Comparative efficacy of two poeciliid fish in indoor cement tanks against chikungunya vector Aedes aegypti in villages in Karnataka, India

<p>Abstract</p> <p>Background</p> <p>In 2006, severe outbreaks of <it>Aedes aegypti</it>-transmitted chikungunya occurred in villages in Karnataka, South India. We evaluated the effectiveness of combined information, education and communication (IEC) campaigns using two potential poeciliid larvivorous fish guppy (<it>Poecilia reticulata</it>) and mosquitofish (<it>Gambusia affinis</it>), in indoor cement tanks for <it>Aedes </it>larval control.</p> <p>Methods</p> <p>Trials were conducted in two villages (Domatmari and Srinivaspura) in Tumkur District from March to May 2006 for <it>Poecilia </it>and one village (Balmanda) in Kolar District from July to October 2006 for <it>Gambusia</it>. A survey on knowledge, attitude and practice (KAP) on chikungunya was initially conducted and IEC campaigns were performed before and after fish release in Domatmari (IEC alone, followed by IEC + <it>Poecilia</it>) and Balmanda (IEC + <it>Gambusia</it>). In Srinivaspura, IEC was not conducted. Larval surveys were conducted at the baseline followed by one-week and one-month post-intervention periods. The impact of fish on <it>Aedes </it>larvae and disease was assessed based on baseline and post-intervention observations.</p> <p>Results</p> <p>Only 18% of respondents knew of the role of mosquitoes in fever outbreaks, while almost all (<it>n </it>= 50 each) gained new knowledge from the IEC campaigns. In Domatmari, IEC alone was not effective (OR 0.54; <it>p </it>= 0.067). Indoor cement tanks were the most preferred <it>Ae. aegypti </it>breeding habitat (86.9%), and had a significant impact on <it>Aedes </it>breeding (Breteau Index) in all villages in the one-week period (<it>p </it>< 0.001). In the one-month period, the impact was most sustained in Domatmari (OR 1.58, <it>p </it>< 0.001) then Srinivaspura (OR 0.45, <it>p </it>= 0.063) and Balmanda (OR 0.51, <it>p </it>= 0.067). After fish introductions, chikungunya cases were reduced by 99.87% in Domatmari, 65.48% in Srinivaspura and 68.51% in Balmanda.</p> <p>Conclusions</p> <p><it>Poecilia </it>exhibited greater survival rates than <it>Gambusia </it>(86.04 <it>vs</it>.16.03%) in cement tanks. Neither IEC nor <it>Poecilia </it>alone was effective against <it>Aedes </it>(<it>p </it>> 0.05). We conclude that <it>Poecilia </it>+ IEC is an effective intervention strategy. The operational cost was 0.50 (US$0.011, 1 US$= 47) per capita per application. Proper water storage practices, focused IEC with <it>Poecilia </it>introductions and vector sanitation involving the local administration and community, is suggested as the best strategy for <it>Aedes </it>control.</p

Additional efficacy analysis of avatrombopag phase III data for the treatment of adults with immune thrombocytopenia

Avatrombopag is an oral thrombopoietin receptor agonist (TPO-RA) that was approved in the US in 2019 for treatment of chronic immune thrombocytopenia (ITP). This post hoc analysis of the pivotal phase III study (NCT01438840) of avatrombopag in adult patients with ITP evaluated platelet count response to avatrombopag during the core study in different subgroups, and durability of response data in patients who responded to avatrombopag treatment both during the core phase (total population) and during the core and extension phase (total population and by subgroup). Loss of response (LOR [platelet count <30 × 109/L]) was defined as LOR over two consecutive scheduled visits. The response was generally similar between subgroups though a few differences were observed. The durability of response analysis showed that avatrombopag-treated patients maintained their response for 84.5% of time on treatment during the core phase and 83.3% during the core and extension phase; 55.2% of patients in the core phase and 52.3% in the core and extension phase never experienced LOR. We conclude that the initial response to avatrombopag is both stable and durable

Barcoding of Macaque Hematopoietic Stem and Progenitor Cells: A Robust Platform to Assess Vector Genotoxicity

Gene therapies using integrating retrovirus vectors to modify hematopoietic stem and progenitor cells have shown great promise for the treatment of immune system and hematologic diseases. However, activation of proto-oncogenes via insertional mutagenesis has resulted in the development of leukemia. We have utilized cellular bar coding to investigate the impact of different vector designs on the clonal behavior of hematopoietic stem and progenitor cells (HSPCs) during in vivo expansion, as a quantitative surrogate assay for genotoxicity in a non-human primate model with high relevance for human biology. We transplanted two rhesus macaques with autologous CD34+ HSPCs transduced with three lentiviral vectors containing different promoters and/or enhancers of a predicted range of genotoxicities, each containing a high-diversity barcode library that uniquely tags each individual transduced HSPC. Analysis of clonal output from thousands of individual HSPCs transduced with these barcoded vectors revealed sustained clonal diversity, with no progressive dominance of clones containing any of the three vectors for up to almost 3 years post-transplantation. Our data support a low genotoxic risk for lentivirus vectors in HSPCs, even those containing strong promoters and/or enhancers. Additionally, this flexible system can be used for the testing of future vector designs. Keywords: lentivirus, genotoxicity, gene therapy, non-human primat

