Anti-HLA alloantibodies of the IgA isotype in re-transplant candidates part II: Correlation with graft survival.

We reported previously on the widespread occurrence of anti-HLA alloantibodies of the IgA isotype (anti-HLA IgA) in the sera of solid-organ re-transplantation (re-tx) candidates (Arnold et al., ). Specifically focussing on kidney re-tx patients, we now extended our earlier findings by examining the impact of the presence and donor specificity of anti-HLA IgA on graft survival. We observed frequent concurrence of anti-HLA IgA and anti-HLA IgG in 27% of our multicenter collective of 694 kidney re-tx patients. This subgroup displayed significantly reduced graft survival as evidenced by the median time to first dialysis after transplantation (TTD 77 months) compared to patients carrying either anti-HLA IgG or IgA (TTD 102 and 94 months, respectively). In addition, donor specificity of anti-HLA IgA had a significant negative impact on graft survival (TTD 74 months) in our study. Taken together, our data strongly indicate that presence of anti-HLA IgA, in particular in conjunction with anti-HLA-IgG, in sera of kidney re-tx patients is associated with negative transplantation outcome.

Benefits and limitations of belatacept in 4 hand-transplanted patients.

Belatacept (cytotoxic T-lymphocyte-associated protein 4 Ig) is an emerging treatment in kidney transplantation. Lack of nephrotoxicity and possibly an inhibitory effect on the development of donor-specific antibodies (DSAs) make it an interesting agent in hand transplantation. To reduce calcineurin inhibitor immunosuppression and preserve kidney function, we have added belatacept to the therapeutic regimen of 4 hand-transplanted patients at month 4 and at 6, 9, and 13 years after hand-forearm transplantation. Patients received 5 mg/kg belatacept every 2 weeks, and the dosing interval was extended to 4 weeks after 5 applications. Belatacept was initially well tolerated in all cases. Two patients were weaned to a low-dose tacrolimus monotherapy together with monthly belatacept applications. One patient is taking belatacept with lowered tacrolimus and sirolimus trough levels. A fourth patient had significant levels of DSAs at time of conversion and progressed to a severe necrotizing rejection early despite an unaltered baseline immunosuppression. Finger skin necrosis and histologic signs of severe chronic allograft vasculopathy eventually led to amputation of the graft. Implementation of belatacept can be beneficial in hand transplantation. However, our findings indicated both potential and caution and reflection of the immunologic state at the time of conversion.

[Objective Criteria in the Medicinal Therapy for Type II Diabetes: An Analysis of the Patients' Perspective with Analytic Hierarchy Process and Best-Worst Scaling]. / Zielkriterien der medikamentösen Therapie des Diabetes Typ II: Eine Analyse der Patientenperspektive mit Analytic Hierarchy Process und Best-Worst Scaling.

BACKGROUND: The patient's perspective with regard to decision criteria of alternative treatment options has hardly been analysed. The objective of any intervention in health-care is to increase the patient's benefit. OBJECTIVE: This study aimed to analyse the patient-relevant decision criteria in the medicinal therapy of type II diabetes. The characteristics of a drug therapy that are relevant for the choice of the patients should be revealed. METHOD: An explorative qualitative study (N=15) in combination with a quantitative survey (in total N=388) using Analytic Hierarchy Process and Best-Worst Scaling aimed at the determination of the importance of patient-relevant decision criteria. RESULTS: The quantitative AHP- and BWS survey resulted in a clear dominance of the attribute "HbA1c level" and its optimal settings, for both with oral anti-diabetics treated patients (OAD) and insulin-treated patients. In the group of the OAD patients both methods independently showed the same ranking of the following 3 ranks: "delay of insulin therapy" (rank 2), "occurrence of hypoglycaemia" (rank 3) and "weight changes" (rank 4). For insulin patients "the occurrence of hypoglycaemia" follows in the AHP on the second rank and in the BWS on the 3(rd) rank. Compared to OAD patients, the relevance of the target criterion "weight changes" decreases in the group of the insulin patients in the AHP on the last rank (rank 7) and in the BWS on the second last rank (rank 6). CONCLUSION: For the first time the methods of AHP and BWS were combined to assess how patients weight between different characteristics of the treatment in type II diabetes and which influence those criteria of therapy have on the patient's benefit. Both patient groups show differences in the horizon of experience and thus in the ranking of the decision criteria.

[Patients' Priorities in the Treatment of Neuroendocrine Tumours: An Analytical Hierarchy Process]. / Die Patientenperspektive in der Behandlung von Neuroendokrinen Tumoren: Eine Analyse mittels Analytic Hierarchy Process.

