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Background Hematopoietic progenitor cells (HPC) circulate at high levels at birth and disappear rapidly afterwards, but the underlying mechanism it is not known. The aim of this study was to assess circulating HPC in cord blood at different gestational ages and shortly after birth and concomitantly study the biologic markers involved in this phenomenon. Methods All samples were analyzed for CD34+ cells, colony-forming units (CFU) and cytokines. Results The results obtained confirmed a slight decrease in HPC concentration during the late stage of fetal life (R2=0.41). After birth, CD34+ cells showed a rapid decline from circulation: 25±29% at 3 h, 51±42% at 12 h and 80±48% at 60 h. CFU cleared following a similar pattern. Cord plasma showed higher concentrations of stem cell factor (SCF), fetal liver tyrosine kinase 3-ligand (FLT3l), erythrpoietin (EPO), granulocyte colony-stimulating factor (G-CSF) and interleukin-11 (IL-11) compared with an adult control. Interestingly, the EPO concentration in newborn plasma correlated with the kinetics of HPC decline after birth. Moreover, we observed an up-regulation of l-selectin and a down-regulation of CXCR4 expression in CD34+ cells 3 h after birth. Discussion These data combined suggest that an active homing process results in the clearance of HPC from the circulation immediately after birth. [ABSTRACT FROM AUTHOR]

Background: The ability to generate a GvL response by infusion of donor leukocytes (DL) in patients following relapse after BMT is now well documented and has been demonstrated to be particularly effective in patients with CML. Methods: We generated T-cell lines from a patient who was undergoing an active GvL response following withdrawal of immunosuppression for cytogenetic relapse of CML. Cryopreserved pre-transplant leukemic cells were used as stimulators, to generate T-cell lines and oligoclonal lines from the lymphocytes.In total 38 sub-lines were generated from different bulk cultures. The lines were tested for their proliferative and cytotoxic capability to patient pre-transplant leukemic cells, PHA-transformed lymphoblasts, allogeneic CML cells, and autologous and allogeneic B-LCL. Results: Four of the cloned lines tested recognized the patient's pre-transplant leukemic cells. Specifically, two were both cytotoxic and proliferative in response to patient leukemic cells and two were cytotoxic only. Six clonal lines recognized PHA blasts only and were proliferative; one was specific for PHA blasts and CML cells. The sub-lines were phenotyped for cell-surface markers and all were CD4 + CD8 - CD 16/56 - . The proliferative response of the leukemia-specific clonal lines could be blocked with anti-MHC Class II MAbs. Discussion: These data suggest that CD4 + cells play a crucial role in mediating the GvL effect in CML patients. Our observations can be used to delineate strategies for enhancing and investigating the GvL effect in CML. [ABSTRACT FROM AUTHOR]

Background Identification of HLA class I-restricted CMV epitopes, and the subsequent synthesis of HLA class I-peptide tetrameric complexes, have provided investigators with an important tool for visualising and quantifying the precise in vivo CTL response to CMV reactivation following stem cell transplantation. In conjunction with PCR-monitoring of the viral load, the magnitude and dynamic of the host's specific CD8[sup +] T cell response to viral replication can be studied. Methods CMV peptide epitopes can be identified be searching the CMV-pp65 antigen for HLA class I allele binding motifs, by testing their binding affinity and ability to generate CTLs, and by screening for CTL responses in as many individuals as possible to assess their general applicability for monitoring large number of patients. HLA tetramers are synthesized by refolding recombinant class I heavy chains and β[sub 2]m with CMV-pp65[sub 495-503] peptide. After biotinylation and tetramerisation to PE-conjugated streptavidin, they are used to stain CD8[sup +] T cells taken from patients at different time points after SCT. Results The T-cell mediated immune response is mainly directed against epitopes derived from the CMV tegument protein pp65. CMV-specific CTL's confer protection against CMV reactivation above a threshold level of 10[sup 7] to 2 × 10[sup 7]/L. CMV reactivation is required to stimulate CTL responses. Transfer of CMV immunity from seropositive donors is associated with better outcome and steroids suppress the Ag-specific immune response. Discussion Initial studies with CMV-specific HLA class I tetramers have helped to define the nature of anti-CMV T cell response in SCT patients and to determine a threshold CTL level required for controlling CMV reactivation. Monitoring patients with HLA-tetramers should therefore allow clinicians to predict and assess the risk of reactivation and to balance the risks and benefits of early anti-viral treatment, thereby avoiding the hazards of anti-viral prohpylaxis. HLA-tetramers can also be used to isolate antigen-specific cells for further in vitro expansion and transfer to patients for antiviral immunotherapy. The threshold level determined from patient monitoring can be used as a guide for estimating an effective target cell dose. [ABSTRACT FROM AUTHOR]

Introduction: Dialysis has been associated with acute changes in the complement activation status, granulocyte markers, macrophage function, T cell activation and the release of pro-inflammatory cytokines. The most common analysis of cytokine production in patients in dialysis has focused on the changes in monokines (particularly IL-1 and TNFα), however it is becoming clear that T cell cytokines play a major role in the impaired lymphocyte function of dialysis patients. [ABSTRACT FROM PUBLISHER]

