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1.  Systematic Evaluation of the Patient-Reported Outcome (PRO) Content of Clinical Trial Protocols 
PLoS ONE  2014;9(10):e110229.
Background
Qualitative evidence suggests patient-reported outcome (PRO) information is frequently absent from clinical trial protocols, potentially leading to inconsistent PRO data collection and risking bias. Direct evidence regarding PRO trial protocol content is lacking. The aim of this study was to systematically evaluate the PRO-specific content of UK National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme trial protocols.
Methods and Findings
We conducted an electronic search of the NIHR HTA programme database (inception to August 2013) for protocols describing a randomised controlled trial including a primary/secondary PRO. Two investigators independently reviewed the content of each protocol, using a specially constructed PRO-specific protocol checklist, alongside the ‘Standard Protocol Items: Recommendations for Interventional Trials’ (SPIRIT) checklist. Disagreements were resolved through discussion with a third investigator. 75 trial protocols were included in the analysis. Protocols included a mean of 32/51 (63%) SPIRIT recommendations (range 16–41, SD 5.62) and 11/33 (33%) PRO-specific items (range 4–18, SD 3.56). Over half (61%) of the PRO items were incomplete. Protocols containing a primary PRO included slightly more PRO checklist items (mean 14/33 (43%)). PRO protocol content was not associated with general protocol completeness; thus, protocols judged as relatively ‘complete’ using SPIRIT were still likely to have omitted a large proportion of PRO checklist items.
Conclusions
The PRO components of HTA clinical trial protocols require improvement. Information on the PRO rationale/hypothesis, data collection methods, training and management was often absent. This low compliance is unsurprising; evidence shows existing PRO guidance for protocol developers remains difficult to access and lacks consistency. Study findings suggest there are a number of PRO protocol checklist items that are not fully addressed by the current SPIRIT statement. We therefore advocate the development of consensus-based supplementary guidelines, aimed at improving the completeness and quality of PRO content in clinical trial protocols.
doi:10.1371/journal.pone.0110229
PMCID: PMC4198237  PMID: 25333349
2.  Patient-Reported Outcome (PRO) Assessment in Clinical Trials: A Systematic Review of Guidance for Trial Protocol Writers 
PLoS ONE  2014;9(10):e110216.
Background
Evidence suggests there are inconsistencies in patient-reported outcome (PRO) assessment and reporting in clinical trials, which may limit the use of these data to inform patient care. For trials with a PRO endpoint, routine inclusion of key PRO information in the protocol may help improve trial conduct and the reporting and appraisal of PRO results; however, it is currently unclear exactly what PRO-specific information should be included. The aim of this review was to summarize the current PRO-specific guidance for clinical trial protocol developers.
Methods and Findings
We searched the MEDLINE, EMBASE, CINHAL and Cochrane Library databases (inception to February 2013) for PRO-specific guidance regarding trial protocol development. Further guidance documents were identified via Google, Google scholar, requests to members of the UK Clinical Research Collaboration registered clinical trials units and international experts. Two independent investigators undertook title/abstract screening, full text review and data extraction, with a third involved in the event of disagreement. 21,175 citations were screened and 54 met the inclusion criteria. Guidance documents were difficult to access: electronic database searches identified just 8 documents, with the remaining 46 sourced elsewhere (5 from citation tracking, 27 from hand searching, 7 from the grey literature review and 7 from experts). 162 unique PRO-specific protocol recommendations were extracted from included documents. A further 10 PRO recommendations were identified relating to supporting trial documentation. Only 5/162 (3%) recommendations appeared in ≥50% of guidance documents reviewed, indicating a lack of consistency.
Conclusions
PRO-specific protocol guidelines were difficult to access, lacked consistency and may be challenging to implement in practice. There is a need to develop easily accessible consensus-driven PRO protocol guidance. Guidance should be aimed at ensuring key PRO information is routinely included in appropriate trial protocols, in order to facilitate rigorous collection/reporting of PRO data, to effectively inform patient care.
doi:10.1371/journal.pone.0110216
PMCID: PMC4198295  PMID: 25333995
3.  Correction: Patient Reported Outcomes (PROs) in Clinical Trials: Is ‘In-Trial’ Guidance Lacking? A Systematic Review 
PLoS ONE  2014;9(1):10.1371/annotation/e7d2b920-2c2a-425e-b500-982cd72f4d64.
doi:10.1371/annotation/e7d2b920-2c2a-425e-b500-982cd72f4d64
PMCID: PMC3879383
4.  Evaluation of the effectiveness of an outreach clinical mentoring programme in support of paediatric HIV care scale-up in Botswana 
AIDS care  2012;25(1):11-19.
