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1.  Update to the study protocol for a randomized controlled trial comparing mindfulness-based cognitive therapy with maintenance anti-depressant treatment depressive relapse/recurrence: the PREVENT trial 
Trials  2014;15:217.
Background
Depression is a common and distressing mental health problem that is responsible for significant individual disability and cost to society. Medication and psychological therapies are effective for treating depression and maintenance anti-depressants (m-ADM) can prevent relapse. However, individuals with depression often express a wish for psychological help that can help them recover from depression in the long-term. A recently developed treatment, mindfulness-based cognitive therapy (MBCT), shows potential as a brief group program for people with recurring depression.
This trial asks the policy research question; is MBCT with support to taper/discontinue antidepressant medication (MBCT-TS) superior to m-ADM in terms of: a primary outcome of preventing depressive relapse/recurrence over 24 months; and secondary outcomes of (a) depression free days, (b) residual depressive symptoms, (c) antidepressant medication (ADM) usage, (d) psychiatric and medical co-morbidity, (e) quality of life, and (f) cost effectiveness? An explanatory research question also asks whether an increase in mindfulness skills is the key mechanism of change.
The design is a single-blind, parallel randomized controlled trial examining MBCT-TS versus m-ADM with an embedded process study. To answer the main policy research question the proposed trial compares MBCT-TS with m-ADM for patients with recurrent depression. Four hundred and twenty patients with recurrent major depressive disorder in full or partial remission will be recruited through primary care.
Results
Depressive relapse/recurrence over two years is the primary outcome variable. Analyses will be conducted following CONSORT standards and overseen by the trial’s Data Monitoring and Safety Committee. Initial analyses will be conducted on an intention-to-treat basis, with subsequent analyses being per protocol. The explanatory question will be addressed in two mutually informative ways: quantitative measurement of potential mediating variables pre- and post-treatment and a qualitative study of service users’ views and experiences.
Conclusions
If the results of our exploratory trial are extended to this definitive trial, MBCT-TS will be established as an alternative approach to maintenance antidepressants for people with a history of recurrent depression. The process studies will provide evidence about the effective components which can be used to improve MBCT and inform theory as well as other therapeutic approaches.
Trial registration
Trial registered 7 May 2009; ISRCTN26666654.
doi:10.1186/1745-6215-15-217
PMCID: PMC4066271  PMID: 24916319
Mindfulness-based cognitive therapy; Randomised controlled trial; Depression; Antidepressant; Trial protocol
2.  Quantitative dynamics of hepatitis B basal core promoter and precore mutants before and after HBeAg seroconversion 
Journal of Hepatology  2011;56(4):795-802.
Background and Aims
Hepatitis B e antigen (HBeAg) seroconversion is an important clinical and virological “landmark” during the chronic hepatitis B virus (HBV) infection. Mutant viruses carrying the precore G1896A and/or the basal core promoter (BCP) A1762T/G1764A mutations are associated with HBeAg seroconversion. However, the exact role of these mutants in HBeAg seroconversion remains unclear, partly because the evolution of these mutant viruses before and after seroconversion has not been well studied.
Methods
Using our novel mutant quantification methods, the percentage of the mutant viruses was analyzed both cross-sectionally and longitudinally, before and after seroconversion.
Results
Cross-sectional analysis showed that the percentage of both precore and BCP mutants gradually increased with age in the HBeAg-positive population. Follow-up of 18 patients revealed that the mutant percentage may stay low and stable for many years prior to seroconversion, followed by a steady increase in the percentage of G1896A and/or A1762T/G1764A mutants, from <10% to 50–100%, within about three years of seroconversion. In all cases, increase of mutant percentage was preceded or accompanied by elevated serum alanine aminotransferase. After the seroconversion, the mutant percentage could remain high or decrease significantly, sometimes to below 20%.
Conclusions
Levels of G1896A and A1762T/G1764A mutants (of genotypes B and C) in the HBeAg-positive patients may predict the time of HBeAg seroconversion. The dominance of these mutants in the HBeAg-positive phase is more likely the result of immune selection rather than the enhanced replication capability of the mutants. However, anti-HBe antibody may not be a major selection force for these mutants.
doi:10.1016/j.jhep.2011.11.012
PMCID: PMC3307917  PMID: 22173170
HBV; G1896A; A1762T/G1764A; mutation; seroconversion; biomarker
3.  Fumonisin B1 and Risk of Hepatocellular Carcinoma in Two Chinese Cohorts 
Food and Chemical Toxicology  2011;50(3-4):679-683.