Association of ABO mismatch with the outcomes of allogeneic hematopoietic cell transplantation for acute leukemia

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). While many factors influence the outcomes of allo-HCT, the independent impact of donor-recipient ABO mismatching remains unclear. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified patients aged ≥18 years with AML or ALL who underwent allo-HCT between 2008 and 2018. Our objectives were to analyze the outcomes of allo-HCT based on the donor-recipient ABO status (match, minor mismatch, major mismatch, bidirectional mismatch). Among 4946 eligible patients, 2741 patients (55.4%) were ABO matched, 1030 patients (20.8%) had a minor ABO mismatch, 899 patients (18.1%) had a major ABO mismatch, and 276 patients (5.6%) had a bidirectional ABO mismatch. In multivariable analyses, compared to ABO matched allo-HCT, the presence of a major ABO mismatch was associated with worse overall survival (HR 1.16, 95% CI 1.05-1.29; p = 0.005), inferior platelet engraftment (HR 0.83, 95% CI 0.77-0.90; p < 0.001), and higher primary graft failure (HR 1.60, 95% CI 1.12-2.30, p = 0.01). Relapse, acute graft versus host disease (GVHD) grades III-IV and chronic GVHD were not significantly associated with ABO status. While donor age was not significantly associated with outcomes, older recipient age was associated with worse survival and non-relapse mortality. Our study demonstrates that donor-recipient ABO status is independently associated with survival and other post-transplantation outcomes in acute leukemia. This underscores the importance of considering the ABO status in donor selection algorithms and its impact in acute leukemia

Combination therapy with carfilzomib, lenalidomide and dexamethasone (KRd) results in an unprecedented purity of the stem cell graft in newly diagnosed patients with myeloma

Still, many physicians give 4 cycles of combination therapy to multiple myeloma patients prior to collection of stem cells for autologous bone marrow transplant. This tradition originates from older doxorubicin-containing regiments which limited the number of cycles due to cumulative cardiotoxicity. Using older regiments, most patients had residual myeloma cells in their autologous stem-cell grafts during collection. Emerging data show that newly diagnosed multiple myeloma patients treated with modern carfilzomib/lenalidomide/dexamethasone (KRd) therapy, on average, take 6 cycles until reaching minimal residual disease (MRD) negativity. We assessed newly diagnosed patients treated with KRd focusing MRD status both in the individual patient's bone marrow, and the corresponding autologous hematopoietic progenitor cell grafts during collection. Per protocol, stem-cell collection was allowed after 4 to 8 cycles of KRd. We found similar stem-cell yield independent of the number of cycles of KRd. At stem-cell collection, 11/30 patients (36.6%) were MRD negative in their bone marrow; all 11 patients had MRD negative hematopoietic progenitor cell grafts. Furthermore, 18/19 patients who were MRD positive in their bone marrows also had MRD negative hematopoietic progenitor cell grafts. These observations support 6 cycles of KRd as an efficacious and safe induction strategy prior to stem-cell collection

CD4/CD8 T-Cell Selection Affects Chimeric Antigen Receptor (CAR) T-Cell Potency and Toxicity: Updated Results From a Phase I Anti-CD22 CAR T-Cell Trial.

PURPOSE: Patients with B-cell acute lymphoblastic leukemia who experience relapse after or are resistant to CD19-targeted immunotherapies have limited treatment options. Targeting CD22, an alternative B-cell antigen, represents an alternate strategy. We report outcomes on the largest patient cohort treated with CD22 chimeric antigen receptor (CAR) T cells. PATIENTS AND METHODS: We conducted a single-center, phase I, 3 + 3 dose-escalation trial with a large expansion cohort that tested CD22-targeted CAR T cells for children and young adults with relapsed/refractory CD22+ malignancies. Primary objectives were to assess the safety, toxicity, and feasibility. Secondary objectives included efficacy, CD22 CAR T-cell persistence, and cytokine profiling. RESULTS: Fifty-eight participants were infused; 51 (87.9%) after prior CD19-targeted therapy. Cytokine release syndrome occurred in 50 participants (86.2%) and was grade 1-2 in 45 (90%). Symptoms of neurotoxicity were minimal and transient. Hemophagocytic lymphohistiocytosis-like manifestations were seen in 19/58 (32.8%) of subjects, prompting utilization of anakinra. CD4/CD8 T-cell selection of the apheresis product improved CAR T-cell manufacturing feasibility as well as heightened inflammatory toxicities, leading to dose de-escalation. The complete remission rate was 70%. The median overall survival was 13.4 months (95% CI, 7.7 to 20.3 months). Among those who achieved a complete response, the median relapse-free survival was 6.0 months (95% CI, 4.1 to 6.5 months). Thirteen participants proceeded to stem-cell transplantation. CONCLUSION: In the largest experience of CD22 CAR T-cells to our knowledge, we provide novel information on the impact of manufacturing changes on clinical outcomes and report on unique CD22 CAR T-cell toxicities and toxicity mitigation strategies. The remission induction rate supports further development of CD22 CAR T cells as a therapeutic option in patients resistant to CD19-targeted immunotherapy

Additional file 6 of Genome-wide profiling of retroviral DNA integration and its effect on clinical pre-infusion CAR T-cell products

Additional file 6: Table S1. Characteristics of CAR T-cell products