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Aim: Invasive mold diseases (IMDs) are associated with significant morbidity and mortality. Approved treatments include voriconazole (VORI), liposomal amphotericin B (L-AMB), posaconazole (POSA) and isavuconazole (ISAV). A UK-based economic model was developed to explore the cost of treating IMDs with ISAV versus L-AMB followed by POSA. Materials & methods: As indirect comparisons have demonstrated similar efficacy between the comparators, a cost-minimization approach was taken. Drug acquisition, administration & monitoring, and hospitalization costs were evaluated from the healthcare system perspective. Results: Per-patient costs were UK£14,842 with ISAV versus UK£18,612 with L-AMB followed by POSA. Savings were driven by drug acquisition, and administration & monitoring costs. Conclusion: ISAV has the potential to reduce IMD treatment costs relative to L-AMB followed by POSA.

Objectives: Voriconazole, amphotericin B (AmB) formulations, and isavuconazole are all included in guideline recommendations for treatment of patients with invasive aspergillosis (IA) but the relative efficacy of isavuconazole versus AmB formulations has not been directly compared. We aimed to estimate the relative efficacy of isavuconazole compared with AmB deoxycholate (AmB-D), liposomal AmB (L-AmB), and voriconazole for the treatment of patients with proven/probable IA. Methods: Nine literature databases were screened for randomized controlled trials comparing treatments with any of voriconazole, AmB-D, L-AmB and isavuconazole for treatment of proven/probable IA. Articles meeting the criteria were included in a meta-analysis to determine the efficacy of AmB-D, L-AmB and voriconazole relative to isavuconazole based on all-cause mortality (ACM) and overall response using a fixed-effects model. Results: Four articles were identified that compared L-AmB with AmB-D (Study 1), standard-dose L-AmB (3–5 mg/kg/day) with high-dose L-AmB (10 mg/kg/day; Study 2), voriconazole with AmB-D (Study 3), and isavuconazole with voriconazole (Study 4). In the network meta-analysis, isavuconazole was statistically superior to AmB-D on both ACM (odds ratio [95% credible intervals] shown as natural log, 1.00 [0.26, 1.74]) and overall response (−1.39 [−2.21, −0.63]). Differences between isavuconazole, and standard-dose L-AmB, high-dose L-AmB and voriconazole were not statistically significant for either ACM (0.18 [−1.17, 1.53], 0.50 [−1.11, 2.13] and 0.32 [−0.19, 0.84], respectively) or overall response (−0.99 [−2.21, 0.29], −0.89 [−2.41, 0.65] and 0.06 [−0.43, 0.57], respectively). Conclusions: This data suggests that the efficacy of isavuconazole for treatment of IA is superior to AmB-D and comparable with both L-AmB and voriconazole.

Aim: Mucormycosis is a fungal infection associated with high mortality. Until recently, the only licensed treatments were amphotericin B (AMB) formulations. Isavuconazole (ISAV) is a new mucormycosis treatment. A UK-based economic model explored treatment costs with ISAV versus liposomal AMB followed by posaconazole. Materials & methods: As a matched case–control analysis showed similar efficacy for ISAV and AMB, a cost-minimization approach was taken. Direct costs – drug acquisition, monitoring and administration, and hospitalization costs – were estimated from the National Health Service perspective. Results: Per-patient costs for ISAV and liposomal AMB + posaconazole were UK£26,810 and UK£41,855, respectively, with savings primarily driven by drug acquisition and hospitalization costs. Conclusion: ISAV may reduce costs compared with standard mucormycosis therapy.

