The People Living with HIV (PLHIV) Resilience Scale: Development and Validation in Three Countries in the Context of the PLHIV Stigma Index.

Supporting resilience among people living with HIV (PLHIV) is crucial to their sustained uptake of HIV services as well as psychological and social wellbeing. However, no measures exist to assess resilience specifically in relation to living with HIV. We developed the PLHIV Resilience Scale and evaluated its performance in surveys with 1207 PLHIV in Cameroon, Senegal and Uganda as part of the PLHIV Stigma Index-the most widely used tool to track stigma and discrimination among PLHIV worldwide. Factor analyses demonstrated satisfactory psychometric properties and reliability (alphas = 0.81-0.92). Levels of resilience (e.g., whether one's self-respect has been positively, negatively, or not affected by one's HIV status) varied substantially within and across countries. Higher resilience was associated with less depression in each country (all p < 0.001), and, in Cameroon and Uganda, better self-rated health and less experience of stigma/discrimination (all p < 0.001). The final 10-item PLHIV Resilience Scale can help inform interventions and policies.

Key findings on legal and regulatory barriers to HIV testing and access to care across Europe.

OBJECTIVE: The aim of this work within OptTEST by HiE has been to demonstrate the role of legal and regulatory barriers in hindering access to HIV testing, treatment and care across Europe and to produce tools to help dismantle them. METHODS: An online survey to assess country-specific data on legal and regulatory barriers distributed widely across the WHO Europe region. Literature reviews conducted in January-October 2015 in English, in November 2015 in Russian, and updated in April 2017. Semi-structured interviews were conducted with 25 key actors within the HIV field to feed into case studies and tip sheets on how to dismantle legal and regulatory barriers. RESULTS: More than 160 individuals and organisations from 49 countries across the WHO European region provided responses which were analysed and cross checked with other data sources and a searchable database produced (legalbarriers.peoplewithhiveurope.org). The conducted literature reviews yielded 88 papers and reports which identify legal and regulatory barriers to key populations' access to HV testing and care. Based on the interviews with key actors, ranging from PLHIV activists to government officials, on lessons-learned, a series of tip sheets and ten case studies were written-up intended to inform and inspire the HIV community to address and overcome existing barriers (opttest.eu/Tools). CONCLUSION: While some of the barriers identified may require major changes to wider health systems, or long term legal reform, many are open to a simple change in regulations or custom and practice. We have the tools. Why can't we finish the job?

Overcoming obstacles to late presentation for HIV infection in Europe.

OBJECTIVE: The central goal of the HIV in Europe Initiative is to promote testing and treatment throughout Europe and Central Asia in order to decrease the number of people living with HIV presenting late for care. This article summarizes the results from the HIV in Europe 2009 Conference and the early results of the projects set up by the initiative, and discusses their implications for the future. METHODS: In November 2009, 100 key stakeholders from 25 countries met in Stockholm at the HIV in Europe Conference. The focus was to address five key issues that contribute to the barriers to testing identified in 2007 at an innovative HIV conference. The conference discussed barriers to testing and other reasons for late presentation and outlined concrete recommendations to address the problem. RESULTS: An early result of the initiative has been stimulation of the process of reaching a consensus definition of what is meant by a 'late presenter', with this definition to be implemented at the European level. Steps are being taken to advocate for appropriate health policies and surveillance data related to HIV throughout Europe. Also, the initiative has set up projects related to the barriers to testing, i.e. criminalization law, stigmatization and lack of offering of testing for people presenting with certain indicator diseases. CONCLUSIONS: The final results of ongoing projects will be published and widely disseminated in 2010 and beyond. The HIV in Europe Initiative will continue to reinforce collaboration, advocacy and networking activities in the field throughout Europe.

Aplastic anaemia in association with coeliac disease: a series of three cases.

We report a series of three patients in whom the diagnoses of aplastic anaemia (AA) and coeliac disease were made concurrently. Haematological manifestations of coeliac disease are well described but this is the first report to suggest an association with aplastic anaemia. 'Silent/atypical coeliac disease', in the absence of gastrointestinal symptoms, is increasingly recognised and patients may present with generalised symptoms, such as malaise and fatigue, which are easily attributable to AA. Immunosuppressive therapy for AA could modulate the course of celiac disease. We recommend clinicians should be vigilant for signs of coeliac disease in patients with AA.