Fumonisin B1 (FB1), a mycotoxin that contaminates corn in certain climates, has been demonstrated to cause hepatocellular cancer (HCC) in animal models. Whether a relationship between FB1 and HCC exists in humans is not known. To examine the hypothesis, we conducted case-control studies nested within two large cohorts in China; the Haimen City Cohort and the General Population Study of the Nutritional Intervention Trials cohort in Linxian. In the Haimen City Cohort, nail FB1 levels were determined in 271 HCC cases and 280 controls. In the General Population Nutritional Intervention Trial, nail FB1 levels were determined in 72 HCC cases and 147 controls. In each population, odds ratios and 95% confidence intervals (95%CI) from logistic regression models estimated the association between measurable FB1 and HCC, adjusting for hepatitis B virus infection and other factors. A meta-analysis that included both populations was also conducted. The analysis revealed no statistically significant association between FB1 and HCC in either Haimen City (OR=1.10, 95%CI=0.64–1.89) or in Linxian (OR=1.47, 95%CI=0.70–3.07). Similarly, the pooled meta-analysis showed no statistically significant association between FB1 exposure and HCC (OR=1.22, 95%CI=0.79–1.89). These findings, although somewhat preliminary, do not support an associated between FB1 and HCC.
doi:10.1016/j.fct.2011.11.029
PMCID: PMC3299856  PMID: 22142693
fumonisin; hepatocellular carcinoma; cohort study; China; epidemiology
4.  Quantification of complex precore mutations of hepatitis B virus by SimpleProbe real time PCR and dual melting analysis 
Background
Hepatitis B virus (HBV) precore G1896A mutation is associated with Hepatitis B e antigen (HBeAg) seroconversion. This mutation and the adjacent G1899A mutation also appear to associate with increased risk of hepatocellular carcinoma. Quantitative mutant dynamics may help determine the potential of these mutants as clinical biomarkers. However, a reliable method to quantify either mutant is not available, partly because the viral genome has polymorphisms in general and the precore mutations are complex.
Objectives
(1) To develop a reliable and ultrasensitive assay for the quantification of HBV G1896A and/or G1899A mutants. (2) To obtain preliminary data on the quantities of the precore mutants in patients.
Study Design
A SimpleProbe real time PCR assay was developed to quantify the HBV precore mutants. Dual melting analysis and a primer-probe partial overlap approach were used to increase detection accuracy. A wild-type selective PCR blocker was also developed to increase mutant detection sensitivity.
Results
The assay correctly identified the precore sequence from all 62 patient samples analyzed. More than 97% of precore sequences in the GenBank can be recognized. Mutant detection sensitivity reached 0.001% using a wild type-selective PCR blocker. At least one precore mutant can be detected from all 20 HBeAg-positive individuals who were negative for precore mutations by DNA sequencing.
Conclusions
The reliability of this ultrasensitive mutation quantification assay was demonstrated. The same approaches may be useful for the detection of other clinically significant mutations. Evolution of the precore mutants warrants further studies.
doi:10.1016/j.jcv.2011.05.020
PMCID: PMC3133867  PMID: 21665530
mutation; HBV; precore; quantification; SimpleProbe; qPCR
5.  Ultrasensitive Quantification of Hepatitis B Virus A1762T/G1764A Mutant by a SimpleProbe PCR Using a Wild-Type-Selective PCR Blocker and a Primer-Blocker-Probe Partial-Overlap Approach ▿ 
Journal of Clinical Microbiology  2011;49(7):2440-2448.
