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Preterm infants develop differently than those born at term and are at higher risk of brain pathology. Thus, an understanding of their development is of particular importance. Diffusion tensor imaging (DTI) of preterm infants offers a window into brain development at a very early age, an age at which that development is not yet fully understood. Recent works have used DTI to analyze structural connectome of the brain scans using network analysis. These studies have shown that, even from infancy, the brain exhibits small-world properties. Here we examine a cohort of 47 normal preterm neonates (i.e., without brain injury and with normal neurodevelopment at 18 months of age) scanned between 27 and 45 weeks post-menstrual age to further the understanding of how the structural connectome develops. We use fullbrain tractography to find white matter tracts between the 90 cortical and sub-cortical regions defined in the University of North Carolina Chapel Hill neonatal atlas. We then analyze the resulting connectomes and explore the differences between weighting edges by tract count versus fractional anisotropy. We observe that the brain networks in preterm infants, much like infants born at term, show high efficiency and clustering measures across a range of network scales. Further, the development of many individual region-pair connections, particularly in the frontal and occipital lobes, is significantly correlated with age. Finally, we observe that the preterm infant connectome remains highly efficient yet becomes more clustered across this age range, leading to a significant increase in its small-world structure.

To cite this article: Scully M, Brown J, Patel R, McDonald V, Brown CJ, Machin S. Human leukocyte antigen association in idiopathic thrombotic thrombocytopenic purpura: evidence for an immunogenetic link. J Thromb Haemost 2010; 8: 257-62.Summary. Background: Thrombotic thrombocytopenic purpura (TTP) is a rare, acute, life-threatening disorder, associated with a deficiency in ADAMTS 13. The majority of acute, idiopathic, adult TTP cases are associated with anti-ADAM-TS 13 IgG antibodies. However, the factor(s) precipitating an acute TTP episode are not always obvious; indeed, a multifactorial etiology is likely. Objectives and Methods: DNA was used for human leukocyte antigen (HLA) class II typing, using polymerase chain reaction (PCR)-sequencespecific primer and PCR-sequence-specific oligonucleotide probe to methodology to investigate 50 European acquired idiopathic TTP cases. Results: There was an increase in the frequency of HLA-DQB1*0301 (HLA-DQ7) in patients with TTP as compared with controls [58.0% vs. 34.5% (P = 0.048)]. The frequencies of HLA-DRB1*11 and HLA-DRB3* were also significantly increased in TTP patients as compared with controls [44.0% vs. 12.0% (P = 0.0024) and 84.0% vs. 58.0% (P = 0.024)], although it remains uncertain whether susceptibility is influenced by HLA-DQ or HLA-DR molecules or other genes in this haplotype. The frequencies of HLA-DRB1*04 and HLA-DRB4 (HLA-DR53) were significantly decreased in the patient group as compared with controls [10.0% vs. 35.0% and 26.0% vs. 61.5% (P = 0.0096 and P = 0.0024, respectively)], and may have a protective effect against the development of TTP. Conclusion: Analysis identified HLA class II types associated with susceptibility to and a protective effect against the development of acute acquired TTP in European patients. This provides the first description of a genetic factor predicting the risk of developing acquired antibody-mediated TTP.

Each year, blood transfusions save millions of lives. However, under current blood-matching practices, sensitization to non–self-antigens is an unavoidable adverse side effect of transfusion. We describe a universal donor typing platform that could be adopted by blood services worldwide to facilitate a universal extended blood-matching policy and reduce sensitization rates. This DNA-based test is capable of simultaneously typing most clinically relevant red blood cell (RBC), human platelet (HPA), and human leukocyte (HLA) antigens. Validation was performed, using samples from 7927 European, 27 South Asian, 21 East Asian, and 9 African blood donors enrolled in 2 national biobanks. We illustrated the usefulness of the platform by analyzing antibody data from patients sensitized with multiple RBC alloantibodies. Genotyping results demonstrated concordance of 99.91%, 99.97%, and 99.03% with RBC, HPA, and HLA clinically validated typing results in 89 371, 3016, and 9289 comparisons, respectively. Genotyping increased the total number of antigen typing results available from 110 980 to >1 200 000. Dense donor typing allowed identification of 2 to 6 times more compatible donors to serve 3146 patients with multiple RBC alloantibodies, providing at least 1 match for 176 individuals for whom previously no blood could be found among the same donors. This genotyping technology is already being used to type thousands of donors taking part in national genotyping studies. Extraction of dense antigen-typing data from these cohorts provides blood supply organizations with the opportunity to implement a policy of genomics-based precision matching of blood.