Objectives: NKG2D is an activating receptor expressed by natural killer (NK) and CD8+ T cells and activation intensity varies by NKG2D expression level or nature of its ligand. An NKG2D gene polymorphism determines high (HNK1) or low (LNK1) expression. MICA is the most polymorphic NKG2D ligand and stronger effector cell activation associates with methionine rather than valine at residue 129. We investigated correlation between cord blood (CB) NKG2D and MICA genotypes and haematopoietic stem cell (HSC) transplant outcome., Methods: We retrospectively studied 267 CB HSC recipients (178 adult and 87 paediatric) who underwent transplant for malignant disease between 2007 and 2018, analysing CB graft DNA for NKG2D and MICA polymorphisms using Sanger sequencing. Multivariate analysis was used to correlate these results with transplant outcomes., Results: In adult patients, LNK1 homozygous CB significantly improved 60-day neutrophil engraftment (hazard ratio (HR) 0.6; 95% confidence interval (CI) 0.4-0.9; p = .003). In paediatrics, HNK1 homozygous CB improved 60-day engraftment (HR 0.4; 95% CI 0.2-0.7; p = .003), as did MICA-129 methionine+ CB grafts (HR 1.7 95% CI 1.1-2.6; p = .02)., Conclusion: CB NKG2D and MICA genotypes potentially improve CB HSC engraftment. However, results contrast between adult and paediatric recipients and may reflect transplant procedure disparities between cohorts., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

An update of the age and growth for juveniles of the short fin mako shark (I. oxyrinchus) from the Mexican Pacific is presented, based on the analysis of growth band counts from dorsal vertebrae of 198 individuals [110 females, 74-231 cm of total length (TL) and 88 males, 72-231 cm TL) caught during 2008-2018. New available information on vertebral growth band periodicity (biannual deposition in juveniles) and the convenience of using vertebrae form the dorsal region over the cervical region to count growth bands, as well as a multimodel approach, were used. The von Bertalanffy (VB) growth model, Gompertz, logistic and two parameters of VB (2-VB) were fitted to the length-at-age. Only ages ≤6 years were used for the fitting of the models and their performance was compared with the small-sample bias-corrected form of the Akaike information criterion (AICc), their differences ( ∆ i ) and weights ( w i ). Following a multimodel inference approach, the model averaged asymptotic length ( L ¯ inf ), length-at-age 0 ( L ¯ 0 ) and their unconditional standard error ( SE ¯ ), were estimated for each sex scenario using the three-parameter version of each model. The precision of growth band counts was acceptable for the different methods used and by two different readers. The centrum edge analysis (CEA) and marginal increment analysis (MIA) did not support the hypothesis of biannual band pair formation for juveniles, likewise for adults the periodicity could not be verified due to the small sample of large animals. Age was estimated assuming the formation of two pairs of growth bands per year during the first 5 years and one pair of bands per year afterwards considering direct validation information. The estimated ages in years ranged from 0-14 for females and 0-6 for males. The Kimura likelihood ratio test showed no differences in the growth curves of juveniles by sex (P > 0.05). According to the AICc, the 2-VB model better fitted the length-at-age data for combined sexes (L inf  = 386.4 cm, k = 0.12 years -1 , L 0  = 70 cm). The model averaged L ¯ inf and L ¯ 0 were 378.3 cm ( SE ¯ = 64.5 ) and 69.5 cm ( SE ¯ = 6.3 ), respectively. The growth parameters determined for juveniles of I. oxyrinchus are similar to those estimated in other regions, showing relatively fast growth rate as previously reported, medium longevity in comparison to other shark species and natural mortality close to that reported in the last stock assessment for the North Pacific Ocean. These life-history parameters should be considered to evaluate the population in the region and to develop better fishery management and conservation measures., (© 2023 The Authors. Journal of Fish Biology published by John Wiley & Sons Ltd on behalf of Fisheries Society of the British Isles.)

During the last five decades different therapies have been developed for the treatment of cancer, and as a result, patients can now live longer and better lives. Among such therapies, hematopoietic cell transplantation and immunotherapy have played key roles. In this short article, we present our particular point of view on the development of these two cellular therapies. We have focused on a historical perspective emphasizing the work of some of the Nobel Prize winners whose studies constituted cornerstones in our knowledge of the biology of cancer and in our fight against this devastating disease., Competing Interests: Conflict of Interest None of the authors has any kind of conflict of interest to declare., (Copyright © 2022. Published by Elsevier Inc.)

Upper limb orientation estimation based on Magnetic, Angular Rate, and Gravity sensors considering multiple body segments is presented in this work. The proposal allowed assessing the activity of two or more body segments individually and jointly, regardless of their spatial relationship. A custom-made system was developed incorporating a complementary filter and a proportional-integral control for data sensor merging and, noise and instrumentation error reduction. Two controlled tests were carried out to assess the performance of the system. The former evaluated the response of the method in motionless conditions, while the latter assessed the feasibility to follow trajectories in 3D space. Ten volunteers were recruited to evaluate the system performance in three semi-controlled and daily life task tests. The system was evaluated using the common parameters in motion tracking methods and relied on a digital motion processor. The system's outcome presented a root mean square error in the range of 2.65°-3.98° for the semi-controlled tests and 0.48°-1.389° for the daily life task test. The system tests analysis proved that the proposal permitted obtaining the articulated body chain information of multiple segments when three or more MARG sensors are used., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 IPEM. Published by Elsevier Ltd. All rights reserved.)

Fall from height is a cause of concern in the construction sector. Appropriate use of a harness can be the difference between an incident or a critical accident. Monitoring the proper use of a harness in the workplace using Bluetooth Low Energy (BLE) devices is a recent and effective approach. The aim of this article is to identify typical limitations in a BLE monitoring system in order to propose solutions according to the existing literature. Alternative solutions found in the literature showed that the integration of BLE with other technologies such as building information modeling, radio-frequency identification or the global positioning system can improve the effectiveness of current monitoring approaches based only on BLE and reduce rates of fall from height accidents. For correct integration, both technological factors (cost, compatibility, data transmission) and cultural factors (social acceptance, procedures, etc.) must be taken into account.