Hepatitis B virus (HBV) carrying the A1762T/G1764A double mutation in the basal core promoter (BCP) region is associated with HBe antigen seroconversion and increased risk of liver cirrhosis and hepatocellular carcinoma (HCC). Quantification of the mutant viruses may help in predicting the risk of HCC. However, the viral genome tends to have nucleotide polymorphism, which makes it difficult to design hybridization-based assays including real-time PCR. Ultrasensitive quantification of the mutant viruses at the early developmental stage is even more challenging, as the mutant is masked by excessive amounts of the wild-type (WT) viruses. In this study, we developed a selective inhibitory PCR (siPCR) using a locked nucleic acid-based PCR blocker to selectively inhibit the amplification of the WT viral DNA but not the mutant DNA. At the end of siPCR, the proportion of the mutant could be increased by about 10,000-fold, making the mutant more readily detectable by downstream applications such as real-time PCR and DNA sequencing. We also describe a primer-probe partial overlap approach which significantly simplified the melting curve patterns and minimized the influence of viral genome polymorphism on assay accuracy. Analysis of 62 patient samples showed a complete match of the melting curve patterns with the sequencing results. More than 97% of HBV BCP sequences in the GenBank database can be correctly identified by the melting curve analysis. The combination of siPCR and the SimpleProbe real-time PCR enabled mutant quantification in the presence of a 100,000-fold excess of the WT DNA.
doi:10.1128/JCM.02472-10
PMCID: PMC3147845  PMID: 21562108
6.  Methylation of the CpG Sites Only on the Sense Strand of the APC Gene Is Specific for Hepatocellular Carcinoma 
PLoS ONE  2011;6(11):e26799.
Hypermethylation of the promoter of the tumor suppressor gene, adenomatous polyposis coli (APC), occurs in various malignancies, including hepatocellular carcinoma (HCC). However, reports on the specificity of the methylation of the APC gene for HCC have varied. To gain insight into how these variations occur, bisulfite PCR sequencing was performed to analyze the methylation status of both sense and antisense strands of the APC gene in samples of HCC tissue, matched adjacent non-HCC liver tissue, hepatitis, cirrhosis, and normal liver tissues. DNA derived from fetal liver and 12 nonhepatic normal tissue was also examined. These experiments revealed liver-specific, antisense strand-biased CpG methylation of the APC gene and suggested that, although methylation of the antisense strand of the APC gene exists in normal liver and other non-HCC disease liver tissue, methylation of the sense strand of the APC gene occurs predominantly in HCC. To determine the effect of the DNA strand on the specificity of the methylated APC gene as a biomarker for HCC detection, quantitative methylation-specific PCR assays for sense and antisense strand DNA were developed and performed on DNA isolated from HCC (n = 58), matched adjacent non-HCC (n = 58), cirrhosis (n = 41), and hepatitis (n = 39). Receiver operating characteristic curves were constructed. With the cutoff value set at the limit of detection, the specificity of sense and antisense strand methylation was 84% and 43%, respectively, and sensitivity was 67.2% and 72.4%, respectively. This result demonstrated that the identity of the methylated DNA strand impacted the specificity of APC for HCC detection. Interestingly, methylation of the sense strand of APC occurred in 40% of HCCs from patients with serum AFP levels less than 20 ng/mL, suggesting a potential role for APC as a biomarker to complement AFP in HCC screening.
doi:10.1371/journal.pone.0026799
PMCID: PMC3206845  PMID: 22073196
7.  Head injury, diagnostic x-rays, and risk of medulloblastoma and primitive neuroectodermal tumor (PNET): A Children’s Oncology Group study 
Cancer causes & control : CCC  2010;21(7):1017-1023.
Objective
A comprehensive case-control study was conducted to determine potential risk factors for medulloblastoma/primitive neuroectodermal tumor (PNET), a common brain tumor in children. This analysis evaluated possible associations between previous head injury and ionizing radiation exposure through diagnostic x-rays and medulloblastoma/PNET.
Methods
Mothers of 318 cases < 6 years of age at diagnosis between 1991 and 1997 and registered with the Children’s Oncology Group were interviewed. Mothers of 318 matching controls were selected through random digit dialing and interviewed.
Results
An association was not detected between previous head injury (OR: 0.78, 95% CI: 0.40–1.5) or head x-ray for any reason including head injury with medulloblastoma/PNET. A statistically non-significant excess of cases reported having an x-ray for reason other than head injury (OR 2.3, 95%CI 0.91–5.7). When cases that received an x-ray for a common symptom of medulloblastoma/PNET were considered unexposed this association weakened (OR: 1.3, 95% CI: 0.49–3.7). No dose-response relationship was observed.
