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Hewitt P.E.,National Health Service Blood and Transplant | Ijaz S.,Blood Borne Virus Unit | Brailsford S.R.,National Health Service Blood and Transplant | Brailsford S.R.,Public Health England | And 18 more authors.
The Lancet | Year: 2014

Findings 79 donors were viraemic with genotype 3 HEV, giving an RNA prevalence of one in 2848. Most viraemic donors were seronegative at the time of donation. The 79 donations had been used to prepare 129 blood components, 62 of which had been transfused before identification of the infected donation. Follow-up of 43 recipients showed 18 (42%) had evidence of infection. Absence of detectable antibody and high viral load in the donation rendered infection more likely. Recipient immunosuppression delayed or prevented seroconversion and extended the duration of viraemia. Three recipients cleared longstanding infection after intervention with ribavirin or alteration in immunosuppressive therapy. Ten recipients developed prolonged or persistent infection. Transaminitis was common, but short-term morbidity was rare; only one recipient developed apparent but clinically mild post-transfusion hepatitis.Interpretation Our findings suggest that HEV genotype 3 infections are widespread in the English population and in blood donors. Transfusion-transmitted infections rarely caused acute morbidity, but in some immunosuppressed patients became persistent. Although at present blood donations are not screened, an agreed policy is needed for the identification of patients with persistent HEV infection, irrespective of origin, so that they can be offered antiviral therapy. Funding Public Health England and National Health Service Blood and Transplant.Background The prevalence of hepatitis E virus (HEV) genotype 3 infections in the English population (including blood donors) is unknown, but is probably widespread, and the virus has been detected in pooled plasma products. HEV-infected donors have been retrospectively identified through investigation of reported cases of possible transfusion-transmitted hepatitis E. The frequency of HEV transmission by transfusion and its outcome remains unknown. We report the prevalence of HEV RNA in blood donations, the transmission of the virus through a range of blood components, and describe the resulting morbidity in the recipients.Methods From Oct 8, 2012, to Sept 30, 2013, 225 000 blood donations that were collected in southeast England were screened retrospectively for HEV RNA. Donations containing HEV were characterised by use of serology and genomic phylogeny. Recipients, who received any blood components from these donations, were identified and the outcome of exposure was ascertained. © 2014 Hewitt et al. Open Access article distributed under the terms of CC BY-NC-ND.

Greenrod E.B.,Moorfields Eye Hospital | Jones M.N.A.,National Health Service Blood and Transplant | Kaye S.,University of Liverpool | Larkin D.F.P.,Moorfields Eye Hospital
American Journal of Ophthalmology | Year: 2014

Purpose: To compare national outcomes of endothelial keratoplasty (EK) and penetrating keratoplasty (PK) during comparable 6-year periods.Design: Prospective cohort study of national registry data.Methods: Setting: United Kingdom National Transplant Registry, 2000 through 2011, inclusive. PATIENT POPULATION: All United Kingdom patients undergoing first EK (n = 2074) for Fuchs endothelial dystrophy or pseudophakic bullous keratopathy from January 2006 through December 2011. Comparison cohort of patients undergoing first PK (n = 2622, same indications, January 2000 through December 2005).Observation Procedure: Year of surgery, surgeon and center experience, corneal diagnosis, donor factors, patient factors, and surgical risk factors were analyzed against graft survival and visual outcomes.Results: For both Fuchs endothelial dystrophy and pseudophakic bullous keratopathy, EK achieved better average best-corrected acuity and lower refractive error. For both groups, graft failure was significantly higher for EK than PK. EK failure in Fuchs endothelial dystrophy was associated with center experience (hazard ratio [HR], 2.3; P < .0001), donor endothelial density (HR, 1.8; P = .01), glaucoma at time of surgery (HR, 2.1; P = .003), and donor age older than 75 years (HR, 1.3; P = .05). EK failure in pseudophakic bullous keratopathy was associated with center experience of fewer than 15 cases (HR, 2.0; P <.0001) and glaucoma at time of surgery (HR, 1.7; P = .002).Conclusion: Prospective national registry data for EK showed higher graft failure than is seen in PK or in retrospective case series of EK. Higher failure rates may be acceptable given established benefits of the procedure, including lower refractive error, structural globe integrity, and faster visual recovery. Center experience influenced EK survival more than surgeon experience, and overall surgical outcomes may be improved by standardized techniques and support within experienced units. © 2014 by Elsevier Inc. All rights reserved.