Many occupational accidents in construction sites are caused by the intrusion of a worker into a hazardous area. Technological solutions based on RFID, BIM, or UWB can reduce accidents, but they still have some limitations.The aim of the current paper is to design and evaluate a new system of "virtual fences" based on Bluetooth Low-Energy (BLE) to avoid intrusions. First of all, the system was designed using a number of beacons, a Bayesian filter, a finite state machine, and an indicator. Secondly, its safety attributes were evaluated based on a scientific questionnaire by an expert panel following the staticized groups' methodology. Results showed that the proposal is inexpensive and easy to integrate and configure. The selected experts evaluated positively all the attributes of the system, and provided valuable insights for further improvements. From the experts' discussions, we concluded that successful adoption of this "virtual fence" system based on BLE beacons should consider the influence of factors such as cost savings, top management support, social acceptance, and compatibility and integration with existing systems, procedures, and company culture. In addition, legislation updates according to technical advances would help with successful adoption of any new safety system.

A Proportional Integral Derivative (PID) controller is commonly used to carry out tasks like position tracking in the industrial robot manipulator controller; however, over time, the PID integral gain generates degradation within the controller, which then produces reduced stability and bandwidth. A proportional derivative (PD) controller has been proposed to deal with the increase in integral gain but is limited if gravity is not compensated for. In practice, the dynamic system non-linearities frequently are unknown or hard to obtain. Adaptive controllers are online schemes that are used to deal with systems that present non-linear and uncertainties dynamics. Adaptive controller use measured data of system trajectory in order to learn and compensate the uncertainties and external disturbances. However, these techniques can adopt more efficient learning methods in order to improve their performance. In this work, a nominal control law is used to achieve a sub-optimal performance, and a scheme based on a cascade neural network is implemented to act as a non-linear compensation whose task is to improve upon the performance of the nominal controller. The main contributions of this work are neural compensation based on a cascade neural networks and the function to update the weights of neural network used. The algorithm is implemented using radial basis function neural networks and a recompense function that leads longer traces for an identification problem. A two-degree-of-freedom robot manipulator is proposed to validate the proposed scheme and compare it with conventional PD control compensation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Soriano, Zamora, Vazquez-Nicolas, Hernández, Barraza Madrigal and Balderas.)

Background: Allogeneic haematopoietic cell transplantation (HCT) is a curative therapy for severe haematological disorders. However, it carries significant risk of morbidity and mortality. To improve patient outcomes, better graft selection strategies are needed, incorporating HLA matching with clinically important graft characteristics. Studies have shown that the cellular content of HCT grafts, specifically higher ratios of T regulatory (Tregs)/T cells, are important factors influencing outcomes when using adult peripheral blood mobilised grafts. So far, no equivalent study exists in umbilical cord blood (CB) transplantation due to the limitations of cryopreserved CB samples., Study Design and Methods: To establish the most robust and efficient way to measure the Treg content of previously cryopreserved CB units, we compared the enumeration of Treg and CD3+ cells using flow cytometry and an epigenetic, DNA-based methodology. The two methods were assessed for their agreement, consistency and susceptibility to error when enumerating Treg and CD3+ cell numbers in both fresh and cryopreserved CB samples., Results: Epigenetic enumeration gave consistent and comparable results in both fresh and frozen CB samples. By contrast, assessment of Tregs and CD3+ cells by flow cytometry was only possible in fresh samples due to significant cell death following cryopreservation and thawing., Conclusion: Epigenetic assessment offers significant advantages over flow cytometry for analysing cryopreserved CB; similar cell numbers were observed both in fresh and frozen samples. Furthermore, multiple epigenetic assessments can be performed from DNA extracted from small cryopreserved CB segments; often the only CB sample available for clinical studies., Competing Interests: The authors have declared that no competing interests exist.

The reported influence of donor Killer-cell Immunoglobulin-like Receptor (KIR) genes on the outcomes of haematopoietic cell transplantation (HCT) are contradictory, in part due to diversity of disease, donor sources, era and conditioning regimens within and between different studies. Here, we describe the results of a retrospective clinical analysis establishing the effect of donor KIR motifs on the outcomes of 119 HLA-matched, unrelated donor HCT for adult acute myeloid leukaemia (AML) using myeloablative conditioning (MAC) in a predominantly T-cell deplete (TCD) cohort. We observed that HCT involving donors with at least one KIR B haplotype were more likely to result in non-relapse mortality (NRM) than HCT involving donors with two KIR A haplotypes (p = 0.019). Upon separation of KIR haplotypes into their centromeric (Cen) and telomeric (Tel) motif structures, we demonstrated that the Cen-B motif was largely responsible for this effect (p = 0.001). When the cause of NRM was investigated further, infection was the dominant cause of death (p = 0.006). No evidence correlating donor KIR B haplotype with relapse risk was observed. The results from this analysis confirm previous findings in the unrelated, TCD, MAC transplant setting and imply a protective role for donor-encoded Cen-A motifs against infection in allogeneic HCT recipients.

Time synchronization among sensor devices connected through non-deterministic media is a fundamental requirement for sensor fusion and other distributed tasks that need a common time reference. In many of the time synchronization methods existing in literature, the estimation of the relation between pairs of clocks is a core concept; moreover, in applications that do not have general connectivity among its devices but a simple pairwise topology, such as embedded systems, mobile robots or home automation, two-clock synchronization is actually the basic form of the time estimation problem. In these kinds of applications, especially for critical ones, not only the quality of the estimation of the relation between two clocks is important, but also the bounds the methods provide for the estimated values, and their computational effort (since many are small systems). In this paper, we characterize, with a thorough parameterization, the possible scenarios where two-clock synchronization is to be solved, and then conduct a rigorous statistical study of both scenarios and methods. The study is based on exhaustive simulations run in a super-computer. Our aim is to provide a sound basis to select the best clock synchronization algorithm depending on the application requirements and characteristics, and also to deduce which ones of these characteristics are most relevant, in general, when solving the problem. For our comparisons we have considered several representative methods for clock synchronization according to a novel taxonomy that we also propose in the paper, and in particular, a few geometrical ones that have special desirable characteristics for the two-clock problem. We illustrate the method selection procedure with practical use-cases of sensory systems where two-clock synchronization is essential.