Conclusions
Head injury and exposure to diagnostic head x-rays were not associated with medulloblastoma/PNET in this study. Future studies should investigate all imaging procedures with ionizing radiation exposure including computed tomography (CT) scans and utilize radiation dose estimations.
doi:10.1007/s10552-010-9529-2
PMCID: PMC3023159  PMID: 20217209
Brain neoplasms; Radiography; Craniocerebral trauma
8.  Central and East European migrant men who have sex with men in London: a comparison of recruitment methods 
Background
Following the expansion of the European Union, there has been a large influx of Central and East European (CEE) migrants to the UK. CEE men who have sex with men (MSM) represent a small minority within this population that are none-the-less important to capture in sexual health research among the CEE migrant community. This paper examines the feasibility of recruiting CEE MSM for a survey of sexual behaviour in London using respondent driven sampling (RDS), via gay websites and in GUM clinics.
Methods
We sought CEE MSM to start RDS chain referral among GUM clinic attendees, our personal contacts and at gay events and venues in central London. We recruited CEE MSM (n = 485) via two popular websites for gay men in Britain (March-May 2009) and at two central London GUM clinics (n = 51) (July 2008-March 2009).
Results
We found seventeen men who knew other CEE MSM in London and agreed to recruit contacts into the study. These men recruited only three men into the study, none of whom recruited any further respondents, and RDS was abandoned after 7 months (July 2008-January 2009). Half of the men that we approached to participate in RDS did not know any other CEE MSM in London. Men who agreed to recruit contacts for RDS were rather more likely to have been in the UK for more than one year (94.1% vs 70.0%, p = 0.052). Men recruited through gay websites and from GUM clinics were similar.
Conclusions
The Internet was the most successful method for collecting data on sexual risk behaviour among CEE MSM in London. CEE MSM in London were not well networked. RDS may also have failed because they did not fully understand the procedure and/or the financial incentive was not sufficient motivation to take part.
doi:10.1186/1471-2288-11-69
PMCID: PMC3112197  PMID: 21586121
9.  Mechanistic insights into arrhythmogenic right ventricular cardiomyopathy caused by desmocollin-2 mutations 
Cardiovascular Research  2010;90(1):77-87.
Aims
Recent immunohistochemical studies observed the loss of plakoglobin (PG) from the intercalated disc (ID) as a hallmark of arrhythmogenic right ventricular cardiomyopathy (ARVC), suggesting a final common pathway for this disease. However, the underlying molecular processes are poorly understood.
Methods and results
We have identified novel mutations in the desmosomal cadherin desmocollin 2 (DSC2 R203C, L229X, T275M, and G371fsX378). The two missense mutations (DSC2 R203C and T275M) have been functionally characterized, together with a previously reported frameshift variant (DSC2 A897fsX900), to examine their pathogenic potential towards PG's functions at the ID. The three mutant proteins were transiently expressed in various cellular systems and assayed for expression, processing, localization, and binding to other desmosomal components in comparison to wild-type DSC2a protein. The two missense mutations showed defects in proteolytic cleavage, a process which is required for the functional activation of mature cadherins. In both cases, this is thought to cause a reduction of functional DSC2 at the desmosomes in cardiac cells. In contrast, the frameshift variant was incorporated into cardiac desmosomes; however, it showed reduced binding to PG.
Conclusion
Despite different modes of action, for all three variants, the reduced ability to provide a ligand for PG at the desmosomes was observed. This is in agreement with the reduced intensity of PG at these structures observed in ARVC patients.
doi:10.1093/cvr/cvq353
PMCID: PMC3058729  PMID: 21062920
Arrhythmogenic right ventricular cardiomyopathy; Desmocollin-2; Desmosome; Functional studies; Mutation
10.  Study protocol for a randomized controlled trial comparing mindfulness-based cognitive therapy with maintenance anti-depressant treatment in the prevention of depressive relapse/recurrence: the PREVENT trial 
Trials  2010;11:99.