Background: Neuroendocrine tumours (NET) are relatively rare, usually slow-growing malignant tumours. So far there are no data on the patient preferences/priorities regarding the therapy for NET. This empirical study aimed at the elicitation of patient priorities in the drug treatment of NET. Method: Qualitative patient interviews (N=9) were conducted. To elicit the patient's perspective regarding various treatment aspects of NET a self-administered questionnaire using the Analytical Hierarchy Process (AHP) was developed. The data collection was carried out using paper questionnaires supported by an item response system in a group discussion. To evaluate the patient-relevant outcomes, the eigenvector method was applied. Results: N=24 patients, experts and relatives participated in the AHP survey. In the AHP all respondents had clear priorities for all considered attributes. The attribute "overall survival" was the most significant feature of a drug therapy for all respondents. As in the qualitative interviews, "efficacy attributes" dominated the side effects in the AHP as well. The evaluation of all participants thus showed the attributes "overall survival" (Wglobal:0.418), "progression-free survival" (Wglobal:0.172) and "response to treatment" (Wglobal:0.161) to be most relevant. "Occurrence of abdominal pain" (Wglobal:0.051) was ranked sixth, with "tiredness/fatigue" and "risk of a hypoglycaemia" (Wglobal:0.034) in a shared seventh place. Conclusion: The results thus provide evidence about how much influence a treatment capacity has on therapeutic decisions. Using the AHP major aspects of drug therapy from the perspective of those affected were captured, and positive and negative therapeutic properties could be related against each other. Based on the assessment of the patient's perspective further investigation must elicit patient preferences for NET drug therapy. In the context of a discrete choice experiment or another choice-based method of preference measurement, the results obtained here can be validated and the therapeutic features weighted according to their preferability.

Head-to-head comparison between two screening systems for HBsAG, anti-HBc, anti-HCV and HIV combination immunoassays in an international, multicentre evaluation study.

BACKGROUND: Mandatory screening of blood donations for hepatitis B and hepatitis C viruses and human immunodeficiency viruses 1 and 2 requires assays with exceptional sensitivity and specificity. This study reports the results from a direct head-to-head comparison of the Elecsys HBsAG II, Elecsys Anti-HBc, Elecsys Anti-HCV II and Elecsys HIV combi PT immunoassays with the respective ABBOTT PRISM/Architect instrument immunoassays in a multicentre blood bank evaluation study. STUDY DESIGN AND METHODS: Assay validation was performed in the blood screening laboratories of four blood bank centres in Austria, Germany, Spain and Thailand, where both first-time donor samples (approximately 6000 donors) and repeat donor samples (approximately 14,000 donors) were screened. RESULTS: Of all screened donor samples, 93 (0.46%) were confirmed to be positive using assays from both manufacturers. The specificity of all immunoassays was >99.5% and was comparable between first-time and multiple-time donors. A direct comparison between the assays from Roche and ABBOTT according to Bland and Altman analysis demonstrated equivalent quality. CONCLUSIONS: These results suggest that the Elecsys immunoassays for HBV, HCV and HIV infection, with a comparative sensitivity of 100% and a specificity exceeding the common technical specification threshold of >99.5%, meet the stringent performance criteria stipulated for blood donor screening for these infectious agents. Significant differences in the specificity between first-time and repeat donors were not detectable.

[Characteristics of integrated care programmes and their impact on patient benefit: a discrete-choice experiment for integrated care networks]. / Eigenschaften von integrierten Versorgungs-programmen und deren Einfluss auf den Patientennutzen: Ein Discrete-Choice Experiment für Versorgungsnetzwerke.

PURPOSE: Innovative care models shall reduce the frictional losses in health-care. The successful implementation of care networks requires the acceptance by the health care providers, by the patients and citizens as well as by the payers. The consideration of preferences is an essential factor for success. The aim of this study is to analyse patient preferences. METHODS: With the help of Discrete-Choice experiment 21 patient-relevant attributes of innovative healthcare programmes were examined. On the basis of a balanced overlapping design (sawtooth) a total of 140 choice sets with the highest possible D efficiency was generated. The 21 attributes were divided into 4 thematic priorities for analysis. The cost attribute was integrated as a uniform comparator. The evaluation was done by a random effects logit estimation (STATA). RESULTS: The representative samples (N=1 322) revealed that in all 4 DCE blocks the attribute "additional costs" had the strongest influence on the patients choice (1: coeff.; 1.047; 2: coeff.: 1.105; 3.: coeff.: 0.956; 4.: coeff.: 0.954). This was followed by "medical apparatus and facilities", "waiting time for an appointment", "professional experience", "travelling time to treatment site", and "exchange of clinical information". "Transfer management" and "consideration of individual circumstances" for example, had a small influence on patient choice. CONCLUSION: In order to increase the acceptance of innovative health-care programmes preferences must be known and integrated into the design of the services. The present study has attempted to depict the patients' perspectives towards the new care systems. The individual selection decisions were not, as would be expected, influenced by the innovative approaches such as case management or shared decision making but rather by the quality of the infrastructure, the waiting times and professional experience.