Purpose: The main aim of this study was to evaluate the significance of HLA-DPB1 expression in acute graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT) from HLA-A, -B, -C, -DRB1, -DQB1-matched and -mismatched unrelated donors., Patients and Methods: Between January 1, 2017, and January 10, 2019, we assessed 19,136 patients who received HCT from an HLA-A, -B, -C, -DRB1, -DQB1-matched or -mismatched unrelated donor performed in Australia, the European Union, Japan, North America, and the United Kingdom between 1988 and 2016. Among transplant recipients with one HLA-DPB1 mismatch, the patient's mismatched HLA-DPB1 allotype was defined as low or high expression. Multivariable regression models were used to assess risks of GVHD associated with high expression relative to low expression HLA-DPB1 mismatches. The effect of increasing numbers of HLA-DPB1 mismatches on clinical outcome was assessed in HLA-mismatched transplant recipients., Results: In HLA-A, -B, -C, -DRB1,-DQB1-matched transplant recipients, donor mismatching against one high-expression patient HLA-DPB1 increased moderate (odds ratio [OR], 1.36; P = .001) and severe acute GVHD (OR, 1.32; P = .0016) relative to low-expression patient mismatches, regardless of the expression level of the donor's mismatched HLA-DPB1. Among transplant recipients with one HLA-A, -B, -C, -DRB1, or -DQB1 mismatch, the odds of acute GVHD increased with increasing numbers of HLA-DPB1 mismatches (OR, 1.23 for one; OR, 1.40 for two mismatches relative to zero mismatches for moderate GVHD; OR, 1.19 for one; OR, 1.40 for two mismatches relative to zero for severe GVHD), but not with the level of expression of the patient's mismatched HLA-DPB1 allotype., Conclusion: The level of expression of patient HLA-DPB1 mismatches informs the risk of GVHD after HLA-A, -B, -C, -DRB1, -DQB1-matched unrelated HCT, and the total number of HLA-DPB1 mismatches informs the risk of GVHD after HLA-mismatched unrelated HCT. Prospective consideration of HLA-DPB1 may help to lower GVHD risks after transplantation.

Range sensors are currently present in countless applications related to perception of the environment. In mobile robots, these devices constitute a key part of the sensory apparatus and enable essential operations, that are often addressed by applying methods grounded on probabilistic frameworks such as Bayesian filters. Unfortunately, modern mobile robots have to navigate within challenging environments from the perspective of their sensory devices, getting abnormal observations (e.g., biased, missing, etc.) that may compromise these operations. Although there exist previous contributions that either address filtering performance or identification of abnormal sensory observations, they do not provide a complete treatment of both problems at once. In this work we present a statistical approach that allows us to study and quantify the impact of abnormal observations from range sensors on the performance of Bayesian filters. For that, we formulate the estimation problem from a generic perspective (abstracting from concrete implementations), analyse the main limitations of common robotics range sensors, and define the factors that potentially affect the filtering performance. Rigorous statistical methods are then applied to a set of simulated experiments devised to reproduce a diversity of situations. The obtained results, which we also validate in a real environment, provide novel and relevant conclusions on the effect of abnormal range observations in these filters.

Hematopoietic cell transplantation (HCT) from HLA-mismatched unrelated donors can cure life-threatening blood disorders, but its success is limited by graft-versus-host disease (GVHD). HLA-B leaders encode methionine (M) or threonine (T) at position 2 and give rise to TT, MT, or MM genotypes. The dimorphic HLA-B leader informs GVHD risk in HLA-B-mismatched HCT. If the leader influences outcome in other HLA-mismatched transplant settings, the success of HCT could be improved for future patients. We determined leader genotypes for 10 415 patients receiving a transplant between 1988 and 2016 from unrelated donors with one HLA-A, HLA-B, HLA-C, HLA-DRB1, or HLA-DQB1 mismatch. Multivariate regression methods were used to evaluate risks associated with patient leader genotype according to the mismatched HLA locus and with HLA-A, HLA-B, HLA-C, HLA-DRB1, or HLA-DQB1 mismatching according to patient leader genotype. The impact of the patient leader genotype on acute GVHD and mortality varied across different mismatched HLA loci. Nonrelapse mortality was higher among HLA-DQB1-mismatched MM patients compared with HLA-DQB1-mismatched TT patients (hazard ratio, 1.35; P = .01). Grades III to IV GVHD risk was higher among HLA-DRB1-mismatched MM or MT patients compared with HLA-DRB1-mismatched TT patients (odds ratio, 2.52 and 1.51, respectively). Patients tolerated a single HLA-DQB1 mismatch better than mismatches at other loci. Outcome after HLA-mismatched transplantation depends on the HLA-B leader dimorphism and the mismatched HLA locus. The patient's leader variant provides new information on the limits of HLA mismatching. The success of HLA-mismatched unrelated transplantation might be enhanced through the judicious selection of mismatched donors for a patient's leader genotype.

