Publications by authors named "Helen Powell"

50 Publications

Pathogens associated with linear growth faltering in children with diarrhea and impact of antibiotic treatment: The Global Enteric Multicenter Study.

J Infect Dis 2021 Sep 16. Epub 2021 Sep 16.

Centro de Investigação em Saúde de Manhiça (CISM), Maputo, Mozambique.

Background: The association between childhood diarrheal disease and linear growth faltering in developing countries is well-described. However, the impact attributed to specific pathogens has not been elucidated, nor has the impact of recommended antibiotic treatment.

Methods: The Global Enteric Multicenter Study (GEMS) enrolled children seeking healthcare with moderate-to-severe diarrhea (MSD) at seven sites in sub-Saharan Africa and South Asia. At enrollment, we collected stool samples to identify enteropathogens. Length/height was measured at enrollment and follow-up, ~60 days later, to calculate change in length/height for age Z scores (ΔHAZ). The association of pathogens with ΔHAZ was tested by linear mixed effects regression models.

Results: Among 8,077 MSD cases analyzed, the proportion with stunting (HAZ<-1) increased from 59% at enrollment to 65% at follow-up (p<.0001). Pathogens significantly associated with linear growth decline were Cryptosporidium (p<0.001), typical enteropathogenic Escherichia coli (p=0.013), and untreated Shigella (p=0.009) among infants (0-11 months), and enterotoxigenic E. coli encoding heat stable toxin (p<0.001) and Cryptosporidium (p=0.03) among toddlers (12-23 months). Shigella-infected toddlers given antibiotics had improved linear growth (p=0.02).

Conclusion: Linear growth faltering among children aged 0-23 months with MSD is associated with specific pathogens and can be mitigated with targeted treatment strategies, as demonstrated for Shigella.
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http://dx.doi.org/10.1093/infdis/jiab434DOI Listing
September 2021

The NICE Evidence Standards Framework for digital health and care technologies - Developing and maintaining an innovative evidence framework with global impact.

Digit Health 2021 Jan-Dec;7:20552076211018617. Epub 2021 Jun 24.

Digital, Information and Technology Directorate, NICE, Manchester, UK.

Objective: In 2018, the UK National Institute for Health and Care Excellence (NICE), in partnership with Public Health England, NHS England, NHS Improvement and others, developed an evidence standards framework (ESF) for digital health and care technologies (DHTs). The ESF was designed to provide a standardised approach to guide developers and commissioners on the levels of evidence needed for the clinical and economic evaluation of DHTs by health and care systems.

Methods: The framework was developed using an agile and iterative methodology that included a literature review of existing initiatives and comparison of these against the requirements set by NHS England; iterative consultation with stakeholders through an expert working group and workshops; and questionnaire-based stakeholder input on a publicly available draft document.

Results: The evidence standards framework has been well-received and to date the ESF has been viewed online over 55,000 times and downloaded over 19,000 times.

Conclusions: In April 2021 we published an update to the ESF. Here, we summarise the process through which the ESF was developed, reflect on its global impact to date, and describe NICE's ongoing work to maintain and improve the framework in the context for a fast moving, innovative field.
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http://dx.doi.org/10.1177/20552076211018617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236783PMC
June 2021

Left atrial appendage occlusion in the UK: prospective registry and data linkage to Hospital Episode Statistics.

Eur Heart J Qual Care Clin Outcomes 2021 Sep;7(5):468-475

The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.

Aims: Non-valvular atrial fibrillation (AF) greatly increases the risk of ischaemic stroke. For people with contraindications to oral anticoagulation, left atrial appendage occlusion (LAAO) provides a non-pharmacological management alternative. The aim of this study was to measure the procedural safety and longer-term effectiveness of LAAO for AF in a UK setting.

Methods And Results: This was a prospective, single-armed registry of patients with AF for whom anticoagulation was unsuitable. Registry data were collected between October 2014 and April 2018 and linked to routine data sources for follow-up. Data from 583 LAAO procedures were entered into the registry, of which 537 (from 525 patients) were eligible for inclusion (median CHA2DS2-VASc score 4). A closure device was successfully implanted in 93.4% of cases, with a procedural success rate (device implanted without major complication) of 88.9%. Five patients (1.0%) died in hospital. During follow-up [median 729 (Q1:Q3, 523:913) days] 45 patients experienced neurological events; 33 of which were ischaemic. The ischaemic neurological event rate was 3.3 (1.6-5.0)% at 1 year (n = 387) and 7.0 (4.3-9.6)% at 2 years (n = 196). There were significant improvements in overall patient health (via Visual Analogue Scale) measured at 6 weeks and 6 months, but no significant improvements observed in patient utility over time.

Conclusion: The findings of our study suggest that LAAO is not without procedural risk, but that this risk may be justified in high-risk patients with AF who cannot take an anticoagulant. Moreover, the data do not provide support for more widespread use of LAAO as the complication rate was relatively high and would be difficult to justify in many patients with AF who tolerate anticoagulation.
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http://dx.doi.org/10.1093/ehjqcco/qcab042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445086PMC
September 2021

Safety, effectiveness and costs of percutaneous mitral valve repair: A real-world prospective study.

PLoS One 2021 12;16(5):e0251463. Epub 2021 May 12.

The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, United Kingdom.

Aims: Percutaneous mitral valve leaflet repair is a treatment option for some people with severe mitral valve regurgitation for whom conventional mitral valve surgery is clinically inappropriate. This study aimed to determine the safety, efficacy, and costs of percutaneous mitral valve leaflet repair, using the MitraClip device in a UK setting.