Background Voriconazole is well established as standard treatment for invasive aspergillosis (IA). In 2017, isavuconazole, a new antifungal from the azole class, with a broader pathogen spectrum, was introduced in Sweden. A model has therefore been developed to compare the cost-effectiveness of isavuconazole and voriconazole in the treatment of possible IA in adults in Sweden. Methods The cost-effectiveness of isavuconazole versus voriconazole was evaluated using a decision-tree model. Patients with possible IA entered the model, with 6% assumed to actually have mucormycosis. It was also assumed that pathogen information would become available during the course of treatment for only 50% of patients, with differential diagnosis unavailable for the remainder. Patients who were considered unresponsive to first-line treatment were switched to second-line treatment with liposomal amphotericin-B. Data and clinical definitions included in the model were taken from the published randomised clinical trial comparing isavuconazole with voriconazole for the treatment of IA and other filamentous fungi (SECURE) and the single-arm, open-label trial and case-control analysis of isavuconazole for the treatment of mucormycosis (VITAL). A probabilistic sensitivity analysis was used to estimate the combined parameter uncertainty, and a deterministic sensitivity analysis and a scenario analysis were performed to test the robustness of the model assumptions. The model followed a Swedish healthcare payer perspective, therefore only considering direct medical costs. Results The base case analysis showed that isavuconazole resulted in an incremental cost-effectiveness ratio (ICER) of 174,890 Swedish krona (SEK) per additional quality adjusted life-year (QALY) gained. This was mainly due to the efficacy of isavuconazole against IA and mucormycosis, as opposed to voriconazole, which is only effective against IA. Sensitivity and scenario analyses of the data showed that the average ICER consistently fell below the willingness to pay (WTP) threshold of 1,000,000 SEK. The probability of isavuconazole being cost-effective at a WTP of 170,000 SEK per QALY gained was 50% and at a WTP of 500,000 SEK per QALY gained was 100%. Conclusions This model suggests that the treatment of possible IA with isavuconazole is cost-effective compared with treatment with voriconazole from a Swedish healthcare payer perspective. Electronic supplementary material The online version of this article (10.1186/s12879-019-3683-2) contains supplementary material, which is available to authorized users.

Bloom’s syndrome (BS) is an autosomal recessive disease, caused by mutations in the BLM gene. This gene codes for BLM protein, which is a helicase involved in DNA repair. DNA repair is especially important for the development and maturation of the T and B cells. Since BLM is involved in DNA repair, we aimed to study if BLM deficiency affects T and B cell development and especially somatic hypermutation (SHM) and class switch recombination (CSR) processes. Clinical data of six BS patients was collected, and immunoglobulin serum levels were measured at different time points. In addition, we performed immune phenotyping of the B and T cells and analyzed the SHM and CSR in detail by analyzing IGHA and IGHG transcripts using next-generation sequencing. The serum immunoglobulin levels were relatively low, and patients had an increased number of infections. The absolute number of T, B, and NK cells were low but still in the normal range. Remarkably, all BS patients studied had a high percentage (20–80%) of CD4+ and CD8+ effector memory T cells. The process of SHM seems normal; however, the Ig subclass distribution was not normal, since the BS patients had more IGHG1 and IGHG3 transcripts. In conclusion, BS patients have low number of lymphocytes, but the immunodeficiency seems relatively mild since they have no severe or opportunistic infections. Most changes in the B cell development were seen in the CSR process; however, further studies are necessary to elucidate the exact role of BLM in CSR. Electronic supplementary material The online version of this article (10.1007/s10875-017-0454-y) contains supplementary material, which is available to authorized users.

Chronic hand eczema places a heavy burden on patients, often affecting their ability to work. This paper compares the cost-of-illness and treatment approaches for patients with refractory chronic hand eczema, in relation to whether the disease was occupational or unrelated to work factors. Data from 2 surveys, comprising 310 patients with chronic hand eczema insured by German statutory health insurance (SHI) (including work-impaired patients, work-unaffected patients and non-working patients) and known work-related chronic hand eczema insured by occupational health insurance (OHI). Annual healthcare costs of managing work-impaired patients (SHI) and patients with work-related chronic hand eczema (OHI) were €3,164 and €3,309, respectively, approximately double the costs of managing non-working and work-unaffected (SHI) patients. This analysis shows that the costs associated with chronic hand eczema are affected by the correlation of chronic hand eczema with work, with costs being higher for occupational patients with chronic hand eczema.

Background Recovery of thymopoiesis after allogeneic hematopoietic stem cell transplantation is considered pivotal for full immune competence. However, it is still unclear to what extent insufficient recovery of thymopoiesis predicts for subsequent opportunistic infections and non-relapse mortality. Design and Methods A detailed survey of all post-engraftment infectious complications, non-relapse mortality and overall survival during long-term follow-up was performed in 83 recipients of allogeneic stem cell grafts after myeloablative conditioning. Recovery of thymopoiesis was assessed using analysis of signal joint T-cell receptor rearrangement excision circles. The impact of recovery of thymopoiesis at 2, 6, 9 and 12 months post-transplantation on clinical outcome beyond those time points was evaluated by univariate and multivariate Cox regression analyses. Results The cumulative incidence of severe infections at 12 months after transplantation was 66% with a median number of 1.64 severe infectious episodes per patient. Patients in whom thymopoiesis did not recover were at significantly higher risk of severe infections according to multivariable analysis. Hazard ratios indicated 3- and 9-fold increases in severe infections at 6 and 12 months, respectively. Impaired recovery of thymopoiesis also translated into a higher risk of non-relapse mortality and outweighed pre-transplant risk factors including age, donor type, and disease risk-status. Conclusions These results indicate that patients who fail to recover thymopoiesis after allogeneic hematopoietic stem cell transplantation are at very high risk of severe infections and adverse clinical outcome.