This retrospective study explored the incidence of autoimmune cytopenia (AIC) in 530 paediatric and adult patients with acquired aplastic anaemia (aAA) who underwent first allogeneic HSCT between 2002 and 2012. AIC was a rare complication with a cumulative incidence of AIC at 1, 3, 5 and 10 years post HSCT of 2.5% (1.2-3.9 95% CI), 4.4% (2.6-6.2 95% CI), 4.6% (2.8-6.5 95% CI) and 5.1% (3.1-7.2 95% CI). Overall survival at 5 years after diagnosis of AIC was 85.9% (71-100 95% CI). Twenty-five patients were diagnosed with AIC at a median of 10.6 (2.6-91.5) months post HSCT. Eight (32%) patients were diagnosed with immune thrombocytopenia (ITP), seven (28%) with autoimmune haemolytic anaemia (AIHA), seven (24%) with Evans syndrome and four (16%) with autoimmune neutropenia (AIN). Treatment strategies were heterogeneous. Complete responses were seen in 12 of 25 patients, with death in three patients. In multivariable Cox analysis of a subgroup of 475 patients, peripheral blood stem cell (PBSC) transplant was associated with higher risk of AIC compared with bone marrow (BM) when conditioning regimens contained fludarabine and/or alemtuzumab (2.81 [1.06-7.49 95% CI]; p = 0.038), or anti-thymocyte globulin (ATG) (2.86 [1.11-7.37 95% CI]; p = 0.029). Myeloablative conditioning was associated with a lower risk of AIC compared with reduced intensity conditioning (RIC) in fludarabine and/or alemtuzumab (0.34 [0.12-0.98 95% CI]; p = 0.046) and ATG containing regimens (0.34 [0.12-0.95 95% CI]; p = 0.04). These findings provide clinically useful information regarding the incidence of a rare and potentially life-threatening complication of allogeneic HSCT for aAA, and further support for BM as the preferred stem cell source for transplant of patients with aAA.

Background: The success of unrelated haemopoietic cell transplantation (HCT) is limited by graft-versus-host disease (GVHD), which is the main post-transplantation challenge when HLA-matched donors are unavailable. A sequence dimorphism in exon 1 of HLA-B gives rise to leader peptides containing methionine (Met; M) or threonine (Thr; T), which differentially influence natural killer and T-cell alloresponses. The main aim of the study was to evaluate the role of the leader dimorphism in GVHD after HLA-B-mismatched unrelated HCT., Methods: We did a retrospective cohort study of 33 982 patients who received an unrelated HCT done in Australia, Europe, Japan, North America, and the UK between Jan 1, 1988, and Dec 31, 2016. Data were contributed by participants of the International Histocompatibility Working Group in Hematopoietic Cell Transplantation. All cases were included and there were no exclusion criteria. Multivariate regression models were used to assess risks associated with HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 mismatching. Among the 33 982 transplantations, the risks of GVHD associated with HLA-B M and T leaders were established in 17 100 (50·3%) HLA-matched and 1457 (4·3%) single HLA-B-mismatched transplantations using multivariate regression models. Leader frequencies were defined in 2 004 742 BeTheMatch US registry donors., Findings: Between Jan 20, 2017, and March 11, 2019, we assessed 33 982 HCTs using multivariate regression models for the role of HLA mismatching on outcome. Median follow-up was 1841 days (IQR 909-2963). Mortality and GVHD increased with increasing numbers of HLA mismatches. A single HLA-B mismatch increased grade 3-4 acute GVHD (odds ratio [OR] 1·89, 95% CI 1·53-2·33; p<0·0001). Among the single HLA-B-mismatched transplantations, acute GVHD risk was higher with leader mismatching than with leader matching (OR 1·73, 1·02-2·94; p=0·042 for grade 2-4) and with an M leader shared allotype compared with a T leader shared allotype (OR 1·98, 1·39-2·81; p=0·0001 for grade 3-4). The preferred HLA-B-mismatched donor is leader-matched and shares a T leader allotype. The majority (1 836 939 [91·6%]) of the 2 004 742 US registry donors have the TT or MT genotype., Interpretation: The HLA-B leader informs GVHD risk after HLA-B-mismatched unrelated HCT and differentiates high-risk HLA-B mismatches from those with lower risk. The leader of the matched allotype could be considered to be as important as the leader of the mismatched allotype for GVHD. Prospective identification of leader-matched donors is feasible for most patients in need of a HCT, and could lower GVHD and increase availability of HCT therapy. These findings are being independently validated and warrant further research in prospective trials., Funding: The National Institutes of Health, USA., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The age of 296 juvenile scalloped hammerhead sharks Sphyrna lewini caught by several fisheries in the Mexican Pacific Ocean from March 2007 to September 2017 were estimated from growth band counts in thin-sectioned vertebrae. Marginal-increment analysis (MIA) and centrum-edge analysis (CEA) were used to verify the periodicity of formation of the growth bands, whereas elemental profiles obtained from LA-ICP-MS transect scans in vertebrae of 15 juveniles were used as an alternative approach to verify the age of the species for the first time. Age estimates ranged from 0 to 10+ years (42-158.7 cm total length; L T ). The index of average percentage error (I APE 3.6%), CV (5.2%), bias plots and Bowker's tests of symmetry showed precise and low-biased age estimation. Both MIA and CEA indicated that in the vertebrae of juveniles of S. lewini a single translucent growth band was formed during winter (November-March) and an opaque band during summer (July-September), a period of faster growth, apparently correlated with a higher sea surface temperature. Peaks in vertebral P and Mn content spatially corresponded with the annual banding pattern in most of the samples, displaying 1.19 and 0.88 peaks per opaque band, respectively, which closely matched the annual deposition rate observed in this study. Although the periodicity of growth band formation needs to be verified for all sizes and ages representing the population of the species in the region, this demonstration of the annual formation of the growth bands in the vertebrae of juveniles should lead to a re-estimation of the growth parameters and productivity of the population to ensure that it is harvested at sustainable levels., (© 2019 The Fisheries Society of the British Isles.)