Clinical mentoring by providers skilled in HIV management has been identified as a cornerstone of scaling-up antiretroviral treatment in Africa, particularly in settings where expertise is limited. However, little data exist on its effectiveness and impact on improving the quality-of-care and clinical outcomes, especially for HIV-infected children. Since 2008, the Botswana-Baylor Children’s Clinical Centre of Excellence (COE) has operated an outreach mentoring programme at clinical sites around Botswana. This study is a retrospective review of 374 paediatric charts at four outreach mentoring sites (Mochudi, Phutadikobo, Molepolole, Thamaga) evaluating the effectiveness of the programme as reflected in a number of clinically-relevant areas. Charts from one visit prior to initiation of mentoring and from one visit after approximately one year of mentoring were assessed for statistically-significant differences (p<0.05) in the documentation of clinically-relevant indicators. Mochudi showed notable improvements in all indicators analyzed, with particular improvements in documentation of pill count, viral load (VL) results, correct laboratory monitoring and correct antiretroviral therapy (ART) dosing (p<0.0001, p<0.0001, p<0.0001 and p<0.0001, respectively). Broad and substantial improvements were also seen in Molepolole, with the most improvement in disclosure documentation of all four sites. At Thamaga, improvements were restricted to CD4 documentation(p<0.001), recent VL and documented pill count (p<0.05 and p<0.05, respectively). Phuthadikobo showed the least amount of improvement across indicators, with only VL documentation and correct ART dosing showing statistically-significant improvements (p<0.05 and p<0.0001, respectively). These findings suggest that clinical mentoring may assist improvements in a number of important areas, including ART dosing and monitoring; adherence assessment and assurance; and disclosure. Clinical mentoring may be a valuable tool in scale-up of quality paediatric HIV care-and-treatment outside specialized centres. Further study will help refine approaches to clinical mentoring, including assuring mentoring translates into improved clinical outcomes for HIV-infected children.
doi:10.1080/09540121.2012.674096
PMCID: PMC3426665  PMID: 22533352
6.  Inconsistencies in Quality of Life Data Collection in Clinical Trials: A Potential Source of Bias? Interviews with Research Nurses and Trialists 
PLoS ONE  2013;8(10):e76625.
Background
Patient-reported outcomes (PROs), such as health-related quality of life (HRQL) are increasingly used to evaluate treatment effectiveness in clinical trials, are valued by patients, and may inform important decisions in the clinical setting. It is of concern, therefore, that preliminary evidence, gained from group discussions at UK-wide Medical Research Council (MRC) quality of life training days, suggests there are inconsistent standards of HRQL data collection in trials and appropriate training and education is often lacking. Our objective was to investigate these reports, to determine if they represented isolated experiences, or were indicative of a potentially wider problem.
Methods And Findings
We undertook a qualitative study, conducting 26 semi-structured interviews with research nurses, data managers, trial coordinators and research facilitators involved in the collection and entry of HRQL data in clinical trials, across one primary care NHS trust, two secondary care NHS trusts and two clinical trials units in the UK. We used conventional content analysis to analyze and interpret our data. Our study participants reported (1) inconsistent standards in HRQL measurement, both between, and within, trials, which appeared to risk the introduction of bias; (2), difficulties in dealing with HRQL data that raised concern for the well-being of the trial participant, which in some instances led to the delivery of non-protocol driven co-interventions, (3), a frequent lack of HRQL protocol content and appropriate training and education of trial staff, and (4) that HRQL data collection could be associated with emotional and/or ethical burden.
Conclusions
Our findings suggest there are inconsistencies in the standards of HRQL data collection in some trials resulting from a general lack of HRQL-specific protocol content, training and education. These inconsistencies could lead to biased HRQL trial results. Future research should aim to develop HRQL guidelines and training programmes aimed at supporting researchers to carry out high quality data collection.
doi:10.1371/journal.pone.0076625
PMCID: PMC3790726  PMID: 24124580
7.  Informing Potential Participants about Research: Observational Study with an Embedded Randomized Controlled Trial 
PLoS ONE  2013;8(10):e76435.
Objectives
To assess: 1) the feasibility of electronic information provision; 2) gather evidence on the topics and level of detail of information potential research participant’s accessed; 3) to assess satisfaction and understanding.