Vascularization is still one of the most important limitations for the survival of engineered tissues after implantation. In this study, we aim to improve the in vivo vascularization of engineered adipose tissue by preforming vascular structures within in vitro-engineered adipose tissue constructs that can integrate with the host vascular system upon implantation. Different cell culture media were tested and different amounts of human adipose tissue-derived mesenchymal stromal cells (ASC) and human umbilical vein endothelial cells (HUVEC) were combined in spheroid cocultures to obtain optimal conditions for the generation of prevascularized adipose tissue constructs. Immunohistochemistry revealed that prevascular structures were formed in the constructs only when 20% ASC and 80% HUVEC were combined and cultured in a 1:1 mixture of endothelial cell medium and adipogenic medium. Moreover, the ASC in these constructs accumulated lipid and expressed the adipocyte-specific gene fatty acid binding protein-4. Implantation of prevascularized ASC/HUVEC constructs in nude mice resulted in a significantly higher amount of vessels (37 ± 17 vessels/mm2) within the constructs compared to non-prevascularized constructs composed only of ASC (3 ± 4 vessels/mm2). Moreover, a subset of the preformed human vascular structures (3.6 ± 4.2 structures/mm2) anastomosed with the mouse vasculature as indicated by the presence of intravascular red blood cells. Our results indicate that preformed vascular structures within in vitro-engineered adipose tissue constructs can integrate with the host vascular system and improve the vascularization upon implantation.

Rats allowed extended daily access (6 h) to cocaine, consume high doses of the drug and escalate their cocaine intake over days, resembling the pattern of cocaine use seen in human addicts. The current study was designed to test whether such animals would also demonstrate the heightened motivation to seek cocaine seen in human addicts. Rats were trained to lever press for i.v. cocaine (0.25 mg/infusion) over a 5-day period of 1 h sessions. Subjects were then assigned to either a brief-access (1 h/day) or an extended-access condition for an additional 10 days. Control rats lever pressed for i.v. saline. Following the final self-administration session animals were tested for their motivation to receive cocaine in an operant runway apparatus. Extended-access animals exhibited significantly higher motivation for cocaine in the runway (where they received 1.0 mg/kg cocaine i.v. upon goal-box entry) as was evident by faster run times and less ambivalence about entering the goal box (i.e. retreat behavior) than either brief-access or control subjects. Brief and extended-access animals, tested in the Elevated Plus Maze, exhibited comparable and significant increases in anxiety following a single 1.0 mg/kg i.v. injection of cocaine, as compared to saline control animals that were challenged with i.v. saline infusion. Together, these data suggest that extended access to cocaine results in an especially high motivation for the drug that is not accounted for by reductions in the anxiogenic properties of cocaine.

Interleukin-7 (IL-7) has been shown to enhance thymic output of newly developed T cells following bone marrow transplantation (BMT) in mice. In addition, IL-7 may affect peripheral expansion of T cells. In order to study the relative contribution of thymopoiesis versus peripheral T-cell expansion in the setting of compromised thymopoiesis, we have applied IL-7 in an experimental stem cell transplantation model using T cell–deficient RAG-1–/– mice. C57BL/6 RAG-1–/– mice received transplants of syngeneic T-cell–depleted (TCD) bone marrow (Ly5.1) with or without supplemented T cells (Ly5.2). IL-7 was administered until day 63 after BMT. Peripheral blood T- and B-cell recovery was quantified by flow cytometry and thymopoiesis was studied by quantification of T-cell receptor rearrangement excision circles (TRECs). In mice receiving a T-cell–replete BMT, IL-7 selectively expanded mature CD45.2+ T cells without affecting the recovery of new bone marrow–derived CD45.1+ T cells. In contrast, IL-7 significantly enhanced the recovery of bone marrow–derived T cells after TCD BMT. Quantification of TRECs in mice receiving a TCD BMT revealed that enhanced T-cell recovery following IL-7 treatment resulted from a strong expansion of newly developed naive T cells. These results suggest that peripheral expansion of recent thymic emigrants or mature T cells may be a preferential mechanism by which IL-7 enhances T-cell recovery after BMT.