Methods And Results: This was a prospective, single-armed registry with a follow-up of 2 years that reported a range of procedural, clinical and patient-orientated outcomes. Registry data were linked to routine data sources to allow for more comprehensive follow up concerning mortality and healthcare resource use. The registry received data for 199 mainly elective patients with mixed mitral regurgitation aetiology. A MitraClip device was implanted in 187 patients (94%), with a procedural success rate of 86%, with 8% of patients having a serious in-hospital adverse event (including 5% mortality). Percutaneous mitral valve leaflet repair reduced mitral regurgitation from 100% MR grade ≥ 3+ to 7% at discharge. There were corresponding improvements in New York Heart Association functional class, reducing from 92% (class ≥ 3) at baseline to 18% at 6 weeks. There were significant improvements in generic and disease specific quality of life indicators up to 2 years. The all-cause mortality rate was estimated to be 12.7% (95% CI 7.5 to 17.7%) at 1 year. Percutaneous mitral valve leaflet repair was associated with reduced hospital readmissions and potential cost-savings in post-procedural care.

Conclusion: This study shows that percutaneous mitral valve leaflet repair using MitraClip is a relatively safe and effective treatment in patients unable to tolerate surgery and has the potential to reduce ongoing healthcare costs in the UK.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251463PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115844PMC
May 2021

An evaluation of 4 commercial assays for the detection of SARS-CoV-2 antibodies in a predominantly mildly symptomatic low prevalence Australian population.

J Clin Virol 2021 05 17;138:104797. Epub 2021 Mar 17.

Department of Microbiology, Sullivan Nicolaides Pathology, Queensland, Australia.

A total of 1080 individual patient samples (158 positive serology samples from confirmed, predominantly mildly symptomatic COVID-19 patients and 922 serology negative including 496 collected pre-COVID) from four states in Australia were analysed on four commercial SARS-CoV-2 serological assays targeting antibodies to different antigens (Roche Elecsys and Abbott Architect: nucleocapsid; Diasorin Liaison and Euroimmun: spike). A subset was compared to immunofluorescent antibody (IFA) and micro-neutralisation. Sensitivity and specificity of the Roche (n = 1033), Abbott (n = 806), Diasorin (n = 1034) and Euroimmun (n = 175) were 93.7 %/99.5 %, 90.2 %/99.4 %, 88.6 %/98.6 % and 91.3 %/98.8 %, respectively. ROC analysis with specificity held at 99 % increased the sensitivity for the Roche and Abbott assays from 93.7% to 98.7% (cut-off 0.21) and 90.2 % to 94.0 % (cut-off 0.91), respectively. Overall seropositivity of samples increased from a maximum of 23 % for samples 0-7 days-post-onset of symptoms (dpos), to 61 % from samples 8-14dpos and 93 % from those >14dpos. IFA and microneutralisation values correlated best with assays targeting antibodies to spike protein with values >80 AU/mL on the Diasorin assay associated with neutralising antibody. Detectable antibody was present in 22/23 (96 %), 20/23 (87 %), 15/23 (65 %) and 9/22 (41 %) patients with samples >180dpos on the Roche, Diasorin, Abbott and microneutralisation assays respectively. Given the low prevalence in this community, two-step algorithms on initial positive results saw an increase in the positive predictive value (PPV) of positive samples (39 %-65 % to ≥98 %) for all combinations. Similarly accuracy increased from a range of 98.5 %-99.4 % to ≥99.8 % assuming a 1 % seroprevalence. Negative predictive value (NPV) was high (≥99.8 %) regardless of which assay was used initially.
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http://dx.doi.org/10.1016/j.jcv.2021.104797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968170PMC
May 2021

Characteristics of Salmonella Recovered From Stools of Children Enrolled in the Global Enteric Multicenter Study.

Clin Infect Dis 2021 08;73(4):631-641

Medical Research Council Unit, The Gambia at the London School of Hygiene and Tropical Medicine, Banjul, The Gambia.

Background: The Global Enteric Multicenter Study (GEMS) determined the etiologic agents of moderate-to-severe diarrhea (MSD) in children under 5 years old in Africa and Asia. Here, we describe the prevalence and antimicrobial susceptibility of nontyphoidal Salmonella (NTS) serovars in GEMS and examine the phylogenetics of Salmonella Typhimurium ST313 isolates.

Methods: Salmonella isolated from children with MSD or diarrhea-free controls were identified by classical clinical microbiology and serotyped using antisera and/or whole-genome sequence data. We evaluated antimicrobial susceptibility using the Kirby-Bauer disk-diffusion method. Salmonella Typhimurium sequence types were determined using multi-locus sequence typing, and whole-genome sequencing was performed to assess the phylogeny of ST313.

Results: Of 370 Salmonella-positive individuals, 190 (51.4%) were MSD cases and 180 (48.6%) were diarrhea-free controls. The most frequent Salmonella serovars identified were Salmonella Typhimurium, serogroup O:8 (C2-C3), serogroup O:6,7 (C1), Salmonella Paratyphi B Java, and serogroup O:4 (B). The prevalence of NTS was low but similar across sites, regardless of age, and was similar among both cases and controls except in Kenya, where Salmonella Typhimurium was more commonly associated with cases than controls. Phylogenetic analysis showed that these Salmonella Typhimurium isolates, all ST313, were highly genetically related to isolates from controls. Generally, Salmonella isolates from Asia were resistant to ciprofloxacin and ceftriaxone, but African isolates were susceptible to these antibiotics.

Conclusions: Our data confirm that NTS is prevalent, albeit at low levels, in Africa and South Asia. Our findings provide further evidence that multidrug-resistant Salmonella Typhimurium ST313 can be carried asymptomatically by humans in sub-Saharan Africa.
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http://dx.doi.org/10.1093/cid/ciab051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366818PMC
August 2021

Effects of the Argus II Retinal Prosthesis System on the Quality of Life of Patients With Ultra-Low Vision Due to Retinitis Pigmentosa: Protocol for a Single-Arm, Mixed Methods Study.