Comparison of long-term outcomes after allogeneic hematopoietic stem cell transplantation from matched sibling and unrelated donors.

Long-term survivors of hematopoietic stem cell transplants remain at risk of potentially fatal complications that detract from life quality. Long-term morbidity and mortality were compared between matched recipient cohorts surviving 2 or more years and defined by donor type, HLA matched sibling donor (MSD) or volunteer unrelated donor (URD). Patients were previously entered into the prospective multicenter International Unrelated Search and Transplant Study. Thirty-nine centers provided data on 108 URD and 355 MSD recipients surviving more than 2 years. Long-term survival, performance status, chronic GvHD (c-GvHD), secondary malignancy, endocrine dysfunction, cataracts, bone necrosis and dental pathology were compared between cohorts. Twelve year survival was 77+/-5% for the MSD and 67+/-11% for the URD cohort (P=0.1). Late death occurred in 105 of 463 recipients alive at 2 years, 73 after 355 (21%) MSD and 32 after 108 (30%) URD transplants, P=0.10. Of 105 deaths, the cause was relapse in 60 and unrelated to relapse in 45 cases. Cumulative incidence of extensive c-GvHD (P=0.002), cataracts (P=0.02) and bone necrosis (P=0.02) was higher after URD transplants. No long-term difference in endocrine dysfunction, secondary malignancy and major dental pathology was detected. This landmark study will assist physicians counseling patients pre-transplant and with their long-term care post transplant.

Bone marrow transplants from mismatched related and unrelated donors for severe aplastic anemia.

For patients with acquired severe aplastic anemia without a matched sibling donor and not responding to immunosuppressive treatment, bone marrow transplantation from a suitable alternative donor is often attempted. We examined risks of graft failure, graft-versus-host disease and overall survival after 318 alternative donor transplants between 1988 and 1998. Sixty-six patients received allografts from 1-antigen and 20 from >1-antigen mismatched related donors; 181 from matched and 51 from mismatched unrelated donors. Most patients were young, had had multiple red blood cell transfusions and poor performance score at transplantation. We did not observe differences in risks of graft failure and overall mortality by donor type. The probabilities of graft failure at 100 days after 1-antigen mismatched related donor, >1-antigen mismatched related donor, matched unrelated donor and mismatched unrelated donor transplants were 21, 25, 15 and 18%, respectively. Corresponding probabilities of overall survival at 5 years were 49, 30, 39 and 36%, respectively. Although alternative donor transplantation results in long-term survival, mortality rates are high. Poor performance score and older age adversely affect outcomes after transplantation. Therefore, early referral for transplantation should be encouraged for patients who fail immunosuppressive therapy and have a suitable alternative donor.

Incidence and specificity of HLA antibodies in multitransfused patients with acquired aplastic anemia.

BACKGROUND: This study aimed to establish the prevalence and characteristics of anti-HLA in antibody acquired aplastic anemia patients following cessation of antithymocyte globulin therapy and to characterize antibody in terms of epitope specificity. STUDY DESIGN AND METHODS: One hundred and fifty multitransfused, untransplanted patients from eight European centers were investigated by serologic methods. RESULTS: Sixty-two percent were antibody positive. Eighteen HLA-Class-I-specific antibodies (15 IgG, 3 IgM) were identified in 13 patients; 13 antibodies were specific for HLA-A epitopes and 5 for HLA-B. Epitope analysis identified significant correlation between serum reactivity and amino acid substitutions associated with HLA-Class-I epitopes. An excess of antibodies to HLA-A1-associated cross-reactive groups was identified. There was no significant difference in antibody frequency in patients taking cyclosporine compared to those who were not. CONCLUSION: Data suggested a contribution from B cell memory of alloantigens introduced during pregnancy. In some cases, antibody production continued many years after the last transfusion, and although the target varied between individual patients, the antibody to HLA was focused on a few specific Class I epitopes, the majority of which mapped to the HLA-A molecule.