Background
Depression is a common and distressing mental health problem that is responsible for significant individual disability and cost to society. Medication and psychological therapies are effective for treating depression and maintenance anti-depressants (m-ADM) can prevent relapse. However, individuals with depression often express a wish for psychological help that can help them recover from depression in the long-term. We need to develop psychological therapies that prevent depressive relapse/recurrence. A recently developed treatment, Mindfulness-based Cognitive Therapy (MBCT, see http://www.mbct.co.uk) shows potential as a brief group programme for people with recurring depression. In two studies it has been shown to halve the rates of depression recurring compared to usual care.
This trial asks the policy research question, is MBCT superior to m-ADM in terms of: a primary outcome of preventing depressive relapse/recurrence over 24 months; and, secondary outcomes of (a) depression free days, (b) residual depressive symptoms, (c) antidepressant (ADM) usage, (d) psychiatric and medical co-morbidity, (e) quality of life, and (f) cost effectiveness? An explanatory research question asks is an increase in mindfulness skills the key mechanism of change?
Methods/Design
The design is a single blind, parallel RCT examining MBCT vs. m-ADM with an embedded process study. To answer the main policy research question the proposed trial compares MBCT plus ADM-tapering with m-ADM for patients with recurrent depression. Four hundred and twenty patients with recurrent major depressive disorder in full or partial remission will be recruited through primary care. Depressive relapse/recurrence over two years is the primary outcome variable. The explanatory question will be addressed in two mutually informative ways: quantitative measurement of potential mediating variables pre/post-treatment and a qualitative study of service users' views and experiences.
Discussion
If the results of our exploratory trial are extended to this definitive trial, MBCT will be established as an alternative approach to maintenance anti-depressants for people with a history of recurrent depression. The process studies will provide evidence about the effective components which can be used to improve MBCT and inform theory as well as other therapeutic approaches.
Trial registration number
ISRCTN26666654
doi:10.1186/1745-6215-11-99
PMCID: PMC2972263  PMID: 20961444
11.  Men who have sex with men in Great Britain: comparison of a self‐selected internet sample with a national probability sample 
Sexually Transmitted Infections  2006;83(3):200-205.
Objectives
To compare the characteristics of a self‐selected, convenience sample of men who have sex with men (MSM) recruited through the internet with MSM drawn from a national probability survey in Great Britain.
Methods
The internet sample (n = 2065) was recruited through two popular websites for homosexual men in Great Britain in May and June 2003. This sample was compared with MSM (n = 117) from the National Survey of Sexual Attitudes and Lifestyles (Natsal), a probability sample survey of adults resident in Great Britain conducted between May 1999 and February 2001.
Results
No significant differences were observed between the samples on a range of sociodemographic and behavioural variables (p>0.05). However, men from the internet sample were younger (p<0.001) and more likely to be students (p = 0.001), but less likely to live in London (p = 0.001) or report good health (p = 0.014). Although both samples were equally likely to report testing for HIV, men from the internet sample were more likely to report a sexually transmitted infection in the past year (16.9% v 4.8%, adjusted odds ratio 4.14, 95% CI 1.76 to 9.74; p = 0.001), anal intercourse (76.9% v 63.3%; p = 0.001) and unprotected anal intercourse in the past 3 months (45% v 36.6%; p = 0.064).
Conclusions
The internet provides a means of recruiting a self‐selected, convenience sample of MSM whose social and demographic characteristics are broadly similar to those of MSM drawn from a national probability survey. However, estimates of high‐risk sexual behaviour based on internet convenience samples are likely to overestimate levels of sexual risk behaviour in the wider MSM population.
doi:10.1136/sti.2006.023283
PMCID: PMC2659092  PMID: 17135330
12.  The sexual attitudes and lifestyles of London's Eastern Europeans (SALLEE Project): design and methods 
BMC Public Health  2009;9:399.
Background
Since May 2004, ten Central and Eastern European (CEE) countries have joined the European Union, leading to a large influx of CEE migrants to the United Kingdom (UK). The SALLEE project (sexual attitudes and lifestyles of London's Eastern Europeans) set out to establish an understanding of the sexual lifestyles and reproductive health risks of CEE migrants. CEE nationals make up a small minority of the population resident in the UK with no sampling frame from which to select a probability sample. There is also difficulty estimating the socio-demographic and geographical distribution of the population. In addition, measuring self-reported sexual behaviour which is generally found to be problematic, may be compounded among people from a range of different cultural and linguistic backgrounds. This paper will describe the methods adopted by the SALLEE project to address these challenges.