JMIR Res Protoc 2021 Jan 20;10(1):e17436. Epub 2021 Jan 20.

Department of Ophthalmology, King's College London, London, United Kingdom.

Background: Retinitis pigmentosa is an incurable, degenerative retinal condition causing progressive sight loss, significantly affecting patients' quality of life. The Argus II Retinal Prosthesis is a surgically implanted medical device that delivers electrical stimulation to the retina. It is intended to produce a form of artificial vision for blind people with severe-to-profound retinitis pigmentosa by stimulating the remaining viable retinal cells to induce visual perception. This study has been initiated by National Health Service England's Commissioning through Evaluation program and funded through the National Institute of Health Research of the United Kingdom.

Objective: The aim of this study was to assess the effect of the Argus II device on patient's daily activities and quality of life.

Methods: This protocol is a prospective, single-arm, open-label, mixed methods study on 10 consecutive participants receiving the Argus II device. The patient representatives played an integral role in the design of this study. Eligibility criteria include ultra-low vision in both eyes as a result of end-stage retinitis pigmentosa and a willingness and capacity to complete the postimplantation rehabilitation program. Participants will be interviewed by independent researchers at baseline and 12 months later by using a semistructured, in-depth approach, alongside validated questionnaires (Impact of Vision Impairment-Very Low Vision, 5-level EuroQoL-5 dimensions scale, EuroQoL-visual analog scale, and Hospital Anxiety and Depression Scale) and a bespoke device-related questionnaire, which includes questions about users' experiences with the procedure, the device, and rehabilitation. The effect of the device on patients' functional vision and activities of daily living will be assessed by vision rehabilitation specialists using a set of tests measured on an ordinal scale (eg, ability to locate objects and avoid obstacles). Clinical outcomes include full-field stimulus light threshold, square localization, direction of motion, grating visual acuity, Landolt-C, procedural success, and adverse events. Qualitative and quantitative outcomes will be linked in a single database to enable individual participant measures to be considered in toto, comparing baseline to the final review.

Results: This study was approved by the local ethics committee on April 24, 2019 (London-Camberwell St. Giles Research Ethics Committee, reference 19/LO/0429). It has also been approved by the Health Research Authority and Health and Care Research Wales. At the time of protocol writing, Argus II was available for use in the United Kingdom; however, the manufacturer recently withdrew the Argus II device from sale in the United Kingdom. Therefore, the study is not going ahead at this time.

Conclusions: The mixed methods approach provides a rich and in-depth assessment of the effect of the device on participants' quality of life. Despite the work not going ahead, the publication of this publicly funded protocol is important for researchers planning similar work.

International Registered Report Identifier (irrid): PRR1-10.2196/17436.
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http://dx.doi.org/10.2196/17436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857949PMC
January 2021

Stereotactic ablative body radiotherapy in patients with oligometastatic cancers: a prospective, registry-based, single-arm, observational, evaluation study.

Lancet Oncol 2021 01;22(1):98-106

The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London, UK.

Background: Stereotactic ablative body radiotherapy (SABR) is increasingly being used to treat oligometastatic cancers, but high-level evidence to provide a basis for policy making is scarce. Additional evidence from a real-world setting is required. We present the results of a national study of patients with extracranial oligometastases undergoing SABR, representing the largest dataset, to our knowledge, on outcomes in this population so far.

Methods: In 2015, National Health Service (NHS) England launched a Commissioning through Evaluation scheme that funded a prospective, registry-based, single-arm, observational, evaluation study of patients with solid cancer and extracranial oligometastases treated with SABR. Prescribed doses ranged from 24-60 Gy administered in three to eight fractions. The study was done at 17 NHS radiotherapy centres in England. Patients were eligible for the scheme if aged 18 years or older with confirmed primary carcinoma (excluding haematological malignancies), one to three extracranial metastatic lesions, a disease-free interval from primary tumour development to metastases of longer than 6 months (with the exception of synchronous colorectal liver metastases), a WHO performance status of 2 or lower, and a life expectancy of at least 6 months. The primary outcome was overall survival at 1 year and 2 years from the start of SABR treatment. The study is now completed.

Findings: Between June 15, 2015, and Jan 30, 2019, 1422 patients were recruited from 17 hospitals in England. The median age of the patients was 69 years (IQR 62-76), and the most common primary tumour was prostate cancer (406 [28·6%] patients). Median follow-up was 13 months (IQR 6-23). Overall survival was 92·3% (95% CI 90·5-93·9) at 1 year and 79·2% (76·0-82·1) at 2 years. The most common grade 3 adverse event was fatigue (28 [2·0%] of 1422 patients) and the most common serious (grade 4) event was increased liver enzymes (nine [0·6%]). Notreatment-related deaths were reported.

Interpretation: In patients with extracranial oligometastatic cancer, use of SABR was associated with high overall survival and low toxicity. 'The study findings complement existing evidence from a randomised, phase 2 trial, and represent high-level, real-world evidence supporting the use of SABR in this patient cohort, with a phase 3 randomised, controlled trial to confirm these findings underway. Based on the selection criteria in this study, SABR was commissioned by NHS England in March, 2020, as a treatment option for patients with oligometastatic disease.

Funding: NHS England Commissioning through Evaluation scheme.
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http://dx.doi.org/10.1016/S1470-2045(20)30537-4DOI Listing
January 2021

Selective dorsal rhizotomy; evidence on cost-effectiveness from England.