The role of occupational and environmental exposures in the aetiology of acquired severe aplastic anaemia: a case control investigation.

Aplastic anaemia is a rare but serious disorder with a high morbidity and mortality rate. The causes of aplastic anaemia are, for the most part, unknown. We report on the hypothesis that aplastic anaemia may be caused by occupational and/or environmental exposures to certain chemicals. The UK Aplastic Anaemia Study was an interview-based case-control study covering the whole of Great Britain. Those patients diagnosed between 1 July 1993 and 20 October 1997, aged < or =75 years and born and diagnosed in the UK were eligible for the study. Two hundred eligible cases of aplastic anaemia were compared with 387 age- and sex-matched controls. A number of occupational exposures showed increases in risk. In a multivariate model of these exposures the odds ratios (ORs) for solvents/degreasing agents, pesticides and radiation were >2 and statistically significant. Reported chemical treatment of houses within 5 years of diagnosis had a significantly raised risk for adults [OR = 2.51, 95% confidence interval (CI) 1.02-12.01], particularly for woodworm treatment (OR = 5.1, 95% CI 1.5-17.4). This study identified significant risks associated with self-reported exposure to solvents, radiation and pesticides in the workplace. Self-reported chemical treatment of houses was also associated with an increased risk of developing aplastic anaemia, in keeping with previous literature.

In vitro expansion of cord blood does not prevent engraftment of severe combined immunodeficient repopulating cells.

This study aimed to assess the potential of human cord blood (CB) cells to engraft in the xenogenic non-obese diabetic/severe combined immunodeficient (NOD/SCID) mouse model after in vitro expansion culture. We also studied the quality of human haemopoiesis arising from the transplantation of fresh or expanded cells in this model. Cord blood CD34(+) cells were cultured for 3, 7 or 10 d with stem cell factor, Flt3, thrombopoietin, interleukin 3 (IL-3), IL-6 and granulocyte colony-stimulating factor, all at 10 ng/ml in serum-replete conditions. Transplantation of mice with fresh CB containing 3 x 10(4) CD34(+) cells and 1-2 SCID repopulating cells (SRC) resulted in a median of 7.4% (0.4%-76.8%) human engraftment. When mice received the expanded product of 1-2 SRC, the ability to repopulate NOD/SCID mice was maintained even after 10 d of in vitro culture. Serial dilution of the expanded cells suggested that in vitro expansion had increased SRC numbers two- to fourfold. Expanded SRC produced long-term culture-initiating cells, clonogenic cells and CD34(+) cells in the same proportions as fresh cells after successful engraftment. Therefore, expanded SRC were able to differentiate in the same way as fresh SRC. There was a trend towards lower levels of engraftment when d 7 cultured cells were transplanted (median engraftment 0.8%, range 0.0-24.0%) compared with 1-2 fresh SRC. Our data suggest that this is owing to reduced proliferation of cultured cells in vivo. By utilizing limiting numbers of CB SRC, we confirmed that the engraftment potential of SRC in the NOD/SCID model was preserved after in vitro expansion. Furthermore, dilution experiments strongly suggest two- to fourfold expansion of SRC in vitro. These studies are relevant for developing clinical stem cell expansion strategies.

Status of umbilical cord blood transplantation in the year 2001.

Umbilical cord blood (UCB) transplantation is limited to small recipients because of the low haemopoietic cell dose. Children from ethnic minority groups may benefit most from cord blood transplantation. Cohort controlled retrospective data indicate that there is significantly less acute and chronic graft versus host disease associated with the transplantation of human major histocompatibility complex (HLA) identical sibling cord blood compared with HLA identical sibling marrow. Controlled data are not yet available to confirm this observation in unrelated donor cord blood transplantation. The difference in leukaemic relapse seen after cord blood compared with bone marrow transplantation is also unknown. Tentative recommendations for the use of umbilical cord blood for transplantation are as follows. Collection is indicated from healthy newborn siblings when urgent transplantation is required for an older child in a family. The haematologist responsible for the older child, with the approval of the family and the obstetric team, should contact the medical director of the nearest cord blood bank to discuss arrangements for the UCB to be collected and HLA typed. Antenatal blood sampling to HLA type the fetus is not recommended. Umbilical cord blood should be considered when allogeneic transplantation is the treatment of choice for a child who does not have an HLA identical sibling, or a well matched unrelated adult volunteer donor. The potential advantages and disadvantages of using an HLA haplotype matched peripheral blood stem cell family donor rather than an unrelated cord blood donation should be discussed. There are no comparative data available as yet. At present, UCB transplantation should only be considered if a suitably matched donation contains at least 2 x 10(7)/kg nucleated cells. Effectively, this means that most adults and larger children are not suitable recipients.