Methods
The research was undertaken using quantitative and qualitative methods: a cross-sectional survey of CEE migrants based on three convenience samples (recruited from community venues, sexual health clinics and from the Internet) and semi-structured in-depth interviews with a purposively selected sample of CEE migrants. A detailed social mapping exercise of the CEE community was conducted prior to commencement of the survey to identify places where CEE migrants could be recruited. A total of 3,005 respondents took part in the cross-sectional survey, including 2,276 respondents in the community sample, 357 in the clinic sample and 372 in the Internet sample. 40 in-depth qualitative interviews were undertaken with a range of individuals, as determined by the interview quota matrix.
Discussion
The SALLEE project has benefited from using quantitative research to provide generalisable data on a range of variables and qualitative research to add in-depth understanding and interpretation. The social mapping exercise successfully located a large number of CEE migrants for the community sample and is recommended for other migrant populations, especially when little or no official data are available for this purpose. The project has collected timely data that will help us to understand the sexual lifestyles, reproductive health risks and health service needs of CEE communities in the UK.
doi:10.1186/1471-2458-9-399
PMCID: PMC2777871  PMID: 19878564
14.  A Proteomic Approach for the Discovery of Early Detection Markers of Hepatocellular Carcinoma 
Disease Markers  2002;17(3):179-189.
Individuals chronically infected with hepatitis B or C virus (HBV, HCV) are at high risk for the development of hepatocellular carcinoma (HCC), with disease progression occurring relentlessly over many years. The diagnosis of HCC usually occurs at late stages in the disease when there are few effective treatment options and the prognosis for patients with HCC is very poor. The long latency period, together with clearly identified at risk populations, provide opportunities for earlier detection that will allow more timely and effective treatment of this devastating cancer. We are using a proteomic approach to test the hypothesis that changes in the amount of certain serum polypeptides, or changes in their post-translational modifications, can be used to predict the onset of HCC. Advances in the standardization of two dimensional gel electrophoresis (2DE) coupled with computerized image analysis now permit the reproducible resolution of thousands of polypeptides per run. Serum polypeptides from individuals at different stages in the disease continuum are being resolved by 2DE to identify those that change with disease progression. Polypeptides found by this method can be further characterized by mass spectrometry. In addition, the potential for changes in the glycan structure of certain polypeptides to serve as a marker for disease progression can be explored. The proteomic approach is expected to liberate us from the need to “cherry pick” or guess the best biomarkers and let the data tell us which are the best indicators of disease. Information may also be gleaned about the pathobiology of the disease process.
doi:10.1155/2001/963023
PMCID: PMC3851119  PMID: 11790885
15.  Characteristics of a Pathogenic Molecular Clone of an End-Stage Serum-Derived Variant of Simian Immunodeficiency Virus (SIVF359) 
Journal of Virology  2001;75(19):9328-9338.
End-stage simian immunodeficiency virus (SIV) isolates are suggested to be the most fit of the evolved virulent variants that precipitate the progression to AIDS. To determine if there were common characteristics of end-stage variants which emerge from accelerated cases of AIDS, a molecular clone was derived directly from serum following in vivo selection of a highly virulent SIV isolate obtained by serial end-stage passage in rhesus monkeys (Macaca mulatta). This dominant variant caused a marked cytopathic effect and replicated to very high levels in activated but not resting peripheral blood lymphocytes. Furthermore, although this clone infected but did not replicate to detectable levels in rhesus monocyte-derived macrophages, these cells were able to transmit infection to autologous T cells upon contact. Interestingly, although at low doses this end-stage variant did not use any of the known coreceptors except CCR5, it was able to infect and replicate in human peripheral blood mononuclear cells homozygous for the Δ32 deletion of CCR5, suggesting the use of a novel coreceptor. It represents the first pathogenic molecular clone of SIV derived from viral RNA in serum and provides evidence that not only the genetic but also the biological characteristics acquired by highly fit late-stage disease variants may be distinct in different hosts.
doi:10.1128/JVI.75.19.9328-9338.2001
PMCID: PMC114501  PMID: 11533196

Results 1-16 (16)