PLoS One 2020 10;15(8):e0236783. Epub 2020 Aug 10.

King's Technology Evaluation Centre, School of Biomedical Engineering & Imaging Sciences, King's College London, London, United Kingdom.

Objectives: Selective dorsal rhizotomy (SDR) has gained interest as an intervention to reduce spasticity and pain, and improve quality of life and mobility in children with cerebral palsy mainly affecting the legs (diplegia). We evaluated the cost-effectiveness of SDR in England.

Methods: Cost-effectiveness was quantified with respect to Gross Motor Function Measure (GMFM-66) and the pain dimension of the Cerebral Palsy Quality of Life questionnaire for Children (CPQOL-Child). Data on outcomes following SDR over two years were drawn from a national evaluation in England which included 137 children, mean age 6.6 years at surgery. The incremental impact of SDR on GMFM-66 was determined through comparison with data from a historic Canadian cohort not undergoing SDR. Another single centre provided data on hospital care over ten years for 15 children undergoing SDR at a mean age of 7.0 years, and a comparable cohort managed without SDR. The incremental impact of SDR on pain was determined using a before and after comparison using data from the national evaluation. Missing data were imputed using multiple imputation. Incremental costs of SDR were determined as the difference in costs over 5 years for the patients undergoing SDR and those managed without SDR. Uncertainty was quantified using bootstrapping and reported as the cost-effectiveness acceptability curve.

Results: In the base case, the incremental cost-effectiveness ratios (ICERs) for SDR are £1,382 and £903 with respect to a unit improvement in GMFM-66 and the pain dimension of CPQOL-Child, respectively. Inclusion of data to 10 years indicates SDR is cheaper than management without SDR. Incremental costs and ICERs for SDR rose in sensitivity analysis applying an alternative regression model to cost data.

Conclusions: Data on outcomes from a large observational study of SDR and long-term cost data on children who did and did not receive SDR indicates SDR is cost-effective.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236783PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416930PMC
October 2020

Diarrhoeal disease and subsequent risk of death in infants and children residing in low-income and middle-income countries: analysis of the GEMS case-control study and 12-month GEMS-1A follow-on study.

Lancet Glob Health 2020 02 18;8(2):e204-e214. Epub 2019 Dec 18.

Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine, Banjul, The Gambia.

Background: The Global Enteric Multicenter Study (GEMS) was a 3-year case-control study that measured the burden, aetiology, and consequences of moderate-to-severe diarrhoea (MSD) in children aged 0-59 months. GEMS-1A, a 12-month follow-on study, comprised two parallel case-control studies, one assessing MSD and the other less-severe diarrhoea (LSD). In this report, we analyse the risk of death with each diarrhoea type and the specific pathogens associated with fatal outcomes.

Methods: GEMS was a prospective, age-stratified, matched case-control study done at seven sites in Africa and Asia. Children aged 0-59 months with MSD seeking care at sentinel health centres were recruited along with one to three randomly selected matched community control children without diarrhoea. In the 12-month GEMS-1A follow-on study, children with LSD and matched controls, in addition to children with MSD and matched controls, were recruited at six of the seven sites; only cases of MSD and controls were enrolled at the seventh site. We compared risk of death during the period between enrolment and one follow-up household visit done about 60 days later (range 50-90 days) in children with MSD and LSD and in their respective controls. Approximately 50 pathogens were detected using, as appropriate, classic bacteriology, immunoassays, gel-based PCR and reverse transcriptase PCR, and quantitative real-time PCR (qPCR). Specimens from a subset of GEMS cases and controls were also tested by a TaqMan Array Card that compartmentalised probe-based qPCR for 32 enteropathogens.

Findings: 223 (2·0%) of 11 108 children with MSD and 43 (0·3%) of 16 369 matched controls died between study enrolment and the follow-up visit at about 60 days (hazard ratio [HR] 8·16, 95% CI 5·69-11·68, p<0·0001). 12 (0·4%) of 2962 children with LSD and seven (0·2%) of 4074 matched controls died during the follow-up period (HR 2·78, 95% CI 0·95-8·11, p=0·061). Risk of death was lower in children with dysenteric MSD than in children with non-dysenteric MSD (HR 0·20, 95% CI 0·05-0·87, p=0·032), and lower in children with LSD than in those with non-dysenteric MSD (HR 0·29, 0·14-0·59, p=0·0006). In children younger than 24 months with MSD, infection with typical enteropathogenic Escherichia coli, enterotoxigenic E coli encoding heat-stable toxin, enteroaggregative E coli, Shigella spp (non-dysentery cases), Aeromonas spp, Cryptosporidium spp, and Entamoeba histolytica increased risk of death. Of 61 deaths in children aged 12-59 months with non-dysenteric MSD, 31 occurred among 942 children qPCR-positive for Shigella spp and 30 deaths occurred in 1384 qPCR-negative children (HR 2·2, 95% CI 1·2-3·9, p=0·0090), showing that Shigella was strongly associated with increased risk of death.

Interpretation: Risk of death is increased following MSD and, to a lesser extent, LSD. Considering there are approximately three times more cases of LSD than MSD in the population, more deaths are expected among children with LSD than in those with MSD. Because the major attributable LSD-associated and MSD-associated pathogens are the same, implementing vaccines and rapid diagnosis and treatment interventions against these major pathogens are rational investments.

Funding: Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S2214-109X(19)30541-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025325PMC
February 2020

Inherited Melanoma Risk Variants Associated with Histopathologically Amelanotic Melanoma.

J Invest Dermatol 2020 04 27;140(4):918-922.e7. Epub 2019 Sep 27.