Objective Thymic output of newly developed ab T cells in humans can be measured via signal joint T-cell receptor rearrangement excision circles (sjTRECs). Deletion of the TCRD locus via dRec to ψJa recombination during TCRA rearrangement results in the production of such sjTRECs. The deleting elements dRec and ψJa are highly conserved between humans and mice and used in a comparable manner. We developed and evaluated a real-time quantitative PCR (RQ-PCR) to detect and quantify dRec-ψJa sjTRECs in murine peripheral blood leukocytes for estimation of thymic output of newly developed ab T cells in mice. Methods The threshold cycle (Ct) of the sjTREC RQ-PCR was related to the Ct value of an endogenous reference gene. The difference in Ct value (DCt) was correlated to the absolute numbers of CD45 + and CD3 + cells per mL of blood, as obtained by a single platform flow cytometric assay, resulting in the frequency of sjTRECs in CD45 + and CD3 + cells. Results The RQ-PCR proved to be sensitive with a detection level of approximately one sjTREC copy in 100 ng of DNA. SjTRECs could not be detected in peripheral blood leukocytes of RAG-1 −/− mice, demonstrating the specificity of the assay. As in humans and primates, sjTREC levels declined in aging and thymectomized mice. Remarkably, significant mouse strain–dependent differences in sjTREC levels were observed. 129Sv and C57BL/6 mice had significantly lower sjTREC levels in blood than Balb/c and DBA2 mice. Conclusion Quantification of murine sjTRECs by RQ-PCR may allow for accurate assessment of thymic output in mice.

Contains fulltext : 125560.pdf (Publisher’s version ) (Open Access) Patients with hypogammaglobulinemia who do not fulfill all the classical diagnostic criteria for common variable immunodeficiency (reduction of two immunoglobulin isotypes and a reduced response to vaccination) constitute a diagnostic and therapeutic dilemma, because information concerning the clinical and immunological characteristics of these patients with idiopathic primary hypogammaglobulinemia is not available. In 44 common variable immunodeficiency and 21 idiopathic primary hypogammaglobulinemia patients we determined the clinical phenotypes and performed flow cytometric immunophenotyping to assess the pathophysiological B-cell patterns and memory B-cell subset counts. Age-matched B-cell subset reference values of 130 healthy donors were generated. Severe pneumonia and bronchiectasis occurred at similar frequencies in idiopathic primary hypogammaglobulinemia and common variable immunodeficiency. Although IgG levels were only moderately reduced compared to common variable immunodeficiency, 12 of 21 idiopathic primary hypogammaglobulinemia patients required immunoglobulin replacement. Non-infectious disease-related clinical phenotypes (autoimmune cytopenia, polyclonal lymphocytic proliferation and persistent unexplained enteropathy) were exclusively observed in common variable immunodeficiency and were associated with early peripheral B-cell maturation defects or B-cell survival defects. T-cell dependent memory B-cell formation was more severely affected in common variable immunodeficiency. Furthermore, 14 of 21 idiopathic primary hypogammaglobulinemia patients showed normal peripheral B-cell subset counts, suggestive for a plasma cell defect. In conclusion, idiopathic primary hypogammaglobulinemia patients who do not fulfill all diagnostic criteria of common variable immunodeficiency have moderately decreased immunoglobulin levels and often a normal peripheral B-cell subset distribution, but still suffer from serious infectious complications. 01 oktober 2013

Success of adipose tissue engineering for soft tissue repair has been limited by insufficient adipogenic differentiation, an unfavorable host response, and insufficient vascularization. In this study, we examined how scaffold-free spheroid and fibrin-based environments impact these parameters in human adipose-derived stromal cell (ASC)-based adipose constructs. ASCs were differentiated in spheroids or fibrin-based constructs. After 7 days, conditioned medium was collected and spheroids/fibrin-based constructs were either harvested or implanted subcutaneously in athymic mice. Following 7 days of implantation, the number of blood vessels in fibrin-based constructs was significantly higher than in spheroids (93 ± 45 vs. 23 ± 11 vessels/mm2) and the inflammatory response to fibrin-based constructs was less severe. The reasons for these results were investigated further in vitro. We found that ASCs in fibrin-based constructs secreted significantly higher levels of the angiogenic factors VEGF and HGF and lower levels of the inflammatory cytokine IL-8. Furthermore, ASCs in fibrin-based constructs secreted significantly higher levels of leptin and showed a 2.5-fold upregulation of the adipogenic transcription factor PPARG and a fourfold to fivefold upregulation of the adipocyte-specific markers FABP4, perilipin, and leptin. These results indicate that fibrin-based ASC constructs are potentially more suitable for ASC-based adipose tissue reconstruction than scaffold-free spheroids.