SummaryCord blood units (n ¼ 5500) stored at the London Cord Blood Bank, including 59 units transplanted into a high risk and heterogeneous group of patients, were analysed. Transplant outcome data was available for 44 patients with a median clinical follow-up of 14 months (range 3-44 months). Over 40% of the collected units were of ethnic minority origin with a median volume of 79 ml (range 40-240 ml) and a median total nucleated cell (TNC) count of 11AE9 · 10 9 /l (range 10AE0-24AE8 · 10 9 /l). The average patient's weight was 28 kg (range 5-80 kg) and the median age was 8 years (range 0AE7-40 years). The median number of nucleated cells infused was 4 · 10 7 / kg (range 1AE10-16 · 10 7 /kg). Neutrophil engraftment of 0AE5 · 10 9 /l was observed in 33 (74±%) patients with an average time of 28 days (range 11-60). The Kaplan-Meier estimate of acute graft-versus-host disease (grade II >) at day 100 was 37 ± 7% and in 27 (62%) patients, it was grade I or absent. The overall survival and disease-free survival at 2 years was 49 ± 8% and 41 ± 8%, respectively. Two years after transplantation the survival rate was 69% and 54% for patients receiving a 6/6 or 5/6 HLA matched units, respectively. Infection was the main cause of transplanted related mortality in these patients.

BackgroundCord blood is an important source of stem cells. However, nearly 90% of public cord blood banks have declared that they are struggling to maintain their financial sustainability and avoid bankruptcy. The objective of this study is to evaluate how characteristics of cord blood units influence their utilization, then use this information to model the economic viability and therapeutic value of different banking strategies.MethodsRetrospective analysis of cord blood data registered between January 1st, 2009 and December 31st, 2011 in Bone Marrow Donor Worldwide. Data were collected from four public banks in France, Germany and the USA. Samples were eligible for inclusion in the analysis if data on cord blood and maternal HLA typing and biological characteristics after processing were available (total nucleated and CD34+ cell counts). 9,396 banked cord blood units were analyzed, of which 5,815 were Caucasian in origin. A multivariate logistic regression model assessed the influence of three parameters on the CBU utilization rate: ethnic background, total nucleated and CD34+ cell counts. From this model, we elaborated a Utilization Score reflecting the probability of transplantation for each cord blood unit. We stratified three Utilization Score thresholds representing four different banking strategies, from the least selective (scenario A) to the most selective (scenario D). We measured the cost-effectiveness ratio for each strategy by comparing performance in terms of number of transplanted cord blood units and level of financial deficit.ResultsWhen comparing inputs and outputs over three years, Scenario A represented the most extreme case as it delivered the highest therapeutic value for patients (284 CBUs transplanted) along with the highest financial deficit (USD 5.89 million). We found that scenario C resulted in 219 CBUs transplanted with a limited deficit (USD 0.98 million) that charities and public health could realistically finance over the long term. We also found that using a pre-freezing level of 18 x 108 TNC would be the most cost-effective strategy for a public bank.ConclusionOur study shows that a swift transition from strategy A to C can play a vital role in preventing public cord blood banks worldwide from collapsing.

Molecular cloning techniques and V gene phage display have revolutionised the production of human monoclonal antibodies. Antibodies of a defined specificity can be obtained by selecting phage display libraries on antigen in a process known as panning. We have applied these techniques to the isolation of three HLA-A2-specific single chain variable domain fragments (scFv) from a patient alloimmunised by blood transfusion. Analysis of specificity with cells of HLA genotyped donors revealed the following: i) in addition to the major reactivity with HLA-A2, cross-reactivity with the HLA-A28 epitope; and ii) inhibition of scFv binding to the antigen by the patients' antibodies. The heavy chain variable genes of all three were derived from the germline gene Cos-3, carry the hallmarks of somatic hypermutation, and are most likely derived from clonally related B cells. The light chain variable domains were encoded by DPK1 and DPK8 from the VkappaI family. These data show that phage display can be used to clone HLA-specific alloantibodies that recognise the native antigen from alloimmunised patients.

The SEL-I-METRY trial (EudraCT No 2015-002269-47) is the first multicentre trial to investigate the role of 123I and 131I SPECT/CT-based tumour dosimetry to predict response to radioiodine therapy. Standardised dosimetry methodology is essential to provide a robust evidence-base for absorbed dose–response thresholds for molecular radiotherapy (MRT). In this paper a practical standardised protocol is used to establish the first network of centres with consistent methods of radioiodine activity quantification. Nine SPECT/CT systems at eight centres were set-up for quantitative radioiodine imaging. The dead-time of the systems was characterised for up to 2.8 GBq 131I. Volume dependent calibration factors were measured on centrally reconstructed images of 123I and 131I in six (0.8–196 ml) cylinders. Validation of image quantification using these calibration factors was performed on three systems, by imaging a 3D-printed phantom mimicking a patient’s activity distribution. The percentage differences between the activities measured in the SPECT/CT image and those measured by the radionuclide calibrator were calculated. Additionally uncertainties on the SPECT/CT-based activities were calculated to indicate the limit on the quantitative accuracy of this method. For systems set-up to image high 131I count rates, the count rate versus activity did not peak below 2.8 GBq and fit a non-paralysable model. The dead-times and volume-dependent calibration factors were comparable between systems of the same model and crystal thickness. Therefore a global calibration curve could be fitted to each. The errors on the validation phantom activities’ were comparable to the measurement uncertainties derived from uncertainty analysis, at 10% and 16% on average for 123I and 131I respectively in a 5 cm sphere. In conclusion, the dead-time and calibration factors varied between centres, with different models of system. However, global calibration factors may be applied to the same system model with the same crystal thickness, to simplify set-up of future multi-centre MRT studies.