Department of Dermatology, University of North Carolina, Chapel Hill, North Carolina; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2019.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093215PMC
April 2020

Selective dorsal rhizotomy in ambulant children with cerebral palsy: an observational cohort study.

Lancet Child Adolesc Health 2019 07 30;3(7):455-462. Epub 2019 Apr 30.

School of Population Health and Environmental Sciences, King's College London, London, UK.

Background: Selective dorsal rhizotomy (SDR) is an irreversible surgical procedure involving the division of selected sensory nerve roots, followed by intensive physiotherapy. The aim is to improve function and quality of life in children with cerebral palsy and a Gross Motor Function Classification System (GMFCS) level of II or III (walks with or without assistive devices, respectively). We assessed gross motor function before and after SDR and postoperative quality of life in a study commissioned by NHS England.

Methods: We did a prospective observational study in five hospitals in England who were commissioned to perform SDR on children aged 3-9 years with spastic diplegic cerebral palsy. The primary outcome was score changes in the 66-item Gross Motor Function Measure (GMFM-66) and seven domains of the Cerebral Palsy Quality of Life Questionnaire ([CP-QoL] social wellbeing and acceptance, feelings about functioning, participation and physical health, emotional wellbeing and self-esteem, access to services, family health, and pain and impact of disability) from before to 24 months after SDR.

Findings: From Sept 4, 2014, to March 21, 2016, 137 children underwent SDR. The mean age was 6·0 years (SD 1·8). The mean GMFM-66 score increased after SDR with an annual change of 3·2 units (95% CI 2·9 to 3·5, n=137). Of the seven CP-QoL domains, five showed significant improvements over time: feelings about functioning mean annual change 3·0 units (95% CI 2·0 to 4·0, n=133), participation and physical health 3·9 units (2·5 to 5·3, n=133), emotional wellbeing and self-esteem 1·3 units (0·2 to 2·3, n=133), family health 2·0 units (0·7 to 3·3, n=132), and pain and impact of disability -2·5 units (-3·9 to -1·2, n=133). 17 adverse events were reported in 15 children, of which none were severe and 15 (88%) resolved.

Interpretation: SDR improved function and quality of life in the 24 months after surgery in children with cerebral palsy classified as GMFCS levels II and III. On the basis of these findings, an interim national policy decision was made that SDR would be funded for eligible children in England from 2018.

Funding: National Institute for Health and Care Excellence, National Institute for Health Research Biomedical Research Centre, NHS England.
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http://dx.doi.org/10.1016/S2352-4642(19)30119-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153769PMC
July 2019

Socioeconomic deprivation and inequalities in lung cancer: time to delve deeper?

Authors:
Helen A Powell

Thorax 2019 01 31;74(1):11-12. Epub 2018 Oct 31.

Thoracic Medicine, Frimley Park Hospital, Frimley Health NHS Foundation Trust, Frimley.

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http://dx.doi.org/10.1136/thoraxjnl-2018-212362DOI Listing
January 2019

Outcomes for Invasive Melanomas Treated With Mohs Micrographic Surgery: A Retrospective Cohort Study.

Dermatol Surg 2019 02;45(2):223-228

Department of Dermatology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina.

Background: Mohs micrographic surgery (MMS) has been used effectively to treat invasive melanoma.

Objective: To further study the safety and efficacy of MMS in the treatment of invasive melanoma.

Methods And Materials: A retrospective cohort study evaluated 123 melanomas excised using MMS with MART-1 immunostain. Local recurrence, metastasis, overall survival, and disease-free survival rates were calculated. These were compared with historical controls.

Results: Among included patients, 78 were men (63%) and 45 were women (37%), with a mean age of 66.48 years. Mean follow-up time was 1,273 days (3.49 years). Local recurrence was identified in 2/123 (1.63%; 95% confidence interval, 0.20%-5.75%) lesions. Local recurrence was identified in 1/70 (1.43%; 95% confidence interval, 0.04%-7.70%) of head and neck cases. Tumor location was head and neck in 70 lesions (56.9%). Overall survival was 95.12% and disease-specific survival was 100%.

Conclusion: Mohs micrographic surgery is an effective treatment method for invasive melanoma, as evidenced by low recurrence rates and high rates of disease-free survival.
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http://dx.doi.org/10.1097/DSS.0000000000001658DOI Listing
February 2019

Occupational and Hand Dermatitis: a Practical Approach.

Clin Rev Allergy Immunol 2019 Feb;56(1):60-71

University of North Carolina School of Medicine, 321 S Columbia Street, Chapel Hill, NC, 27516, USA.

Occupational skin disease is common. It affects workers more often than reported. Contact dermatitis, both irritant and allergic, accounts for the majority of occupational skin diagnoses. Occupational contact dermatitis (OCD) frequently affects the hands and may have a profound impact on an employee's ability to perform a job. Severe OCD can affect a worker's activities of daily living and can even lead to job loss. Numerous irritants have been described in the workplace, from the common (wet work) to the more obscure (warm, dry air). Several contact allergens may be work-related, and the majority of established occupational allergens are also known nonoccupational allergens. Emerging occupational allergens are continually described in the literature. Patch testing is the gold standard for the workup of allergic contact dermatitis. Patch testing in the setting of OCD may require extended or unique allergen trays, as well as a thorough occupational history and collection of workplace Material Safety Data Sheets (MSDS). These MSDS contain valuable information but may not be complete or accurate. Proof of occupational causation can be aided by employing the Mathias criteria. Certain industries and occupations are associated with higher rates of OCD, and as expected, the industries with direct contact with irritants and allergens are highly represented. The differential diagnosis for occupational dermatitis is broad and should be considered when evaluating an employee with suspected OCD. Some other diagnoses to consider include atopic dermatitis, psoriasis, and manifestations of internal disease, as well as an overlap syndrome of more than one diagnosis. OCD treatment should ideally follow the public health hazard controls' stepwise approach. Prevention and early intervention are key to promoting occupational health and preventing OCD. Multidisciplinary teams have been successful in the treatment of OCD, and newly described topical treatments may provide additional modalities for use in the occupational setting.
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http://dx.doi.org/10.1007/s12016-018-8706-zDOI Listing
February 2019

Squamous cell carcinoma arising in a chronic perineal wound in a patient with long-standing cutaneous Crohn's disease.

