Duvelisib for critically ill patients with coronavirus disease 2019: An investigator-initiated, randomized, placebo-controlled, double-blind pilot trial

BACKGROUND: Despite improvements in prevention and treatment, severe coronavirus disease 2019 (COVID-19) is associated with high mortality. Phosphoinositide 3-kinase (PI3K) pathways contribute to cytokine and cell-mediated lung inflammation. We conducted a randomized, placebo-controlled, double-blind pilot trial to determine the feasibility, safety, and preliminary activity of duvelisib, a PI3Kδγ inhibitor, for the treatment of COVID-19 critical illness. METHODS: We enrolled adults aged ≥18 years with a primary diagnosis of COVID-19 with hypoxic respiratory failure, shock, and/or new cardiac disease, without improvement after at least 48 hours of corticosteroid. Participants received duvelisib (25 mg) or placebo for up to 10 days. Participants had daily semi-quantitative viral load measurements performed. Dose modifications were protocol driven due to adverse events (AEs) or logarithmic change in viral load. The primary endpoint was 28-day overall survival (OS). Secondary endpoints included hospital and intensive care unit length of stay, 60-day OS, and duration of critical care interventions. Safety endpoints included viral kinetics and AEs. Exploratory endpoints included serial cytokine measurements and cytometric analysis. RESULTS: Fifteen patients were treated in the duvelisib cohort, and 13 in the placebo cohort. OS at 28 days was 67% (95% confidence interval [CI], 38%-88%) compared to 62% (95% CI, 32%-86%) for placebo ( CONCLUSIONS: In this pilot study, duvelisib did not significantly improve 28-day OS compared to placebo for severe COVID-19. Duvelisib appeared safe in this critically ill population and was associated with reduction in cytokines implicated in COVID-19 and acute respiratory distress syndrome, supporting further investigation. CLINICAL TRIALS REGISTRATION: NCT04372602

Single-cell discovery and multiomic characterization of therapeutic targets in multiple myeloma

UNLABELLED: Multiple myeloma (MM) is a highly refractory hematologic cancer. Targeted immunotherapy has shown promise in MM but remains hindered by the challenge of identifying specific yet broadly representative tumor markers. We analyzed 53 bone marrow (BM) aspirates from 41 MM patients using an unbiased, high-throughput pipeline for therapeutic target discovery via single-cell transcriptomic profiling, yielding 38 MM marker genes encoding cell-surface proteins and 15 encoding intracellular proteins. Of these, 20 candidate genes were highlighted that are not yet under clinical study, 11 of which were previously uncharacterized as therapeutic targets. The findings were cross-validated using bulk RNA sequencing, flow cytometry, and proteomic mass spectrometry of MM cell lines and patient BM, demonstrating high overall concordance across data types. Independent discovery using bulk RNA sequencing reiterated top candidates, further affirming the ability of single-cell transcriptomics to accurately capture marker expression despite limitations in sample size or sequencing depth. Target dynamics and heterogeneity were further examined using both transcriptomic and immuno-imaging methods. In summary, this study presents a robust and broadly applicable strategy for identifying tumor markers to better inform the development of targeted cancer therapy. SIGNIFICANCE: Single-cell transcriptomic profiling and multiomic cross-validation to uncover therapeutic targets identifies 38 myeloma marker genes, including 11 transcribing surface proteins with previously uncharacterized potential for targeted antitumor therapy

Management of retinal vascular diseases: a patient-centric approach

Retinal vascular diseases are a leading cause of blindness in the Western world. Advancement in the clinical management of these diseases has been fast-paced, with new treatments becoming available as well as license extensions of existing treatments. Vascular endothelial growth factor (VEGF) has been implicated in certain retinal vascular diseases, including wet age-related macular degeneration (AMD), diabetic macular oedema (DMO), and retinal vein occlusion (RVO). Treatment of wet AMD and visual impairment due to either DMO or macular oedema secondary to RVO with an anti-VEGF on an as needed basis, rather than a fixed schedule, allows an individualised treatment approach; providing treatment when patients are most likely to benefit from it, while minimising the number of unnecessary intravitreal injections. Thus, an individualised treatment regimen reduces the chances of over-treatment and under-treatment, optimising both the risk/benefit profile of the treatment and the efficient use of NHS resource. Streamlining of treatment for patients with wet AMD and visual impairment due to either DMO or macular oedema secondary to RVO, by using one treatment with similar posology across all three diseases, may help to minimise burden of clinic capacity and complexity and hence optimise patient outcomes. Informed treatment decisions and efficient clinic throughput are important for optimal patient outcomes in the fast-changing field of retinal vascular diseases