Design
Observational study with an embedded randomised controlled trial.
Setting
Low risk intervention study based in primary care.
Participants
White British & Irish, South Asian and African-Caribbean subjects aged between 40-74 years eligible for a blood pressure monitoring study.
Interventions
PDF copy of the standard paper participant information sheet (PDF-PIS) and an electronic Interactive Information Sheet (IIS) where participants could choose both the type and level of detail accessed.
Main Outcome Measures
1) Proportion of participants providing an email address and accessing electronic information 2) Willingness to participate in a recruitment clinic. 3) Type and depth of information accessed on the IIS. 4) Participant satisfaction and understanding.
Results
1160 participants were eligible for the study. Of these, 276 (24%) provided an active email address, of whom 84 did not respond to the email. 106 responded to the email but chose not to access any electronic information and were therefore ineligible for randomisation. 42 were randomised to receive the PDF-PIS and 44 to receive the IIS (with consent rates of 48% and 36%, respectively; odds ratio 0.6, 95% confidence interval 0.25 to 1.4). Electronic observation of information accessed by potential participants showed 41% chose to access no information and only 9% accessed the detail presented on the Research Ethics Committee approved participant information sheet before booking to attend a recruitment clinic for the intervention study. 63 of the 106 participants (59%) who chose not to access any electronic information also booked an appointment.
Conclusions
Current written information about research may not be read, emphasising the importance of the consent interview and consideration of new ways of presenting complex information.
doi:10.1371/journal.pone.0076435
PMCID: PMC3789820  PMID: 24098499
8.  Nine-year follow-up of HIV-infected Romanian children and adolescents receiving lopinavir/ritonavir-containing highly active antiretroviral therapy 
Germs  2013;3(3):90-95.
Introduction
Many Romanian children were infected nosocomially with human immunodeficiency virus (HIV) in the late 1980s. The Romanian-American Children's Center of Excellence in Constanţa continues to follow approximately 450 of these patients. In 2001, 414 of these patients were initiated on triple therapy including lopinavir/ritonavir. Data from this cohort treated through August 2006 were published in April 2007 demonstrating that the treatment was well tolerated, with 337 children (81%) remaining on therapy after a median duration of >4 years. The current article describes the results of continued analysis of this cohort through end 2010. The objective of the study was to determine the long-term clinical outcomes of children and adolescents commenced on antiretroviral therapy (ART) including lopinavir/ritonavir.
Methods
Data were extracted retrospectively from the charts of the 336 patients remaining on lopinavir/ritonavir in August 2006. The following outcomes were analyzed: mortality, current patient status, viral load (VL), CD4 counts and reasons for discontinuation of lopinavir/ritonavir.
Results
The median age at initiation of lopinavir/ritonavir was 14.0 years (range 5.4 to 20.0 years). The median time on lopinavir/ritonavir treatment was 7.5 years (interquartile range 5.7 to 8.6 years). Overall mortality was 13.5%. Of the original 414 patients started on lopinavir/ritonavir in 2001, 199 (48.1%) remained on this therapy at the end of 2010 and of these 63.8% had undetectable viral load.
Conclusion
Despite initial suboptimal ART, a significant proportion of patients subsequently treated with a lopinavir/ritonavir based regimen remained on this therapy for up to nine years.
doi:10.11599/germs.2013.1042
PMCID: PMC3882860  PMID: 24432292
HIV/AIDS; antiretroviral therapy; lopinavir/ritonavir
9.  Doctors’ willingness to give honest answers about end-of-life practices: a cross-sectional study 
BMJ Open  2013;3(5):e002598.
Objectives
We aimed to (1) evaluate the extent to which doctors in New Zealand would be willing to answer honestly questions about their care of patients at the end of their lives and (2) identify the assurances that would encourage this. Results were compared with findings from a previous pilot study from the UK.
Design
Survey study involving a mailed questionnaire.
Setting
New Zealand hospital and community-based medical care settings.
Participants
The questionnaire was mailed to a random sample of 800 doctors in New Zealand who were vocationally registered with the Medical Council of New Zealand in disciplines involving caring for patients at the end of their lives.
Primary and secondary outcome measures
Willingness to provide honest answers about various aspects of end-of-life care; assurances that might increase willingness to provide honest answers to questions about end-of-life practices.