A total of 221 Costa Rican Mestizos from the Central Valley were genotyped at high-resolution for the human leukocyte antigen loci HLA-A, -B, -C, -DRB1, and -DQB1 using sequence-based typing methods. The respective allele and extended haplotype frequencies, as well as Hardy-Weinberg proportions were calculated. The most frequent extended haplotype identified was A*24:02:01-B*40:02:01-C*03:05-DRB1*08:02:01-DQB1*04:02:01, with an estimated frequency of 2.04%. No deviation from Hardy-Weinberg Equilibrium was detected at any of the loci studied. The HLA genotypic data of the population sample reported here are available publicly in the Allele Frequencies Net Database under the population name "Costa Rica Central Valley Mestizo" and the identifier AFN3606., (Copyright © 2019 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

A total of 125 Costa Ricans of Amerindian descent were genotyped at high-resolution for the human leukocyte antigen loci HLA-A, -B, -C, and -DRB1 using sequence-based typing methods. The respective allele and extended haplotype frequencies, as well as Hardy-Weinberg proportions were calculated. The most frequent extended haplotype identified was A*24:02:01-B*40:02:01-C*03:05-DRB1*04:07:01G, with an estimated frequency of 8.26%. A deviation from Hardy-Weinberg Equilibrium was detected at the DRB1 locus (p = 0.099). The HLA genotypic data of the population sample reported here are available publicly in the Allele Frequencies Net Database under the population name "Costa Rica Amerindians" and the identifier AFN3608., (Copyright © 2019 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

A total of 110 Costa Rican Mestizos from the province of Guanacaste were genotyped at high-resolution for the human leukocyte antigen loci HLA-A, -B, -C, and -DRB1 using sequence-based typing methods. The respective allele and extended haplotype frequencies, as well as Hardy-Weinberg proportions were calculated. The most frequent extended haplotype identified was A*24:02:01-B*35:12:01-C*04:01:01-DRB1*04:07:01G, with an estimated frequency of 2.73%. No deviation from Hardy-Weinberg Equilibrium was detected at any of the loci studied. The HLA genotypic data of the population sample reported here are available publicly in the Allele Frequencies Net Database under the population name "Costa Rica Guanacaste Mestizo" and the identifier AFN3609., (Copyright © 2019 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

A total of 155 Nicaraguan Mestizos from across the country were genotyped at high-resolution for the human leukocyte antigen loci HLA-A, -B, -C, and -DRB1 using sequence-based typing methods. The respective allele and extended haplotype frequencies, as well as Hardy-Weinberg proportions were calculated. The most frequent extended haplotype identified was A*24:02:01-B*40:02:01-C*03:05-DRB1*04:07:01G, with an estimated frequency of 2.26%. No deviation from Hardy-Weinberg Equilibrium was detected at any of the loci studied. The HLA genotypic data of the population sample reported here are available publicly in the Allele Frequencies Net Database under the population name "Nicaragua Mestizo" and the identifier AFN3610., (Copyright © 2019 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

A total of 102 Costa Ricans of African-Caribbean descent were genotyped at high-resolution for the human leukocyte antigen loci HLA-A, -B, -C, and -DRB1 using sequence-based typing methods. The respective allele and extended haplotype frequencies, as well as Hardy-Weinberg proportions were calculated. The most frequent extended haplotype identified was A*01:01:01-B*08:01:01-C*07:01:01-DRB1*03:01:01G, with an estimated frequency of 1.96%. No deviation from Hardy-Weinberg Equilibrium was detected at any of the loci studied. The HLA genotypic data of the population sample reported here are available publicly in the Allele Frequencies Net Database under the population name "Costa Rica African-Caribbeans" and the identifier AFN3607., (Copyright © 2019 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

HLA matching at an allelic-level resolution for volunteer unrelated donor (VUD) hematopoietic cell transplantation (HCT) results in improved survival and fewer post-transplant complications. Limitations in typing technologies used for the hyperpolymorphic HLA genes have meant that variations outside of the antigen recognition domain (ARD) have not been previously characterized in HCT. Our aim was to explore the extent of diversity outside of the ARD and determine the impact of this diversity on transplant outcome. Eight hundred ninety-one VUD-HCT donors and their recipients transplanted for a hematologic malignancy in the United Kingdom were retrospectively HLA typed at an ultra-high resolution (UHR) for HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 using next-generation sequencing technology. Matching was determined at full gene level for HLA class I and at a coding DNA sequence level for HLA class II genes. The HLA matching status changed in 29.1% of pairs after UHR HLA typing. The 12/12 UHR HLA matched patients had significantly improved 5-year overall survival when compared with those believed to be 12/12 HLA matches based on their original HLA typing but were found to be mismatched after UHR HLA typing (54.8% versus 30.1%, P = .022). Survival was also significantly better in 12/12 UHR HLA-matched patients when compared with those with any degree of mismatch at this level of resolution (55.1% versus 40.1%, P = .005). This study shows that better HLA matching, found when typing is done at UHR that includes exons outside of the ARD, introns, and untranslated regions, can significantly improve outcomes for recipients of a VUD-HCT for a hematologic malignancy and should be prospectively performed at donor selection., (Copyright © 2019 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