Performance evaluation of a new fourth-generation HIV combination antigen-antibody assay.

Education and diagnostic tests capable of early detection represent our most effective means of preventing transmission of human immunodeficiency virus (HIV). The importance of early detection is underlined by studies demonstrating increased life expectancy following early initiation of antiviral treatment. The Elecsys(®) HIV combi PT assay is a fourth-generation antigen-antibody combination assay developed to allow earlier detection of seroconversion, and to have increased sensitivity and improved specificity. We aimed to determine how early the assay could detect infection compared with existing assays; whether all HIV variants could be detected; and the assay's specificity using samples from blood donors, routine specimens, and patients with potential cross-reacting factors. Samples were identified as positive by the Elecsys(®) assay 4.9 days after a positive polymerase chain reaction result (as determined by the panel supplier), which was earlier than the 5.3-7.1 days observed with comparators. The analytical sensitivity of the Elecsys(®) HIV combi PT assay for the HIV-1 p24 antigen was 1.05 IU/mL, which compares favorably with the comparator assays. In addition, the Elecsys(®) assay identified all screened HIV subtypes and displayed greater sensitivity to HIV-2 homologous antigen and antibodies to HIV-1 E and O and HIV-2 than the other assays. Overall, the specificity of the Elecsys(®) assay was 99.88 % using samples from blood donors and 99.81 % when analyzing unselected samples. Potential cross-reacting factors did not interfere with assay performance. The Elecsys(®) HIV combi PT assay is a sensitive and specific assay that has been granted the CE mark according to Directive 2009/886/EC.

16(th) IHIW: anti-HLA alloantibodies of the of IgA isotype in re-transplant candidates.

In this multicentre study, sera from 803 retransplant candidates, including 775 kidney transplant recipients, were analysed with regard to the presence and specificity of anti-HLA alloantibodies of the IgA isotype using a modified microsphere-based platform. Of the kidney recipients, nearly one-third (n = 237, 31%) had IgA alloantibodies. Mostly, these antibodies were found in sera that also harboured IgG alloantibodies that could be found in a total of 572 (74%) of patients. Interestingly, IgA anti-HLA antibodies were preferentially targeting HLA class I antigens in contrast to those of the IgG isotype, which targeted mostly both HLA class I and II antigens. Donor specificity of the IgA alloantibodies could be established for over half of the 237 patients with IgA alloantibodies (n = 124, 52%). A further 58 patients had specificities against HLA-C or HLA-DP, for which no information regarding donor typing was available. In summary, these data showed in a large cohort of retransplant candidates that IgA alloantibodies occur in about one-third of patients, about half of these antibodies being donor specific.

Clinical evaluation of new automated cytomegalovirus IgM and IgG assays for the Elecsys(®) analyser platform.

Cytomegalovirus (CMV) is a leading cause of physical and neurological abnormalities in newborns. Hence, the diagnosis of CMV infection in pregnant women is necessary in order to allow appropriate management of their pregnancy. New assays have been developed for the Roche Elecsys® immunoassay platform that detect CMV-specific immunoglobulin (Ig)M and IgG, with the IgM assay designed to target IgM produced at the start of infection rather than IgM persisting later in infection. This study aimed to evaluate the performance of the new assays compared with other commercial kits widely distributed in laboratories. The performance of the Elecsys and comparator CMV IgM and IgG assays was assessed using 967 preselected patient samples characterised by CMV infection status, as well as being compared using 1,668 unselected clinical samples. The Elecsys CMV IgM and IgG assays performed consistently with comparator assays using the preselected samples. The Elecsys CMV IgM assay showed improved sensitivity compared with the Enzygnost® assay in primary infection (91.2 % vs. 79.4 %) and improved specificity over the Architect® assay in potentially cross-reacting samples (94.1 % vs. 82.4 %). The Elecsys IgM assay reported fewer positive results in the later stages of CMV infection compared with ETI-CYTOK-M ELISA, while the Elecsys IgG assay reported slightly fewer negative results in the early stages of infection compared with ETI-CYTOK-G ELISA. There was good agreement between Elecsys and comparator assays using unselected clinical samples (range 90.4-99.4 %). The Elecsys CMV IgM and IgG assays compare well with routinely used assays and are suitable for clinical use.

A discrete choice experiment investigating HIV testing preferences in South Africa.