BACKGROUND AND OBJECTIVES: Interleukin-7 (IL-7) has been studied for its possible immunorestorative capacities following stem cell transplantation and has been shown to enhance post-transplant immune recovery predominantly by peripheral T-cell expansion. A major concern of IL-7 is its possible aggravating effect on graft-versus-host and host-versus-graft reactivity. DESIGN AND METHODS: To study the effect of IL-7 on host-versus-graft reactivity, we applied IL-7 in an experimental transplantation model using RAG-1-/- mice supplied with B6 CD45.1 congenic T cells as recipients of T-cell depleted allogeneic bone marrow grafts. RESULTS: Rejection of minor antigen-mismatched bone marrow was significantly reduced in IL-7 treated recipients compared with PBS treated control mice. Rejection was observed in 2 out of 18 IL-7 treated mice compared with 9 out of 17 PBS treated mice (11% vs. 53%; p=0.012). IL-7 administration resulted in enhanced recovery of peripheral blood CD4+CD25+ regulatory T cells (Treg) with a concomitant increase in peripheral blood Foxp3 mRNA expression. IL-7Ra (CD127) was expressed by the vast majority of CD4+Foxp3+ T cells. The incidence of graft rejection following fully MHC mismatched bone marrow transplantation was not reduced nor enhanced by IL-7 administration. INTERPRETATION AND CONCLUSIONS: Post-transplant IL-7 administration protects against minor antigen-mismatched bone marrow rejection, which may be due to enhanced Treg recovery

Abstract 832 Recovery of thymopoiesis after allogeneic hematopoietic stem cell transplantation (alloSCT) is considered pivotal for full immune competence. Failure to recover thymopoiesis after alloSCT is suggested by the absence of newly developed T-cells that contain signal joint T-cell Receptor Excision Circles (sjTREC), which are produced during T-cell receptor rearrangement. Higher age, reduced pre-transplant thymic function, and graft versus host disease have all been associated with impaired thymic recovery after alloSCT. However, it is still unclear to what extent insufficient thymic recovery itself predicts for subsequent opportunistic infections and non-relapse mortality (NRM). A detailed, prospective survey of all post-engraftment infectious complications, NRM, overall survival (OS), and lymphocyte subsets and thymic recovery during long-term follow-up after alloSCT was performed in 83 high-risk recipients of T cell depleted related or unrelated donor grafts after myeloablative conditioning. A cumulative incidence of common toxicity criteria (CTC) grade 3 and 4 severe infections at 12 months after alloSCT was 66% with a median number of 1.6 severe infectious episodes per patient. The rate of severe post-engraftment infections was 0.64 per 100 patient days during the first year and 0.16 in the second year. After a median follow-up of 118 months, OS was 52%, as determined by a NRM of 25% and relapse mortality of 23%. Outcome was significantly predicted for by the European Group for Blood and Marrow Transplantation (EBMT)-risk score (Gratwohl et al, Cancer, 2009), based on age, gender, risk-status, donor-type and time to SCT (p=0.01). Lymphocyte recovery was slow with median CD4+ T cells exceeding 200/ul by 12 months post alloSCT. At that time, median sjTREC content measured 5.629/ml, which was significantly lower than the median sjTREC content in stem cell donors (19.044/ml, p=0.001). The recovery rate of overall lymphocyte counts as well as T cell subsets did not consistently predict for opportunistic infections and NRM. Patients without thymic recovery at 2, 6, 9, or 12 months were at 3- to 9-fold higher risk for severe infections, which remained significant following multivariable analysis (hazard ratio (HR)-6 months: 0.30 (95%CI 0.09–1.02, p=0.04), HR-12 months: 0.11 (0.01-0.93 p=0.02)). Impaired thymic recovery also translated into a higher risk for NRM (HR-6 months: 0.06 (0.01-0.47 p=0.008), HR-12 months: 0.00 (0.00-1.42 p=0.0005)) and outweighed pre-transplant risk factors including age, donor-type, risk-status when evaluated individually or collectively as the EBMT risk score. Impaired thymic recovery at 6 months was also predictive for lower OS (HR; 0.35 (0.12-1.00 p=0.05)). In conclusion, these results indicate that patients, who fail to recover thymopoiesis after alloSCT are at very high risk for severe infections and adverse clinical outcome, independent of other pre-transplant risk factors and despite intensive monitoring and prophylactic antimicrobial measures. These results indicate that monitoring thymopoiesis after alloSCT may be applied more routinely and strategies to reduce NRM should be directed at thymic regeneration. Disclosures: No relevant conflicts of interest to declare.