MICA and MICB genes encode ligands that interact with the natural killer (NK) cell activating receptor, NKG2D. These ligands display a highly polymorphic allelic repertoire, although the true functional significance of this polymorphism remains elusive. We previously reported additional polymorphism in the 5' untranslated region (UTR) proximal promoter region of these genes by sequencing international histocompatibility workshop (IHW) cell line DNA promoter and coding regions. The present study extends this analysis by further characterising the 3'UTR region of the same IHW reference panel to achieve a more complete understanding of MICA and MICB haplotype diversity and possible functional relevance. We found 17 extended MICA haplotypes encompassing the coding region and 3'UTR, including four novel haplotypes identified in IHW cell line DNA. This increased to 21 when also considering the 5'UTR proximal promoter region. Analysis of the MICB 3'UTR revealed two novel sequences in cell lines KLO and WIN designated MICB-UTR8 and UTR9, respectively. A total of 11 MICB haplotypes were identified in this study and five were unique. The present study, characterising MICA/B 3'UTR polymorphism utilising IHW reference cell lines, could be useful for future studies investigating the role of microRNA in post-transcriptional repression of gene expression and for immunotherapy strategies to combat cancer progression., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We previously reported that cord blood plasma (CBP) contains significantly more soluble NKG2D ligands (sNKG2DLs), such as sMICB and sULBP1, than healthy adult plasma. Viral infection or malignant transformation upregulates expression of NKG2D ligand on affected cells, leading to NK group 2, member D (NKG2D)-mediated natural killer (NK) cell lysis. Conversely, sNKG2DL engagement of NKG2D decreases NK cell cytotoxicity leading to viral or tumour immune escape. We hypothesised that sNKG2DLs detected in CBP may represent an additional fetal-maternal tolerance mechanism. To further understand the role of sNKG2DL in pregnancy and individual contributions of the various ligand types, we carried out functional analysis using 181 CBP samples. To test the ability of CBP to suppress the function of NK cells in vitro , we measured expression of NKG2D, CD107a, and IFN-γ in NK cells from control donors after exposure to 181 individual CBP samples and characterised the sMICA, sMICB, and sULBP1 content of each one. Furthermore, to detect possible allelic differences between samples that may also affect function, we carried out umbilical cord blood typing for MHC class I-related chain A (MICA) and MHC class I-related chain B (MICB) coding and promoter allelic types. Strongest functional correlations related to increasing concentration of exosomal sULBP1, which was present in all CBP samples tested. In addition, common MICB alleles, such as MICB*005:02, resulted in increased concentration of sMICB. Interestingly, MICB*005:02 uniquely associated with eight different promoter types. Among promoter polymorphisms, P2 resulted in the highest expression of sMICB and P9 the least and was confirmed using luciferase reporter assays. Higher levels of sMICB associated with lower IFN-γ production, indicating that sMICB also suppressed NK cell function. We also examined the MICA functional dimorphism encoding methionine (met) or valine (val) at residue 129 associated with strong or weak NKG2D binding, respectively. Most sMICA associated with val/val, some with met/val but none with met/met and, counter-intuitively, the presence of sMICA in CBP increased NK cell cytotoxicity. We propose a model for fetal-maternal tolerance, whereby NK cell activity is limited by sULBP1 and sMICB in CBP. The release of 129val sMICA with weak NKG2D signalling may reduce the overall net suppressive signal and break tolerance thus allowing fetal NK cells to overcome immunological threats in utero .

The HLA system shows the most extensive polymorphism in the human genome. Allelic and haplotypic frequencies of HLA genes vary dramatically across human populations. Due to a complex history of migration, populations in Latin America show a broad variety of admixture proportions, usually varying not only between countries, but also within countries. Knowledge of HLA allele and haplotype frequencies is essential for medical fields such as transplantation, but also serves as a means to assess genetic diversity and ancestry in human populations. Here, we have determined high-resolution HLA-A, -B, -C, and -DRB1 allele and haplotype frequencies in a sample of 713 healthy subjects from three Mestizo populations, one population of African descent, and Amerindians of five different groups from Costa Rica and Nicaragua and compared their profiles to a large set of indigenous populations from Iberia, Sub-Saharan Africa, and the Americas. Our results show a great degree of allelic and haplotypic diversity within and across these populations, with most extended haplotypes being private. Mestizo populations show alleles and haplotypes of putative European, Amerindian, and Sub-Saharan African origin, albeit with differential proportions. Despite some degree of gene flow, Amerindians and Afro-descendants show great similarity to other Amerindian and West African populations, respectively. This is the first comprehensive study reporting high-resolution HLA diversity in Central America, and its results will shed light into the genetic history of this region while also supporting the development of medical programs for organ and stem cell transplantation., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Regulatory T cells (Tregs) are CD4 + T cells that are key players of immune tolerance. They are powerful suppressor cells, able to impact the function of numerous immune cells, including key effectors of inflammation such as effector T cells. For this reason, Tregs are an ideal candidate for the development of cell therapy approaches to modulate immune responses. Treg therapy has shown promising results so far, providing key knowledge on the conditions in which these cells can provide protection and demonstrating that they could be an alternative to current pharmacological immunosuppressive therapies. However, a more comprehensive understanding of their characteristics, isolation, activation, and expansion is needed to be able design cost effective therapies. Here, we review the practicalities of making Tregs a viable cell therapy, in particular, discussing the challenges faced in isolating and manufacturing Tregs and defining what are the most appropriate applications for this new therapy.