Results
Completed questionnaires were returned by 436 doctors. The majority of respondents (59.9–91.5%) indicated willingness to provide honest answers to such questions. However, more than a third of doctors were unwilling to give honest answers to certain questions regarding euthanasia. These results are comparable with the UK data. Complete anonymity was the assurance most likely to encourage honest answering, with most of the respondents preferring the use of anonymous written replies. Respondents were less reassured by survey endorsements from regulatory bodies. Themes in free comments included the deterrent effect of medicolegal consequences, fear of censure from society, peers and the media and concerns about the motivations and potential uses of such research.
Conclusions
Many New Zealand doctors were willing to give honest answers to questions about end-of-life practices, particularly if anonymity was guaranteed; others, however, expressed doubts or indicated that they would not be willing to provide honest answers to questions of this sort.
doi:10.1136/bmjopen-2013-002598
PMCID: PMC3664351  PMID: 23793694
Medical Ethics; Medical Law; Palliative Care
10.  Patient Reported Outcomes (PROs) in Clinical Trials: Is ‘In-Trial’ Guidance Lacking? A Systematic Review 
PLoS ONE  2013;8(4):e60684.
Background
Patient reported outcomes (PROs) are increasingly assessed in clinical trials, and guidelines are available to inform the design and reporting of such trials. However, researchers involved in PRO data collection report that specific guidance on ‘in-trial’ activity (recruitment, data collection and data inputting) and the management of ‘concerning’ PRO data (i.e., data which raises concern for the well-being of the trial participant) appears to be lacking. The purpose of this review was to determine the extent and nature of published guidelines addressing these areas.
Methods and Findings
Systematic review of 1,362 articles identified 18 eligible papers containing ‘in-trial’ guidelines. Two independent authors undertook a qualitative content analysis of the selected papers. Guidelines presented in each of the articles were coded according to an a priori defined coding frame, which demonstrated reliability (pooled Kappa 0.86–0.97), and validity (<2% residual category coding). The majority of guidelines present were concerned with ‘pre-trial’ activities (72%), for example, outcome measure selection and study design issues, or ‘post-trial’ activities (16%) such as data analysis, reporting and interpretation. ‘In-trial’ guidelines represented 9.2% of all guidance across the papers reviewed, with content primarily focused on compliance, quality control, proxy assessment and reporting of data collection. There were no guidelines surrounding the management of concerning PRO data.
Conclusions
The findings highlight there are minimal in-trial guidelines in publication regarding PRO data collection and management in clinical trials. No guidance appears to exist for researchers involved with the handling of concerning PRO data. Guidelines are needed, which support researchers to manage all PRO data appropriately and which facilitate unbiased data collection.
doi:10.1371/journal.pone.0060684
PMCID: PMC3613381  PMID: 23560103
11.  What potential research participants want to know about research: a systematic review 
BMJ Open  2012;2(3):e000509.
Objective
To establish the empirical evidence base for the information that participants want to know about medical research and to assess how this relates to current guidance from the National Research Ethics Service (NRES).
Data sources
Medline, Web of Science, Applied Social Sciences Index and Abstracts, Sociological abstracts, Health Management Information Consortium, Cochrane Library, thesis index's, grey literature databases, reference and cited article lists, key journals, Google Scholar and correspondence with expert authors.
Study selection
Original research studies published between 1950 and October 2010 that asked potential participants to indicate how much or what types of information they wanted to be told about a research study or asked them to rate the importance of a specific piece of information were included.
Study appraisal and synthesis methods
Studies were appraised based on the generalisability of results to the UK potential research participant population. A metadata analysis using basic thematic analysis was used to split results from papers into themes based on the sections of information that NRES recommends should be included in a participant information sheet.
Results
14 studies were included. Of the 20 pieces of information that NRES recommend should be included in patient information sheets for research pooled proportions could be calculated for seven themes. Results showed that potential participants wanted to be offered information about result dissemination (91% (95% CI 85% to 95%)), investigator conflicts of interest (48% (95% CI 27% to 69%)), the purpose of the study (76% (95% CI 27% to 100%)), voluntariness (39% (95% CI 2% to 100%)), how long the research would last (61% (95% CI 16% to 97%)), potential benefits (57% (95% CI 7% to 98%)) and confidentiality (44% (95% CI 10% to 82%)). The level of detail participants wanted to know was not explored comprehensively in the studies. There was no empirical evidence to support the level of information provision required by participants on the remaining seven items.
Conclusions
There is limited empirical evidence on what potential participants want to know about research. The existing empirical evidence suggests that individuals may have very different needs and a more tailored evidence-based approach may be necessary.
