolutionary descent of all other strains in the group from the founder. The reliability of eBURST was evaluated using populations simulated with different levels of recombination in which the ancestry of all strains was known.
For strictly clonal simulations, where all allelic change is due to point mutation, the groups of related strains identified by eBURST were very similar to those expected from the true ancestry and most of the true ancestor-descendant relationships (90–98%) were identified by eBURST. Populations simulated with low or moderate levels of recombination showed similarly high performance but the reliability of eBURST declined with increasing recombination to mutation ratio. Populations simulated under a high recombination to mutation ratio were dominated by a single large straggly eBURST group, which resulted from the incorrect linking of unrelated groups of strains into the same eBURST group. The reliability of the ancestor-descendant links in eBURST diagrams was related to the proportion of strains in the largest eBURST group, which provides a useful guide to when eBURST is likely to be unreliable.
Examination of eBURST groups within populations of a range of bacterial species showed that most were within the range in which eBURST is reliable, and only a small number (e.g. Burkholderia pseudomallei and Enterococcus faecium) appeared to have such high rates of recombination that eBURST is likely to be unreliable. The study also demonstrates how three simple tests in eBURST v3 can be used to detect unreliable eBURST performance and recognise populations in which there appears to be a high rate of recombination relative to mutation.
PMCID: PMC1865383  PMID: 17430587
12.  Atypically diffuse functional connectivity between caudate nuclei and cerebral cortex in autism 
Autism is a neurodevelopmental disorder affecting sociocommunicative behavior, but also sensorimotor skill learning, oculomotor control, and executive functioning. Some of these impairments may be related to abnormalities of the caudate nuclei, which have been reported for autism.
Our sample was comprised of 8 high-functioning males with autism and 8 handedness, sex, and age-matched controls. Subjects underwent functional MRI scanning during performance on simple visuomotor coordination tasks. Functional connectivity MRI (fcMRI) effects were identified as interregional blood oxygenation level dependent (BOLD) signal cross-correlation, using the caudate nuclei as seed volumes.
In the control group, fcMRI effects were found in circuits with known participation of the caudate nuclei (associative, orbitofrontal, oculomotor, motor circuits). Although in the autism group fcMRI effects within these circuits were less pronounced or absent, autistic subjects showed diffusely increased connectivity mostly in pericentral regions, but also in brain areas outside expected anatomical circuits (such as visual cortex).
These atypical connectivity patterns may be linked to developmental brain growth disturbances recently reported in autism and suggest inefficiently organized functional connectivity between caudate nuclei and cerebral cortex, potentially accounting for stereotypic behaviors and executive impairments.
PMCID: PMC1635430  PMID: 17042953
13.  Developing a realistic sexual network model of chlamydia transmission in Britain 
A national chlamydia screening programme is currently being rolled out in the UK and other countries. However, much of the epidemiology remains poorly understood. In this paper we present a stochastic, individual based, dynamic sexual network model of chlamydia transmission and its parameterisation. Mathematical models provide a theoretical framework for understanding the key epidemiological features of chlamydia: sexual behaviour, health care seeking and transmission dynamics.
The model parameters were estimated either directly or by systematic fitting to a variety of appropriate data sources. The fitted model was representative of sexual behaviour, chlamydia epidemiology and health care use in England. We were able to recapture the observed age distribution of chlamydia prevalence.
Estimating parameters for models of sexual behaviour and transmission of chlamydia is complex. Most of the parameter values are highly correlated, highly variable and there is little empirical evidence to inform estimates. We used a novel approach to estimate the rate of active treatment seeking, by combining data sources, which improved the credibility of the model results. The model structure is flexible and is broadly applicable to other developed world settings and provides a practical tool for public health decision makers.
PMCID: PMC1388195  PMID: 16426453
15.  An early evaluation of clinical and economic costs and benefits of implementing point of care NAAT tests for Chlamydia trachomatis and Neisseria gonorrhoea in genitourinary medicine clinics in England 
Sexually Transmitted Infections  2013;90(2):104-111.
To estimate the costs and benefits of clinical pathways incorporating a point of care (POC) nucleic acid amplification test (NAAT) for chlamydia and gonorrhoea in genitourinary medicine (GUM) clinics compared with standard off-site laboratory testing.
We simulated 1.2 million GUM clinic attendees in England. A simulation in Microsoft Excel was developed to compare existing standard pathways of management for chlamydia and gonorrhoea with a POC NAAT. We conducted scenario analyses to evaluate the robustness of the model findings. The primary outcome was the incremental cost-effectiveness ratio. Secondary outcomes included the number of inappropriate treatments, complications and transmissions averted.
The baseline cost of using the point of POC NAAT was £103.9 million compared with £115.6 million for standard care. The POC NAAT was also associated with a small increase of 46 quality adjusted life years, making the new test both more effective and cheaper. Over 95 000 inappropriate treatments might be avoided by using a POC NAAT. Patients receive diagnosis and treatment on the same day as testing, which may also prevent 189 cases of pelvic inflammatory disease and 17 561 onward transmissions annually.
Replacing standard laboratory tests for chlamydia and gonorrhoea with a POC test could be cost saving and patients would benefit from more accurate diagnosis and less unnecessary treatment. Overtreatment currently accounts for about a tenth of the reported treatments for chlamydia and gonorrhoea and POC NAATs would effectively eliminate the need for presumptive treatment.
PMCID: PMC3932743  PMID: 24273127
Chlamydia Trachomatis; Diagnosis; Gonorrhoea; Cost-Effectiveness; Mathematical Model

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