The CD34(+)CD38(neg) population is significantly increased in haemopoietic cell expansion cultures in serum-free compared to serum-replete conditions: dissociation of phenotype and function.

Expansion of haemopoietic stem cells is proposed to combat graft failure in adult recipients following cord blood (CB) transplantation. Cultures are traditionally performed in medium containing FCS, but to transfer expansion to the clinic, 'good manufacturing practice' (GMP) standards are required. This study evaluated expansion cultures in culture bags and serum-free (SF) conditions, to comply with GMP, by analysing sub-populations of CD34(+) cells, colony-forming cells (CFC) and long-term culture initiating cells (LTC-IC). CD34(+)cell analysis has previously been used to measure clonogenic capacity and the CD34(+)CD38(neg) surface phenotype to measure primitive cell numbers. In this study, comparison of expansion in serum-replete medium with that in SF conditions demonstrated a lack of expression of CD38 on CD34(+) cells in the absence of serum. These findings must be considered in clinical studies using in vitro expansion in SF conditions, and the CD34(+)CD38(neg) phenotype should not be used to confirm maintenance, or expansion, of primitive progenitor cells.

Quantitation of cyclosporine-sensitive and -resistant allospecific cytotoxic cells at birth.

In the absence of clinically relevant models of acute rejection we have attempted to develop an assay to measure cyclosporine-resistant allospecific cytotoxic cells in vitro, beginning at birth. The principle of limiting dilution analysis was applied to investigate umbilical cord bloods as responders. Responders were incubated for 1 h in different concentrations of cyclosporine and irradiated HLA mismatched stimulator cells from healthy adults added, followed by recombinant IL-2. After 7 days, responders were tested against three europium-labelled PHA blasts: stimulator, responder and third party. A significant number of cyclosporine-resistant allospecific cytotoxic cell precursors were found in cord blood indicating prior activation. They may have been primed in utero against non-inherited maternal HLA antigens. Cyclosporine-resistant allospecific cytotoxic cell precursors were demonstrated in human umbilical cord blood using a quantitative assay. These cells may influence the reaction to subsequent transplants.

Consensus Conference on the Treatment of Aplastic Anemia.

This article presents guidelines for the diagnosis and treatment of aplastic anemia (AA) established by a consensus panel of investigators from various countries. The panel used the scientific evidence presented during the Consensus Conference forum and found in the scientific literature to prepare guidelines categorized as immunosuppressive therapy, unrelated bone marrow transplantation in patients with AA, and myelodysplasia/acute myeloid leukemia after immunosuppressive therapy.

Development of a district Cord Blood Bank: a model for cord blood banking in the National Health Service.

The Bristol Cord Blood Bank was established as a pilot project within existing health services to establish cost-effective recruitment, collection and processing suitable for use in the NHS should cord blood become a routine source of haemopoietic stem cells for transplantation in the UK. An important aim of the project was to evaluate the feasibility of establishing a midwifery-based collection network, thus utilising expertise already in place. Collection was performed on the delivery suite immediately after the placenta was delivered. The clinical experience of the midwife collector/counsellors allowed rapid pre-collection assessment of the condition of the cord and placenta. This prevented collection attempts from diseased or otherwise damaged placentas, leading to conservation of resources by preventing collection of most small volume donations. The bank was established within the National Blood Service, Bristol Centre to achieve Good Manufacturing Practice standards and ensure that processing was subject to the same stringency required for other sources of haemopoietic stem cells. Cord blood is an expensive resource. By utilising existing expertise in district Obstetric and National Blood Services, the Bristol Cord Blood Bank may serve as a model for health economic evaluation of cord blood banking of volunteer donations within the NHS.