Article summary
Article focus
What information do potential participants want to know when they are deciding whether to take part in research?
What is the established empirical evidence base?
How does the current empirical evidence base relate to current guidance from the NRES?
Key messages
There is little empirical evidence of what information potential participants want to know about research when they are making the decision to take part.
The limited empirical evidence available suggests that potential participants may have very different information needs.
Further research is required to determine what potential participants really want to know about research and how this can be delivered in a way that takes into account their different informational needs.
Strengths and limitations of this study
An extensive search strategy ensured that the review was systematic in capturing all available empirical evidence.
Papers included in the review differed in their methodologies and presentation of results, making comparisons between papers extremely difficult.
doi:10.1136/bmjopen-2011-000509
PMCID: PMC3367142  PMID: 22649171
12.  Evaluating the effectiveness of GP endorsement on increasing participation in the NHS Bowel Cancer Screening Programme in England: study protocol for a randomized controlled trial 
Trials  2012;13:18.
Background
The success and cost-effectiveness of bowel cancer screening depends on achieving and maintaining high screening uptake rates. The involvement of GPs in screening has been found to improve patient compliance. Therefore, the endorsement of screening by GPs may increase uptake rates amongst non-responders.
Methods/Design
A two-armed randomised controlled trial will evaluate the effectiveness of a GP endorsed reminder in improving patient participation in the NHS Bowel Cancer Screening Programme (NHSBCSP). Up to 30 general practices in the West Midlands with a screening uptake rate of less than 50% will be recruited and patients identified from the patient lists of these practices. Eligible patients will be those aged 60 to 74, who have previously been invited to participate in bowel screening but who have been recorded by the Midlands and North West Bowel Cancer Screening Hub as non-responders. Approximately 4,380 people will be randomised in equal numbers to either the intervention (GP letter and duplicate FOBt kit) or control (no additional contact) arms of the trial.
The primary outcome measure will be the difference in the uptake rate of FOBt screening for bowel cancer between the intervention and control groups at 13 weeks after the GP endorsed reminder and duplicate FOBt kit are sent. Secondary outcome measures will be subgroup analyses of uptake according to gender, age and deprivation quartile, and the validation of methods for collecting GP, NHSBCSP and patient costs associated with the intervention. Qualitative work (30 to 40 semi-structured interviews) will be undertaken with individuals in the intervention arm who return a FOBt kit, to investigate the relative importance of the duplicate FOBt kit, reminder to participate, and GP endorsement of that reminder in contributing to individuals' decisions to participate in screening.
Discussion
Implementing feasible, acceptable and cost-effective strategies to improve screening uptake amongst non-responders to invitations to participate is fundamentally important for the success of screening programmes. If this feasibility study demonstrates a significant increase in uptake of FOBt screening in individuals receiving the intervention, a definitive, appropriately powered future trial will be designed.
Trial registration number
ISRCTN: ISRCTN86784060
doi:10.1186/1745-6215-13-18
PMCID: PMC3305373  PMID: 22348399
Colorectal cancer; General practitioner; Screening; FOBt; Uptake; Non-responder; Randomised controlled trial; Qualitative; Endorsement
13.  Using e-mail recruitment and an online questionnaire to establish effect size: A worked example 
Background
Sample size calculations require effect size estimations. Sometimes, effect size estimations and standard deviation may not be readily available, particularly if efficacy is unknown because the intervention is new or developing, or the trial targets a new population. In such cases, one way to estimate the effect size is to gather expert opinion. This paper reports the use of a simple strategy to gather expert opinion to estimate a suitable effect size to use in a sample size calculation.
Methods
Researchers involved in the design and analysis of clinical trials were identified at the University of Birmingham and via the MRC Hubs for Trials Methodology Research. An email invited them to participate.
An online questionnaire was developed using the free online tool 'Survey Monkey©'. The questionnaire described an intervention, an electronic participant information sheet (e-PIS), which may increase recruitment rates to a trial. Respondents were asked how much they would need to see recruitment rates increased by, based on 90%. 70%, 50% and 30% baseline rates, (in a hypothetical study) before they would consider using an e-PIS in their research.
Analyses comprised simple descriptive statistics.