JAAD Case Rep 2018 May 4;4(4):346-348. Epub 2018 Apr 4.

Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

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http://dx.doi.org/10.1016/j.jdcr.2017.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911976PMC
May 2018

Medicare Part D payments for brand and generic drugs prescribed by dermatologists.

J Am Acad Dermatol 2018 Sep 1;79(3):575-577. Epub 2018 Mar 1.

Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Cecil G. Sheps Center for Health Services Research, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2018.02.041DOI Listing
September 2018

Treatment recommendations for stage I non-small cell lung cancer: does patient preference matter?

Ann Transl Med 2017 Oct;5(20):411

Department of Respiratory Medicine, David Evans Building, Nottingham University Hospitals NHS Trust, Nottingham, UK.

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http://dx.doi.org/10.21037/atm.2017.08.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673782PMC
October 2017

Exome sequences versus sequential gene testing in the UK highly specialised Service for Limb Girdle Muscular Dystrophy.

Orphanet J Rare Dis 2017 09 6;12(1):151. Epub 2017 Sep 6.

The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.

Background: Limb girdle muscular dystrophies are a group of rare and genetically heterogeneous diseases that share proximal weakness as a common feature; however they are often lacking very specific phenotypic features to allow an accurate differential diagnosis based on the clinical signs only, limiting the diagnostic rate using phenotype driven genetic testing. Next generation sequencing provides an opportunity to obtain molecular diagnoses for undiagnosed patients, as well as identifying novel genetic causes of muscle diseases. We performed whole exome sequencing (WES) on 104 affected individuals from 75 families in who standard gene by gene testing had not yielded a diagnosis. For comparison we also evaluated the diagnostic rate using sequential gene by gene testing for 91 affected individuals from 84 families over a 2 year period.

Results: Patients selected for WES had undergone more extensive prior testing than those undergoing standard genetic testing and on average had had 8 genes screened already. In this extensively investigated cohort WES identified the genetic diagnosis in 28 families (28/75, 37%), including the identification of the novel gene ZAK and two unpublished genes. WES of a single affected individual with sporadic disease yielded a diagnosis in 13/38 (34%) of cases. In comparison, conventional gene by gene testing provided a genetic diagnosis in 28/84 (33%) families. Titinopathies and collagen VI related dystrophy were the most frequent diagnoses made by WES. Reasons why mutations in known genes were not identified previously included atypical phenotypes, reassignment of pathogenicity of variants, and in one individual mosaicism for a COL6A1 mutation which was undetected by prior direct sequencing.

Conclusion: WES was able to overcome many limitations of standard testing and achieved a higher rate of diagnosis than standard testing even in this cohort of extensively investigated patients. Earlier application of WES is therefore likely to yield an even higher diagnostic rate. We obtained a high diagnosis rate in simplex cases and therefore such individuals should be included in exome or genome sequencing projects. Disease due to somatic mosaicism may be increasingly recognised due to the increased sensitivity of next generation sequencing techniques to detect low level mosaicism.
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http://dx.doi.org/10.1186/s13023-017-0699-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5588739PMC
September 2017

Novel variants associated with late-onset de novo status epilepticus and progressive ataxia.

Neurol Genet 2017 Oct 9;3(5):e181. Epub 2017 Aug 9.

Wellcome Centre for Mitochondrial Research (Y.S.N., H.P., D.M.T., R.W.T.), Institute of Neuroscience, Newcastle University, Newcastle upon Tyne; and Sheffield Teaching Hospitals NHS Trust and University of Sheffield (N.H., M.H.), Royal Hallamshire Hospital, Sheffield, United Kingdom.

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http://dx.doi.org/10.1212/NXG.0000000000000181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550380PMC
October 2017

Resectable Clinical N2 Non-Small Cell Lung Cancer; What Is the Optimal Treatment Strategy? An Update by the British Thoracic Society Lung Cancer Specialist Advisory Group.

J Thorac Oncol 2017 09 15;12(9):1434-1441. Epub 2017 Jun 15.

Department of Respiratory Medicine, University Hospitals Birmingham National Health Service Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.

Patients and clinicians are faced with uncertainty as to the optimal treatment strategy for potentially resectable NSCLC in which there is clinical evidence of involvement of the ipsilateral mediastinum. Randomized controlled trials and meta-analyses have failed to demonstrate superiority of one bimodality strategy over another (chemotherapy plus surgery versus chemotherapy plus radiotherapy). One trial of trimodality treatment with chemotherapy, radiotherapy, and surgery demonstrated an improvement in progression-free, but not overall, survival versus chemotherapy and radiotherapy. There are a number of limitations to the data in this complex and heterogenous patient group. No randomized controlled trial has specifically studied patients with single-station N2 disease versus multistation N2 disease. When discussing treatment for fit patients with potentially resectable cN2 NSCLC, lung cancer teams should consider trimodality treatment with chemotherapy, radiotherapy, and surgery or bimodality treatment with chemotherapy and either surgery or radiotherapy. We advocate that all patients see both a thoracic surgeon and the oncology team to discuss these different approaches.
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http://dx.doi.org/10.1016/j.jtho.2017.05.023DOI Listing
September 2017

Risk of venous thromboembolism in people with lung cancer: a cohort study using linked UK healthcare data.