Summers D.M.,University of Cambridge | Summers D.M.,National Health Research Institute | Summers D.M.,National Health Service Blood and Transplant | Johnson R.J.,National Health Service Blood and Transplant | And 6 more authors.
The Lancet | Year: 2013

Background Use of kidneys donated after controlled circulatory death has increased the number of transplants undertaken in the UK but there remains reluctance to use kidneys from older circulatory-death donors and concern that kidneys from circulatory-death donors are particularly susceptible to cold ischaemic injury. We aimed to compare the effect of donor age and cold ischaemic time on transplant outcome in kidneys donated after circulatory death versus brain death. Methods We used the UK transplant registry to select a cohort of first-time recipients (aged.18 years) of deceaseddonor kidneys for transplantations done between Jan 1, 2005, and Nov 1, 2010. We did univariate comparisons of transplants from brain-death donors versus circulatory-death donors with -Ô2 tests for categorical data and Wilcoxon tests for non-parametric continuous data. We used Kaplan-Meier curves to show graft survival. We used Cox proportional hazards regression to adjust for donor and recipient factors associated with graft-survival with tests for interaction effects to establish the relative effect of donor age and cold ischaemia on kidneys from circulatory-death and brain-death donors. Findings 6490 deceased-donor kidney transplants were done at 23 centres. 3 year graft survival showed no difference between circulatory-death (n=1768) and brain-death (n=4127) groups (HR 1.14, 95% CI, p=0.16). Donor age older than 60 years (compared with <40 years) was associated with an increased risk of graft loss for all deceaseddonor kidneys (2.35,, p<0.0001) but there was no increased risk of graft loss for circulatory-death donors older than 60 years compared with brain-death donors in the same age group (p=0.30). Prolonged cold ischaemic time (>24 h vs <12 h) was not associated with decreased graft survival for all deceased-donor kidneys but was associated with poorer graft survival for kidneys from circulatory-death donors than for those from brain-death donors (2.36,, p for interaction=0.004). Interpretation Kidneys from older circulatory-death donors have equivalent graft survival to kidneys from brain-death donors in the same age group, and are acceptable for transplantation. However, circulatory-death donor kidneys tolerate cold storage less well than do brain-death donor kidneys and this finding should be considered when developing organ allocation policy. Funding UK National Health Service Blood and Transplant; Cambridge National Institute for Health Research Biomedical Research Centre.

Desai R.,National Health Service Blood and Transplant | Collett D.,National Health Service Blood and Transplant | Watson C.J.,National Health Research Institute | Johnson P.,University of Birmingham | And 2 more authors.
Transplantation | Year: 2012

Background: Donor origin cancer (DOC) in transplant recipients may be transmitted with the graft (donor-transmitted cancer [DTC]) or develop subsequently from the graft (donor-derived cancer [DDC]). Methods: Recipients with DOC between January 1, 2001, and December 31, 2010, were identified from the United Kingdom Transplant Registry and database search at transplantation centers. Results: Of 30,765 transplants from 14,986 donors, 18 recipients developed DOC from 16 donors (0.06%): 3 were DDC (0.01%) and 15 were DTC (0.05%). Of the 15 DTCs, 6 were renal cell cancer; 5, lung cancer; 2, lymphoma; 1, neuroendocrine cancer; and 1, colon cancer. Recipients with DTC underwent explant/excision (11), chemotherapy (4), and radiotherapy (1). Of 15 recipients, 3 (20%) recipients with DTC died as a direct consequence of cancer. Early DTC (diagnosed ≤6 weeks of transplantation) showed a better outcome (no DTC-related deaths in 11 cases) as opposed to late DTC (DTC-related deaths in 3 of 4 cases). Five-year survival was 83% for kidney recipients with DTC compared with 93% for recipients without DTC (P=0.077). None of the donors resulting in cancer transmission was known to have cancer at donation. Conclusions: DTC is rare but frequently results in graft loss and death. The risk of cancer transmission cannot be eliminated because, in every case, the presence of cancer was not known at donation. This information will allow informed consent for prospective recipients. Explantation/excision is likely to benefit recipients with localized cancer, but in transplants other than kidney/pancreas, the benefits should be balanced against the risks of retransplantation. © 2012 Lippincott Williams & Wilkins.

Abu-Jamous B.,University of Liverpool | Fa R.,University of Liverpool | Roberts D.J.,National Health Service Blood and Transplant | Roberts D.J.,University of Oxford | And 2 more authors.
PLoS ONE | Year: 2013

Clustering analysis has a growing role in the study of co-expressed genes for gene discovery. Conventional binary and fuzzy clustering do not embrace the biological reality that some genes may be irrelevant for a problem and not be assigned to a cluster, while other genes may participate in several biological functions and should simultaneously belong to multiple clusters. Also, these algorithms cannot generate tight clusters that focus on their cores or wide clusters that overlap and contain all possibly relevant genes. In this paper, a new clustering paradigm is proposed. In this paradigm, all three eventualities of a gene being exclusively assigned to a single cluster, being assigned to multiple clusters, and being not assigned to any cluster are possible. These possibilities are realised through the primary novelty of the introduction of tunable binarization techniques. Results from multiple clustering experiments are aggregated to generate one fuzzy consensus partition matrix (CoPaM), which is then binarized to obtain the final binary partitions. This is referred to as Binarization of Consensus Partition Matrices (Bi-CoPaM). The method has been tested with a set of synthetic datasets and a set of five real yeast cell-cycle datasets. The results demonstrate its validity in generating relevant tight, wide, and complementary clusters that can meet requirements of different gene discovery studies. © 2013 Abu-Jamous et al.