Results
The invitation to participate was sent to 122 people; 7 responded to say they were not involved in trial design and could not complete the questionnaire, 64 attempted it, 26 failed to complete it. Thirty-eight people completed the questionnaire and were included in the analysis (response rate 33%; 38/115). Of those who completed the questionnaire 44.7% (17/38) were at the academic grade of research fellow 26.3% (10/38) senior research fellow, and 28.9% (11/38) professor. Dependent upon the baseline recruitment rates presented in the questionnaire, participants wanted recruitment rate to increase from 6.9% to 28.9% before they would consider using the intervention.
Conclusions
This paper has shown that in situations where effect size estimations cannot be collected from previous research, opinions from researchers and trialists can be quickly and easily collected by conducting a simple study using email recruitment and an online questionnaire. The results collected from the survey were successfully used in sample size calculations for a PhD research study protocol.
doi:10.1186/1471-2288-11-89
PMCID: PMC3130700  PMID: 21658219
14.  Paternity fraud and compensation for misattributed paternity 
Journal of Medical Ethics  2007;33(8):475-480.
Claims for reimbursement of child support, the reversal of property settlements and compensation can arise when misattributed paternity is discovered. The ethical justifications for such claims seem to be related to the financial cost of bringing up children, the absence of choice about taking on these expenses, the hard work involved in child rearing, the emotional attachments that are formed with children, the obligation of women to make truthful claims about paternity, and the deception involved in infidelity. In this paper it is argued that there should not be compensation for infidelity and that reimbursement is appropriate where the claimant has made child support payments but has not taken on the social role of father. Where the claimant's behaviour suggests a social view of fatherhood, on the other hand, claims for compensation are less coherent. Where the genetic model of fatherhood dominates, the “other” man (the woman's lover and progenitor of the children) might also have a claim for the loss of the benefits of fatherhood. It is concluded that claims for reimbursement and compensation in cases of misattributed paternity produce the same distorted and thin view of what it means to be a father that paternity testing assumes, and underscores a trend that is not in the interests of children.
doi:10.1136/jme.2005.013268
PMCID: PMC2598159  PMID: 17664309
paternity fraud; misattributed paternity; definition of “father”; genetics; genetic relatedness
15.  Will the NHS continue to function in an influenza pandemic? a survey of healthcare workers in the West Midlands, UK 
BMC Public Health  2009;9:142.
Background
If UK healthcare services are to respond effectively to pandemic influenza, levels of absenteeism amongst healthcare workers (HCWs) must be minimised. Current estimates of the likelihood that HCWs will continue to attend work during a pandemic are subject to scientific and predictive uncertainty, yet an informed evidence base is needed if contingency plans addressing the issues of HCW absenteeism are to be prepared.
Methods
This paper reports the findings of a self-completed survey of randomly selected HCWs across three purposively sampled healthcare trusts in the West Midlands. The survey aimed to identify the factors positively or negatively associated with willingness to work during an influenza pandemic, and to evaluate the acceptability of potential interventions or changes to working practice to promote the continued presence at work of those otherwise unwilling or unable to attend. 'Likelihood' and 'persuadability' scores were calculated for each respondent according to indications of whether or not they were likely to work under different circumstances. Binary logistic regression was used to compute bivariate and multivariate odds ratios to evaluate the association of demographic variables and other respondent characteristics with the self-described likelihood of reporting to work.
Results
The survey response rate was 34.4% (n = 1032). Results suggest absenteeism may be as high as 85% at any point during a pandemic, with potential absence particularly concentrated amongst nursing and ancillary workers (OR 0.3; 95% CI 0.1 to 0.7 and 0.5; 95% CI 0.2 to 0.9 respectively).
Conclusion
Levels of absenteeism amongst HCWs may be considerably higher than official estimates, with potential absence concentrated amongst certain groups of employees. Although interventions designed to minimise absenteeism should target HCWs with a low stated likelihood of working, members of these groups may also be the least receptive to such interventions. Changes to working conditions which reduce barriers to the ability to work may not address barriers linked to willingness to work, and may fail to overcome HCWs' reluctance to work in the face of what may still be deemed unacceptable risk to self and/or family.