BACKGROUND: South Africa (SA) has the world's highest burden of HIV infection, with an estimated 13.7% of the population living with HIV (PLWH/Persons Living With HIV). The early identification of PLWH and rapid engagement of them in HIV treatment are indispensable tools in the fight against HIV transmission. Understanding client preferences for HIV testing may help improve uptake. This study aimed to elicit client preferences for key characteristics of HIV testing options. METHODS: A discrete-choice experiment (DCE) was conducted among individuals presenting for HIV testing at two public primary healthcare facilities in Cape Town, South Africa. Participants were asked to make nine choices between two unlabeled alternatives that differed in five attributes, in line with previous DCEs conducted in Tanzania and Colombia: testing availability, distance from the testing center, method for obtaining the sample, medication availability at testing centers, and confidentiality. Data were analyzed using a random parameter logit model. RESULTS: A total of 206 participants agreed to participate in the study, of whom 199 fully completed the choice tasks. The mean age of the participants was 33.6 years, and most participants were female (83%). Confidentiality was the most important attribute, followed by distance from the testing center and the method of obtaining a sample. Patients preferred finger prick to venipuncture as a method for obtaining the sample. Medication availability at the testing site was also preferred over a referral to an HIV treatment center for a positive HIV test. There were significant variations in preferences among respondents. CONCLUSION: In addition to accentuating the importance of confidentiality, the method for obtaining the sample and the location of sites for collection of medication should be considered in the testing strategy. The variations in preferences within target populations should be considered in identifying optimal testing strategies.

A novel HLA-A allele detected by sequence-based typing: A*68:66.

The novel allele HLA-A*68:66 differs from HLA-A*68:01: 01:01 by a synonymous single nucleotide exchange at position 102 (C→T) and three non-synonymous exchanges at position 257 (G→A), position 259 (A→G) and position 261 (C→G) in exon 2.

The immunosuppressive fungal metabolite gliotoxin specifically inhibits transcription factor NF-kappaB.

Opportunistic infections, such as aspergillosis, are among the most serious complications suffered by immunocompromised patients. Aspergillus fumigatus and other pathogenic fungi synthesize a toxic epipolythiodioxopiperazine metabolite called gliotoxin. Gliotoxin exhibits profound immunosuppressive activity in vivo. It induces apoptosis in thymocytes, splenocytes, and mesenteric lymph node cells and can selectively deplete bone marrow of mature lymphocytes. The molecular mechanism by which gliotoxin exerts these effects remains unknown. Here, we report that nanomolar concentrations of gliotoxin inhibited the activation of transcription factor NF-kappaB in response to a variety of stimuli in T and B cells. The effect of gliotoxin was specific because, at the same concentrations, the toxin did not affect activation of the transcription factor NF-AT or of interferon-responsive signal transducers and activators of transcription. Likewise, the activity of the constitutively DNA-binding transcription factors Oct-1 and cyclic AMP response element binding protein (CREB), as well as the activation of protein tyrosine kinases p56lck and p59fyn, was not altered by gliotoxin. Very high concentrations of gliotoxin prevented NF-kappaB DNA binding in vitro. However, in intact cells, inhibition of NF-kappaB did not occur at the level of DNA binding; rather, the toxin appeared to prevent degradation of IkappaB-alpha, NF-kappaB's inhibitory subunit. Our data raise the possibility that the immunosuppression observed during aspergillosis results in part from gliotoxin-mediated NF-kappaB inhibition.

A multicentre evaluation of the Elecsys® HIV Duo assay.

BACKGROUND: Fourth generation HIV assays, which detect both HIV p24 antigen and HIV antibodies are widely used in HIV screening. The combination of markers enables the fourth generation assays to shorten the window of detection, which is important in real-world testing scenarios. The Elecsys® HIV Duo assay is a fourth generation assay, which provides an overall result based on both the detection of the p24 antigen and HIV antibodies, and lists the sub-results for the antibody and antigen units. OBJECTIVES AND STUDY DESIGN: The performance of the Elecsys® HIV Duo assay was assessed at five international centres and compared with other available fourth generation assays. RESULTS: The specificity of the Elecsys® HIV Duo assay in 13,328 blood donor samples was 99.87% (95% confidence interval [CI] 99.80-99.93) and was 100% (95% CI 99.63-100) in 1000 routine diagnostic samples. Sensitivity was assessed in 139 seroconversion panels; the Elecsys® HIV Duo assay detected a greater number of positive samples/number of bleeds compared with other assays investigated. An individual analysis of those seroconversion panels also shows that the Elecsys® HIV Duo assay compared to other fourth generation assays detected HIV up to 2 days earlier than other assays. The Elecsys® HIV Duo assay also detected 125/130 'early seroconversion' samples assessed, which was greater than the number detected with comparator fourth generation assays. CONCLUSION: These results indicate that the Elecsys® HIV Duo assay is appropriate for use in the diagnosis of HIV and for screening of blood donations and is sensitive for the early detection of HIV.