Current results of bone marrow transplantation in patients with acquired severe aplastic anemia. Report of the European Group for Blood and Marrow transplantation. On behalf of the Working Party on Severe Aplastic Anemia of the European Group for Blood and Marrow Transplantation.

We have analyzed 2,002 patients grafted in Europe between 1976 and 1998 from an identical twin (n = 34), from an HLA-identical sibling (n = 1,699) or from an alternative donor (n = 269), which included unrelated and family mismatched donors. The proportions of patients surviving in these three groups are, respectively, 91, 66 and 37%: major causes of failure were acute graft-versus host disease (GvHD) (11%), infection (12%), pneumonitis (4%), rejection (4%). In multivariate Cox analysis, factors predicting outcome were patient's age (p < 0.0001), donor type (p < 0.0001), interval between diagnosis and bone marrow transplantation (BMT) (p < 0.0005), year of BMT (p = 0.0005) and female donor for a male recipient (p = 0.02). Patients were then divided in two groups according to the year of BMT: up to or after 1990. The overall death rate dropped from 43 to 24% (p < 0.00001). Improvements were seen mostly for grafts from identical siblings (from 54 to 75%, p < 0.0001), and less so for alternative-donor grafts (from 28 to 35%; p = 0.07). Major changes have occurred in the BMT protocol: decreasing use of radiotherapy in the conditioning regimen (from 35 to 24%; p < 0.0001) and increasing use of cyclosporin (with or without methotrexate) for GvHD prophylaxis (from 70 to 98%; p < 0.0001). In conclusion, the outcome of allogeneic BMT for patients with severe aplastic anemia has considerably improved over the past two decades: young patients, grafted early after diagnosis from an identical sibling, have currently an over 80% chance of long-term survival. Transplants from twins are very successful as well. The risk of complications with alternative donor transplants is still high.

Treatment of acquired severe aplastic anemia: bone marrow transplantation compared with immunosuppressive therapy--The European Group for Blood and Marrow Transplantation experience.

Patients with severe aplastic anemia (SAA) can be successfully treated with bone marrow transplantation (BMT) or immunosuppressive therapy (IS). The current outcome using both forms of therapy among 3,669 patients treated in Europe between 1976 and 1998 is reviewed. Significant progress has been made and the overall risk of failure is now low, with survival rates greater than 80% for both treatments. Chronic graft-versus-host disease (GvHD) remains a problem for BMT patients, and carries a high risk of lethal complications. On the other hand, IS patients are exposed to late failure due to relapse or clonal/malignant diseases. First-line BMT from identical siblings is compared with IS therapy in an intent-to-treat analysis of 1,765 patients, regardless of subsequent transplant status. The outcome of SAA patients has improved considerably over time and is influenced by patient variables such as severity of the disease and age, but also by the choice of the initial treatment.

Frequencies of cytotoxic T lymphocyte precursor estimate in three different populations.

There is speculation that high cytotoxic T lymphocyte precursor frequencies (CTLpf) correlate with poor clinical outcome of bone marrow/organ transplantation. It is also believed that human umbilical cord blood is immunologically naive, and, therefore cord blood T cells may be less able to mediate graft versus host disease than marrow-derived T cells. CTLpf were determined in peripheral blood mononuclear cells collected from healthy adults, human umbilical cord blood and renal dialysis patients who were randomly selected and entered into this study. A highly sensitive non-radioactive Europium release cytotoxicity assay was optimized and modified to carry out the CTLpf estimation by using the principle of limiting dilution analysis. The results of CTLpf in healthy adults ranged from 1/694 to 1/66,666, median 1/7,339 (n=10); cord blood ranged from 1/1,562 to 1/35,714, median 1/10,162 (n=6) and dialysis patients ranged from 1/1,054 to 1/17,857 median 1/5,208 (n=9). The results demonstrated that there is little difference of CTLpf median values between the groups, but there is a wide variation of CTLpf between individuals within a population. It suggests that this variation should be taken into account when considering CTLpf assay as pre-transplantation cross-match procedure.