Br J Cancer 2016 06 2;115(1):115-21. Epub 2016 Jun 2.

Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, UK.

Background: Venous thromboembolism (VTE) is a potentially preventable cause of death in people with lung cancer. Identification of those most at risk and high-risk periods may provide the opportunity for better targeted intervention.

Methods: We conducted a cohort study using the Clinical Practice Research Datalink linked to Hospital Episode Statistics and Cancer Registry data. Our cohort comprises 10 598 people with lung cancer diagnosed between 1997 and 2006 with follow-up continuing to the end of 2010. Cox regression analysis was performed to determine which demographic, tumour and treatment-related factors (time-varying effects of chemotherapy and surgery) independently affected VTE risk. We also determined the effect of a VTE diagnosis on the survival of people with lung cancer.

Results: People with lung cancer had an overall VTE incidence of 39.2 per 1000 person-years (95% confidence interval (CI), 35.4-43.5), though rates varied depending on the patient group and treatment course. Independent factors associated with increased VTE risk were metastatic disease (hazard ratio (HR)=1.9, CI 1.2-3.0 vs local disease); adenocarcinoma subtype (HR=2.0, CI 1.5-2.7, vs squamous cell; chemotherapy administration (HR=2.1, CI 1.4-3.0 vs outside chemotherapy courses); and diagnosis via emergency hospital admission (HR=1.7, CI 1.2-2.3 vs other routes to diagnosis). Patients with VTE had an approximately 50% higher risk of mortality than those without VTE.

Conclusions: People with lung cancer have especially high risk of VTE if they have advanced disease, adenocarcinoma or are undergoing chemotherapy. The presence of VTE is an independent risk factor for death.
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http://dx.doi.org/10.1038/bjc.2016.143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931366PMC
June 2016

Predicting death from surgery for lung cancer: A comparison of two scoring systems in two European countries.

Lung Cancer 2016 May 15;95:88-93. Epub 2016 Mar 15.

Division of Public Health and Epidemiology, Clinical Sciences Building, Nottingham City Campus, Hucknall Road, Nottingham NG5 1PB, United Kingdom.

Objectives: Current British guidelines advocate the use of risk prediction scores such as Thoracoscore to estimate mortality prior to radical surgery for non-small cell lung cancer (NSCLC). A recent publication used the National Lung Cancer Audit (NLCA) to produce a score to predict 90 day mortality (NLCA score). The aim of this study is to validate the NLCA score, and compare its performance with Thoracoscore.

Materials And Methods: We performed an internal validation using 2858 surgical patients from NLCA and an external validation using 3191 surgical patients from the Danish Lung Cancer Registry (DLCR). We calculated the proportion that died within 90 days of surgery. The discriminatory power of both scores was assessed by a receiver operating characteristic (ROC) and an area under the curve (AUC) calculation.

Results: Ninety day mortality was 5% in both groups. AUC values for internal and external validation of NLCA score and validation of Thoracoscore were 0.68 (95% CI 0.63-0.72), 0.60 (95% CI 0.56-0.65) and 0.60 (95% CI 0.54-0.66) respectively. Post-hoc analysis was performed using NLCA records on 15554 surgical patients to derive summary tables for 30 and 90 day mortality, stratified by procedure type, age and performance status.

Conclusions: Neither score performs well enough to be advocated for individual risk stratification prior to lung cancer surgery. It may be that additional physiological parameters are required; however this is a further project. In the interim we propose the use of our summary tables that provide the real-life range of mortality for lobectomy and pneumonectomy.
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http://dx.doi.org/10.1016/j.lungcan.2016.03.002DOI Listing
May 2016

Determination of unbound fraction of pazopanib in vitro and in cancer patients reveals albumin as the main binding site.

Invest New Drugs 2016 Feb 16;34(1):41-8. Epub 2015 Nov 16.

Department of Pharmacology, Institut Claudius-Regaud, IUCT-Oncopole, 1, avenue Irène Joliot-Curie, Toulouse, F-31059, France.

Introduction: Pazopanib exhibits wide inter-patient pharmacokinetic variability which may contribute to differences in treatment outcome. Unbound drug concentrations are believed to be more relevant to pharmacological responses than total concentrations. Thus it is desirable to evaluate pazopanib binding on plasma proteins and different factors potentially affecting this process.

Methods: An equilibrium dialysis method coupled with UPLC-MS/MS assay has been optimized and validated for the determination of pazopanib unbound fraction (fu%) in human plasma. Pazopanib binding in the plasma of healthy volunteers and in isolated protein solutions was investigated. The unbound fraction was determined for 24 cancer patients treated daily with pazopanib.

Results: We found that pazopanib was extensively bound in human plasma (>99.9 %) with a mean fu% value of 0.0106 ± 0.0013 % at 40 μg/mL. Protein binding was concentration independent over a clinically relevant range of concentrations. In isolated protein solutions, pazopanib at 40 μg/mL was mainly bound to albumin (40 g/L) and to a lesser extent to α1-acid glycoprotein (1 g/L) and low density lipoproteins (1.2 g/L), with a mean fu% of 0.0073 ± 0.0022 %, 0.992 ± 0.44 % and 7.4 ± 1.7 % respectively. Inter-patient variability (CV%) of fu% in cancer patients was limited (27.2 %). A correlation was observed between individual unbound fraction values and albuminemia.

Conclusions: Pazopanib exhibits extensive binding to plasma proteins in human plasma. Variable albumin concentrations, frequently observed in cancer patients, may affect pazopanib unbound fraction with implications for inter-patient variability in drug efficacy and toxicity.
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http://dx.doi.org/10.1007/s10637-015-0304-9DOI Listing
February 2016

Primary CNS lymphoproliferative disease, mycophenolate and calcineurin inhibitor usage.