Williamson L.M.,National Health Service Blood and Transplant | Devine D.V.,Center for Blood Research
The Lancet | Year: 2013

Although blood suppliers are seeing short-term reductions in blood demand as a result of initiatives in patient blood management, modelling suggests that during the next 5-10 years, blood availability in developed countries will need to increase again to meet the demands of ageing populations. Increasing of the blood supply raises many challenges; new approaches to recruitment and retainment of future generations of blood donors will be needed, and care will be necessary to avoid taking too much blood from these donors. Integrated approaches in blood stock management between transfusion services and hospitals will be important to minimise wastage - eg, by use of supply chain solutions from industry. Cross-disciplinary systems for patient blood management need to be developed to lessen the need for transfusion - eg, by early identification and reversal of anaemia with haematinics or by reversal of the underlying cause. Personalised medicine could be applied to match donors to patients, not only with extended blood typing, but also by using genetically determined storage characteristics of blood components. Growing of red cells or platelets in large quantities from stem cells is a possibility in the future, but challenges of cost, scaling up, and reproducibility remain to be solved.

Abu-Jamous B.,University of Liverpool | Fa R.,University of Liverpool | Roberts D.J.,National Health Service Blood and Transplant | Roberts D.J.,University of Oxford | And 2 more authors.
Journal of the Royal Society Interface | Year: 2013

The binarization of consensus partition matrices (Bi-CoPaM) method has, among its unique features, the ability to perform ensemble clustering over the same set of genes from multiple microarray datasets by using various clustering methods in order to generate tunable tight clusters. Therefore, we have used the Bi-CoPaM method to the most synchronized 500 cell-cycle-regulated yeast genes from different microarray datasets to produce four tight, specific and exclusive clusters of co-expressed genes. We found 19 genes formed the tightest of the four clusters and this included the gene CMR1/YDL156W, which was an uncharacterized gene at the time of our investigations. Two very recent proteomic and biochemical studies have independently revealed many facets of CMR1 protein, although the precise functions of the protein remain to be elucidated. Our computational results complement these biological results and add more evidence to their recent findings of CMR1 as potentially participating in many of the DNA-metabolism processes such as replication, repair and transcription. Interestingly, our results demonstrate the close co-expressions of CMR1 and the replication protein A (RPA), the cohesion complex and the DNA polymerases α, δ and ε, as well as suggest functional relationships between CMR1 and the respective proteins. In addition, the analysis provides further substantial evidence that the expression of the CMR1 gene could be regulated by theMBF complex. In summary, the application of a novel analytic technique in large biological datasets has provided supporting evidence for a gene of previously unknown function, further hypotheses to test, and a more general demonstration of the value of sophisticated methods to explore new large datasets now so readily generated in biological experiments. © 2013 The Authors.

Mahgoub S.,Laboratory of Virology | Candotti D.,National Health Service Blood and Transplant | El Ekiaby M.,Shabrawishi Hospital Blood Bank | Allain J.-P.,University of Cambridge
Journal of Clinical Microbiology | Year: 2011

Sudan is a highly endemic area for hepatitis B virus (HBV), and >5% of blood donors are chronically infected. To examine potential strategies to improve HBV blood safety, 404 replacement donor samples previously screened for HBV surface antigen (HBsAg) were tested for antibody to HBV core (anti-HBc), anti-surface antigen (anti-HBs), and HBV DNA. Of 145 anti-HBc-containing samples (36%) identified, 16 retested were HBsAg positive (11%). Anti-HBs was detected in 43/77 (56%) anti-HBc-reactive samples. Six samples were HBsAg -/anti-HBc+/anti-HBs+ and contained HBV DNA, meeting the definition of occult HBV infection (OBI). OBIs had low HBV DNA loads (<10 IU/ml) and were genotype B (n = 1) or genotype D (n = 5). Pre-S/S and/or whole genome sequences were obtained from 47 randomly selected HBsAg-positive donors added to the previous 16. Genotype E was identified in 27 strains (57.5%), genotype D in 19 strains (40.5%), and genotype A2 in 1 strain (2%). Two outlier strains within genotype D ultimately were identified as recombinants of genotypes D and E with identical recombination points, suggesting circulating, infectious, recombinant strains. Anti-HBc screening does not appear to be a sustainable blood safety strategy because of the cost and the negative impact on the Sudanese blood supply, even when reduced by anti-HBs testing. Being at the junction between two main African HBV genotypes, genetic recombination occurred and became part of the molecular epidemiology of HBV in Sudan. Copyright © 2011, American Society for Microbiology. All Rights Reserved.