The hyperpolymorphic HLA genes play important roles in disease and transplantation and act as genetic markers of migration and evolution. A panel of 107 B-lymphoblastoid cell lines (B-LCLs) was established in 1987 at the 10th International Histocompatibility Workshop as a resource for the immunogenetics community. These B-LCLs are well characterised and represent diverse ethnicities and HLA haplotypes. Here we have applied Pacific Biosciences' Single Molecule Real-Time (SMRT) DNA sequencing to HLA type 126 B-LCL, including the 107 International HLA and Immunogenetics Workshop (IHIW) cells, to ultra-high resolution. Amplicon sequencing of full-length HLA class I genes (HLA-A, -B and -C) and partial length HLA class II genes (HLA-DRB1, -DQB1 and -DPB1) was performed. We typed a total of 931 HLA alleles, 895 (96%) of which were consistent with the typing in the IPD-IMGT/HLA Database (Release 3.27.0, January 20, 2017), with 595 (64%) typed at a higher resolution. Discrepant types, including novel alleles (n = 10) and changes in zygosity (n = 13), as well as previously unreported types (n = 34) were observed. In addition, patterns of linkage disequilibrium were distinguished by four-field resolution typing of HLA-B and HLA-C. By improving and standardising the HLA typing of these B-LCLs, we have ensured their continued usefulness as a resource for the immunogenetics community in the age of next generation DNA sequencing., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Donation of haematopoietic stem cells, either through bone marrow (BM) or peripheral blood stem cell (PBSC) collection, is a generally safe procedure for healthy donors, although side effects are a known risk. Previous research, including our recent quantitative study, has shown that the psychosocial response to donating is usually a positive one and most donors would be willing to donate again in the future. This is often despite experiencing significant side effects during the donation process. Due to the relative recent introduction of PBSC, a comprehensive understanding of the range of physical and emotional issues donors may experience is lacking, as well as an understanding of specific donor characteristics Qualitative research can provide rich narrative data into these areas. This study was set up in order to identify specific donor characteristics and to further explore the relationship between pre-donation physical health and the donation experience, as previously identified in our quantitative study., Methods: It involved in-depth telephone interviews with 14 PBSC donors who participated in our original quantitative study. Thematic analysis was used to analyse the findings and the results provide a summary of participants' characteristics using themes and constituent codes., Results: We identified several donor characteristics, including strong intrinsic motivation, altruism, sense of duty, determination, low levels of ambivalence and the ability to develop a strong emotional relationship with an (unknown/anonymous) recipient whilst being able to manage strong feelings and emotions., Conclusions: These personality traits may explain the resilience that has been observed previously in haematopoietic stem cells donors. Significant feelings of grief were reported after a recipient's death. Possibilities to alleviate these symptoms may include raising awareness of potential poor outcomes in the recipient and offering improved counselling services if the recipient dies. We acknowledge several limitations including the sampling frame.

The balance between immune effector cells and immunosuppressive cells and how this regulates the tumor microenvironment has been well described. A significant contribution of immune regulatory cells, including regulatory T cells, to tumor progression has been widely reported. An emerging body of evidence has recently recognized a role for B cells in modulating the immune response to tumors and lymphoid malignancies. Regulatory B cells (Bregs) are a newly designated subset of B cells that have been shown to play a pivotal role in regulating immune responses involved in inflammation, autoimmunity and, more recently, cancer. Bregs can suppress diverse cell subtypes, including T cells, through the secretion of anti-inflammatory mediators, such as IL-10, and can facilitate the conversion of T cells to regulatory T cells, thus attenuating anti-tumor immune responses. Similar B-cell subpopulations have been reported to be recruited to the tumor but to acquire their immunosuppressive properties within the tumor bed and thereby attenuate anti-tumor immune responses. However, despite a pivotal role for Bregs in promoting inflammation and carcinogenesis, the phenotypic diversity of the cell surface markers that are unique to Bregs remains unclear in mice and humans. In this review, we summarize the characteristics of Bregs and review our current knowledge of Bregs and their inhibition of anti-tumor immune responses in murine tumor models and cancer patients.

Background Aims: Natural killer (NK) cells have the potential to become a successful immunotherapy as they can target malignant cells without being direct effectors of graft-versus-host disease. Our group has previously shown that large numbers of functional NK cells can be differentiated in vitro from umbilical cord blood (CB) CD34 + cells. To produce a clinically relevant and effective immunotherapy, we hypothesized that it is essential that the NK cells are able to proliferate and persist in vivo while maintaining an optimal activation status and killing capacity., Methods: We evaluated the proliferation capacity, telomere length and terminal differentiation markers expressed by NK cells differentiated in vitro. We also determined how their cytotoxicity compared with peripheral blood (PB) NK cells and CBNK cells when targeting patient acute myeloid leukemia (AML) blasts and solid tumor cell lines., Results: We found that the differentiated NK cells could respond to interleukin-2 and proliferate in vitro. Telomere length was significantly increased, whereas CD57 expression was significantly reduced compared with PBNK cells. The cytotoxicity of the differentiated NK cells was equivalent to that of the PBNK and CBNK cell controls, and priming consistently led to higher levels of killing of patient leukemic blasts and solid tumor cell lines in vitro. Interestingly, this activation step was not required to observe killing of patient AML blasts in vivo., Conclusion: We are able to generate NK cells from CBCD34 + cells in high numbers, allowing for multiple infusions of highly cytotoxic NK cells that have potential to further proliferate in vivo, making them a desirable product for application as an immunotherapy in the clinic., (Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Improving haematopoietic cell transplantation outcomes by selection of an HLA-matched unrelated donor is best practice; however, donor selection by secondary characteristics is controversial. We studied 1271 recipients with haematological malignancies who underwent T-cell-depleted allografts and had complete data on HLA-matching status for six loci (HLA-A, -B, -C, -DRB1, -DQB1, -DPB1) and clinical outcome data. Five-year overall survival was 40.6%. HLA mismatching (at HLA-A, -B, -C, -DRB1, -DQB1) relative risk (RR) 1.22, 95% confidence interval (CI) 1.2-1.5, P=0.033 for 1 mismatch and RR 1.46, 95% CI 1.1-1.9, P=0.009 for >1 mismatch) and CMV mismatching (RR 1.37, 95% CI 1.2-1.6, P<0.001) were significantly associated with inferior survival. Donors aged <30 years showed a trend towards better survival. The multivariate model for mortality, combining CMV and HLA-match status, found an RR of 1.36 (95% CI 1.1-1.7, P=0.003) for HLA matched/CMV mismatched, an RR of 1.22 (95% CI 0.99-1.5, P=0.062) for HLA mismatched/CMV matched and an RR of 1.81 (95% CI 1.4-2.3, P=<0.001) for HLA/ CMV mismatched, compared with the HLA/CMV-matched recipients. These data suggest that HLA and CMV matching status should be considered when selecting unrelated donors and that CMV matching may abrogate the effect of an HLA mismatch.