Oncotarget 2015 Oct;6(32):33849-66

Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Immunosuppression for solid organ transplantation increases lymphoproliferative disease risk. While central nervous system (CNS) involvement is more rare, we noticed an increase in primary CNS (PCNS) disease. To investigate a potential association with the immunosuppressive regimen we identified all post-transplant lymphoproliferative disease (PTLD) cases diagnosed over a 28-year period at our institution (174 total, 29 PCNS) and all similar cases recorded in a United Network for Organ Sharing-Organ Procurement and Transplant Network (UNOS-OPTN) datafile. While no PCNS cases were diagnosed at our institution between 1986 and 1997, they comprised 37% of PTLD cases diagnosed from 2011-2014. PCNS disease was more often associated with renal vs. other organ transplant, Epstein-Barr virus, large B-cell morphology and mycophenolate mofetil (MMF) as compared to PTLD that did not involve the CNS. Calcineurin inhibitors were protective against PCNS disease when given alone or in combination with MMF. A multivariate analysis of a larger UNOS-OPTN dataset confirmed these findings, where both MMF and lack of calcineurin inhibitor usage were independently associated with risk for development of PCNS PTLD. These findings have significant implications for the transplant community, particularly given the introduction of new regimens lacking calcineurin inhibitors. Further investigation into these associations is warranted.
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http://dx.doi.org/10.18632/oncotarget.5292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741807PMC
October 2015

Ambient Coarse Particulate Matter and Hospital Admissions in the Medicare Cohort Air Pollution Study, 1999-2010.

Environ Health Perspect 2015 Nov 14;123(11):1152-8. Epub 2015 Apr 14.

Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

Background: In recent years a number of studies have examined the short-term association between coarse particulate matter (PM(10-2.5)) and mortality and morbidity outcomes. These studies, however, have produced inconsistent conclusions.

Objectives: We estimated both the national- and regional-level associations between PM(10-2.5) and emergency hospitalizations for both cardiovascular and respiratory disease among Medicare enrollees ≥ 65 years of age during the 12-year period 1999 through 2010.

Methods: Using air pollution data obtained from the U.S. Environmental Protection Agency air quality monitoring network and daily emergency hospitalizations for 110 large urban U.S. counties assembled from the Medicare Cohort Air Pollution Study (MCAPS), we estimated the association between short-term exposure to PM(10-2.5) and hospitalizations using a two-stage Bayesian hierarchical model and Poisson log-linear regression models.

Results: A 10-μg/m3 increase in PM(10-2.5) was associated with a significant increase in same-day cardiovascular hospitalizations [0.69%; 95% posterior interval (PI): 0.45, 0.92]. After adjusting for PM2.5, this association remained significant (0.63%; 95% PI: 0.38, 0.88). A 10-μg/m3 increase in PM(10-2.5) was not associated with a significant increase in respiratory-related hospitalizations.

Conclusions: We found statistically significant evidence that daily variation in PM(10-2.5) is associated with emergency hospitalizations for cardiovascular diseases among Medicare enrollees ≥ 65 years of age. This association was robust to adjustment for concentrations of PM2.5.

Citation: Powell H, Krall JR, Wang Y, Bell ML, Peng RD. 2015. Ambient coarse particulate matter and hospital admissions in the Medicare Cohort Air Pollution Study, 1999-2010. Environ Health Perspect 123:1152-1158; http://dx.doi.org/10.1289/ehp.1408720.
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http://dx.doi.org/10.1289/ehp.1408720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4629736PMC
November 2015

Metabolism by conjugation appears to confer resistance to paracetamol (acetaminophen) hepatotoxicity in the cynomolgus monkey.

Xenobiotica 2015 Mar 22;45(3):270-7. Epub 2014 Oct 22.

Centre for Drug Safety and Research (CDSER), Shanghai Institute of Materia Medica (SIMM) , Pudong, Shanghai , PR China .

1. Paracetamol overdose remains the leading cause of acute liver failure in humans. This study was undertaken in cynomolgus monkeys to study the pharmacokinetics, metabolism and the potential for hepatotoxic insult from paracetamol administration as a possible model for human toxicity. 2. No adverse effects were observed for doses of up to 900 mg/kg/d for 14 d. Only minor sporadic increases in alanine aminotransferase, aspartate aminotransferase and glutamate dehydrogenase in a number of animals were observed, with no clear dose response. 3. Toxicokinetic analysis showed good plasma exposure, albeit with less than proportional rises in Cmax and AUC, with increasing dose. The Cmax values in monkey were up to 3.5 times those associated with human liver toxicity and the AUC approx. 1000 times those associated with liver enzyme changes in 31-44% of human subjects. 4. Metabolite profiling of urine by (1)H NMR spectroscopy revealed paracetamol and its glucuronide and sulphate metabolites. Glutathione-derived metabolites, e.g. the cysteinyl conjugate, were only present in very low concentrations whilst the mercapturate was not detected. 5. These in vivo observations demonstrated that the cynomolgus monkey is remarkably resistant to paracetamol-induced toxicity and a poor model for investigating paracetamol-related hepatotoxicity in humans.
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http://dx.doi.org/10.3109/00498254.2014.973000DOI Listing
March 2015

Venous thromboembolism in people with idiopathic pulmonary fibrosis: a population-based study.

Eur Respir J 2014 Dec 16;44(6):1714-5. Epub 2014 Oct 16.

Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK

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http://dx.doi.org/10.1183/09031936.00099614DOI Listing
December 2014
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