Keenan T.D.L.,University of Manchester | Keenan T.D.L.,Manchester Royal Eye Hospital | Jones M.N.A.,National Health Service Blood and Transplant | Rushton S.,National Health Service Blood and Transplant | Carley F.M.,Manchester Royal Eye Hospital
Archives of Ophthalmology | Year: 2012

Objective: To examine trends in the indications for corneal graft surgery in the United Kingdom. Methods: National Health Service Blood and Transplant data were analyzed for keratoplasty operations performed in the United Kingdom between April 1, 1999, and March 31, 2009, distinguishing the type of graft and the surgical indication. Results: The total number of annual keratoplasty operations increased from 2090 in 1999-2000 to 2511 in 2008-2009. Among these, the annual number of grafts performed for endothelial failure increased from 743 (35.6%) in 1999-2000 to 939 (37.4%) in 2008-2009. The performance of penetrating keratoplasty (PK) for endothelial failure decreased from 98.3% of all grafts in 1999-2000 to 46.6% of all grafts in 2008-2009, while the performance of endothelial keratoplasty increased from 0.3% of all grafts in 1999-2000 to 51.2% of all grafts in 2008-2009. The annual number of grafts performed for keratoconus increased from 514 (24.6%) in 1999 to 564 (22.5%) in 2008-2009. The performance of PK for keratoconus decreased from 88.4% of all grafts in 1999- 2000 to 57.1% of all grafts in 2008-2009, while the performance of deep anterior lamellar keratoplasty increased from 8.8% of all grafts in 1999-2000 to 40.1% of all grafts in 2008-2009. The number of annual regraft operations increased from 249 (11.9%) in 1999-2000 to 401 (16.0%) in 2008-2009, most commonly for endothelial failure. In 2008-2009, PK regrafts (78.1%) far outnumbered endothelial keratoplasty regrafts (17.0%). Conclusions: Endothelial failure is the most common indication for keratoplasty in the United Kingdom, and endothelial keratoplasty is performed more commonly than PK for this indication. The number of grafts performed for pseudophakic bullous keratopathy has remained stable, while the number of grafts performed for Fuchs endothelial dystrophy is likely to continue increasing. Keratoconus is the second most common indication for keratoplasty, and deep anterior lamellar keratoplasty numbers are approaching those for PK. Regraft surgery is the third most common indication for keratoplasty, required in most cases because of endothelial failure.

Enjalbert F.,University of Cambridge | Krysztof D.E.,Red Cross | Candotti D.,Red Cross | Candotti D.,National Health Service Blood and Transplant | And 2 more authors.
Transfusion | Year: 2014

Background Sensitive triplex nucleic acid tests (NATs) are implemented for blood donation screening worldwide. Assays have variable ability to detect low-level hepatitis B virus (HBV) DNA. At borderline DNA detection levels, where Poisson distribution impacts results, distinguishing true-positive from false-positive results is challenging. Algorithms are needed to confirm such low-level HBV DNA-positive samples.Study Design and Methods A total of 135 blood donor samples reactive by one or more HBV markers that provided discrepant results were tested undiluted with four commercial NATs: Ultrio, Ultrio Plus, MPX, and a quantitative assay (SuperQuant). To further explore discrepancies, three additional in-house NATs including real-time polymerase chain reaction (PCR) and nested PCR and sequencing were performed.Results The numbers reactive of these 135 "difficult" samples by four commercial NATs were as follows: 39 of 107 (36%) with SuperQuant, 40 (30%) with Ultrio, 100 (74%) with Ultrio Plus, and 102 (76%) with MPX. Of the seven NATs, 109 (81%) samples were reactive by at least two assays and thus considered confirmed positive of which 67 (50%) generated a sequence. Ultrio Plus and MPX performed similarly as above (80%-85% detected of 109 and 81%-90% of 67, respectively). Older (median, 49 years), HBV core antibody-reactive donors carried predominantly Genotype A (58%) with high-frequency amino acid substitutions in the major hydrophilic region of the S-protein. Younger (median, 24 years) hepatitis B surface antigen-positive donors carried wild-type strains predominantly Genotype B (32%) and E (24%), the latter in an apparent cluster. Conclusions Highly sensitive NATs require new confirmatory algorithms as presented optimally using different genomic regions or sequence generation. The introduction of immigration-related HBV genotypes may impact HBV epidemiology in the United States. © 2014 AABB.

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