doi:10.1186/1471-2458-9-142
PMCID: PMC2690584  PMID: 19442272
16.  The DNA sequence of the human X chromosome 
Ross, Mark T. | Grafham, Darren V. | Coffey, Alison J. | Scherer, Steven | McLay, Kirsten | Muzny, Donna | Platzer, Matthias | Howell, Gareth R. | Burrows, Christine | Bird, Christine P. | Frankish, Adam | Lovell, Frances L. | Howe, Kevin L. | Ashurst, Jennifer L. | Fulton, Robert S. | Sudbrak, Ralf | Wen, Gaiping | Jones, Matthew C. | Hurles, Matthew E. | Andrews, T. Daniel | Scott, Carol E. | Searle, Stephen | Ramser, Juliane | Whittaker, Adam | Deadman, Rebecca | Carter, Nigel P. | Hunt, Sarah E. | Chen, Rui | Cree, Andrew | Gunaratne, Preethi | Havlak, Paul | Hodgson, Anne | Metzker, Michael L. | Richards, Stephen | Scott, Graham | Steffen, David | Sodergren, Erica | Wheeler, David A. | Worley, Kim C. | Ainscough, Rachael | Ambrose, Kerrie D. | Ansari-Lari, M. Ali | Aradhya, Swaroop | Ashwell, Robert I. S. | Babbage, Anne K. | Bagguley, Claire L. | Ballabio, Andrea | Banerjee, Ruby | Barker, Gary E. | Barlow, Karen F. | Barrett, Ian P. | Bates, Karen N. | Beare, David M. | Beasley, Helen | Beasley, Oliver | Beck, Alfred | Bethel, Graeme | Blechschmidt, Karin | Brady, Nicola | Bray-Allen, Sarah | Bridgeman, Anne M. | Brown, Andrew J. | Brown, Mary J. | Bonnin, David | Bruford, Elspeth A. | Buhay, Christian | Burch, Paula | Burford, Deborah | Burgess, Joanne | Burrill, Wayne | Burton, John | Bye, Jackie M. | Carder, Carol | Carrel, Laura | Chako, Joseph | Chapman, Joanne C. | Chavez, Dean | Chen, Ellson | Chen, Guan | Chen, Yuan | Chen, Zhijian | Chinault, Craig | Ciccodicola, Alfredo | Clark, Sue Y. | Clarke, Graham | Clee, Chris M. | Clegg, Sheila | Clerc-Blankenburg, Kerstin | Clifford, Karen | Cobley, Vicky | Cole, Charlotte G. | Conquer, Jen S. | Corby, Nicole | Connor, Richard E. | David, Robert | Davies, Joy | Davis, Clay | Davis, John | Delgado, Oliver | DeShazo, Denise | Dhami, Pawandeep | Ding, Yan | Dinh, Huyen | Dodsworth, Steve | Draper, Heather | Dugan-Rocha, Shannon | Dunham, Andrew | Dunn, Matthew | Durbin, K. 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Nature  2005;434(7031):325-337.
The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence.
doi:10.1038/nature03440
PMCID: PMC2665286  PMID: 15772651
17.  Healthcare workers' attitudes to working during pandemic influenza: a qualitative study 
BMC Public Health  2009;9:56.
Background
Healthcare workers (HCWs) will play a key role in any response to pandemic influenza, and the UK healthcare system's ability to cope during an influenza pandemic will depend, to a large extent, on the number of HCWs who are able and willing to work through the crisis. UK emergency planning will be improved if planners have a better understanding of the reasons UK HCWs may have for their absenteeism, and what might motivate them to work during an influenza pandemic.
This paper reports the results of a qualitative study that explored UK HCWs' views (n = 64) about working during an influenza pandemic, in order to identify factors that might influence their willingness and ability to work and to identify potential sources of any perceived duty on HCWs to work.
Methods
A qualitative study, using focus groups (n = 9) and interviews (n = 5).
Results
HCWs across a range of roles and grades tended to feel motivated by a sense of obligation to work through an influenza pandemic. A number of significant barriers that may prevent them from doing so were also identified. Perceived barriers to the ability to work included being ill oneself, transport difficulties, and childcare responsibilities. Perceived barriers to the willingness to work included: prioritising the wellbeing of family members; a lack of trust in, and goodwill towards, the NHS; a lack of information about the risks and what is expected of them during the crisis; fear of litigation; and the feeling that employers do not take the needs of staff seriously. Barriers to ability and barriers to willingness, however, are difficult to separate out.
Conclusion
Although our participants tended to feel a general obligation to work during an influenza pandemic, there are barriers to working, which, if generalisable, may significantly reduce the NHS workforce during a pandemic. The barriers identified are both barriers to willingness and to ability. This suggests that pandemic planning needs to take into account the possibility that staff may be absent for reasons beyond those currently anticipated in UK planning documents. In particular, staff who are physically able to attend work may nonetheless be unwilling to do so. Although there are some barriers that cannot be mitigated by employers (such as illness, transport infrastructure etc.), there are a number of remedial steps that can be taken to lesson the impact of others (providing accommodation, building reciprocity, provision of information and guidance etc). We suggest that barriers to working lie along an ability/willingness continuum, and that absenteeism may be reduced by taking steps to prevent barriers to willingness becoming perceived barriers to ability.
doi:10.1186/1471-2458-9-56
PMCID: PMC2654560  PMID: 19216738
18.  Healthcare workers' attitudes towards working during pandemic influenza: A multi method study 
BMC Public Health  2008;8:192.
Background
Healthcare workers (HCWs) will be key players in any response to pandemic influenza, and will be in the front line of exposure to infection. Responding effectively to a pandemic relies on the majority of medical, nursing, laboratory and hotel services staff continuing to work normally. Planning assumes that during a pandemic normal healthcare service levels will be provided, although it anticipates that as caseloads increase only essential care will be provided. The ability of the NHS to provide expected service levels is entirely dependent upon HCWs continuing to work as normal.
Methods/design
This study is designed as a two-phase multi-method study, incorporating focus groups and a questionnaire survey. In phase one, qualitative methods will be used to collect the views of a purposive sample of HCWs, to determine the range of factors associated with their responses to the prospect of working through pandemic influenza. In phase two, the findings from the focus groups, combined with the available literature, will be used to inform the design of a survey to determine the generalisability of these factors, enabling the estimation of the likely proportion of HCWs affected by each factor, and how likely it is that they would be willing and/or able to continue to work during an influenza pandemic.
Discussion
There are potentially greater than normal health risks for some healthcare workers working during a pandemic, and these workers may be concerned about infecting family members/friends. HCWs will be as liable as other workers to care for sick family members and friends. It is vital to have information about how motivated HCWs will be to continue to work during such a crisis, and what factors might influence their decision to work/not to work. Through the identification and subsequent management of these factors it may be possible to implement strategies that will alleviate the concerns and fears of HCWs and remove potential barriers to working.
doi:10.1186/1471-2458-8-192
PMCID: PMC2423372  PMID: 18518971
24.  GRANDPARENTS' ENTITLEMENTS AND OBLIGATIONS 
Bioethics  2013;27(6):309-316.
In this article, it is argued that grandparents' obligations originate from parental obligations (i.e from the relationship they have with their children, the parents of their grandchildren) and not from the role of grandparent per se, and any entitlements flow from the extent to which these obligations are met. The position defended is, therefore, that grandparents qua grandparents are not entitled to form or continue relationships with their grandchildren. A continuation of grandparent-grandchildren relationships may be in the interests of children, but the grandparental nature of the relationship is not decisive. What counts is the extent to which relationships children have with any adults who are not their parents are is significant to them. Sometimes, however, grandparents become parents or co-parents of their grandchildren. They then gain parental rights, and as such are as entitled, ceteris parius, as any parent to expect their relationship with the child to continue. The issue of grandparents' entitlements can come to the fore when parents separate, and grandparents are unhappy with the access they have to their grandchildren. Grandparents' obligations may become a particular issue when parents die, struggle, or fail to care for their children. This article focuses particularly on these kinds of circumstances.
doi:10.1111/bioe.12028
PMCID: PMC3770958  PMID: 23718643
grandparents; obligations; entitlements; grandchildren; visitation rights; responsibilities; relationships
25.  Altruism in organ donation: an unnecessary requirement? 
Journal of Medical Ethics  2013;40(2):134-138.
Altruism has long been taken to be the guiding principle of ethical organ donation in the UK, and has been used as justification for rejecting or allowing certain types of donation. We argue that, despite this prominent role, altruism has been poorly defined in policy and position documents, and used confusingly and inconsistently. Looking at how the term has been used over recent years allows us to define ‘organ donation altruism’, and comparing this with accounts in the philosophical literature highlights its theoretical shortcomings. The recent report from the Nuffield Council on Bioethics reaffirmed the importance of altruism in organ donation, and offered a clearer definition. This definition is, however, more permissive than that of altruism previously seen in UK policy, and as a result allows some donations that previously have been considered unacceptable. We argue that while altruistic motivation may be desirable, it is not necessary.
doi:10.1136/medethics-2012-100528
PMCID: PMC3913211  PMID: 23538329
Donation/Procurement of Organs/Tissues; Allocation of Organs/Tissues; Philosophical Ethics; Public Policy

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