Analysis of DLA-DQB1 and polymorphisms in CTLA4 in Cocker spaniels affected with immune-mediated haemolytic anaemia

BACKGROUND: Cocker spaniels are predisposed to immune-mediated haemolytic anaemia (IMHA), suggesting that genetic factors influence disease susceptibility. Dog leukocyte antigen (DLA) class II genes encode major histocompatibility complex (MHC) molecules that are involved in antigen presentation to CD4(+) T cells. Several DLA haplotypes have been associated with autoimmune disease, including IMHA, in dogs, and breed specific differences have been identified. Cytotoxic T lymphocyte antigen 4 (CTLA4) is a critical molecule involved in the regulation of T-cell responses. Single nucleotide polymorphisms (SNPs) in the CTLA4 promoter have been shown to be associated with several autoimmune diseases in humans and more recently with diabetes mellitus and hypoadrenocorticism in dogs. The aim of the present study was to investigate whether DLA-DQB1 alleles or CTLA4 promoter variability are associated with risk of IMHA in Cocker spaniels. RESULTS: There were a restricted number of DLA-DQB1 alleles identified, with a high prevalence of DLA-DQB1*007:01 in both groups. A high prevalence of DLA-DQB1 homozygosity was identified, although there was no significant difference between IMHA cases and controls. CTLA4 promoter haplotype diversity was limited in Cocker spaniels, with all dogs expressing at least one copy of haplotype 8. There was no significant difference comparing haplotypes in the IMHA affected group versus control group (p = 0.23). Homozygosity for haplotype 8 was common in Cocker spaniels with IMHA (27/29; 93 %) and in controls (52/63; 83 %), with no statistically significant difference in prevalence between the two groups (p = 0.22). CONCLUSIONS: DLA-DQB1 allele and CTLA4 promoter haplotype were not found to be significantly associated with IMHA in Cocker spaniels. Homozygosity for DLA-DQB1*007:01 and the presence of CTLA4 haplotype 8 in Cocker spaniels might increase overall susceptibility to IMHA in this breed, with other genetic and environmental factors involved in disease expression and progression

Development of Play for Peace Website (semester?), IPRO 328: Play for Peace IPRO 328 Midterm Report Sp06

At this point, most of the requirements from the client have been obtained (in table below). Based off of this, we have selected the Joomla Client Management System to develop the web-site. The decision was made between Joomla, Mambo, and PHP-Nuke. All three are CMS systems with varying capabilities and weaknesses. The description for each of the CMS systems is provided below. What is left is to continue getting feedback from the client as well as continuing to adapt and modify Joomla as needed to fit our needs.Deliverables for IPRO 328: Development of Play for Peace Website for the Spring 2006 semester

Development of Play for Peace Website (semester?), IPRO 328: Play for Peace IPRO 328 IPRO Day Presentation Sp06

At this point, most of the requirements from the client have been obtained (in table below). Based off of this, we have selected the Joomla Client Management System to develop the web-site. The decision was made between Joomla, Mambo, and PHP-Nuke. All three are CMS systems with varying capabilities and weaknesses. The description for each of the CMS systems is provided below. What is left is to continue getting feedback from the client as well as continuing to adapt and modify Joomla as needed to fit our needs.Deliverables for IPRO 328: Development of Play for Peace Website for the Spring 2006 semester

Development of Play for Peace Website (semester?), IPRO 328: Play for Peace IPRO 328 Project Plan Sp06

At this point, most of the requirements from the client have been obtained (in table below). Based off of this, we have selected the Joomla Client Management System to develop the web-site. The decision was made between Joomla, Mambo, and PHP-Nuke. All three are CMS systems with varying capabilities and weaknesses. The description for each of the CMS systems is provided below. What is left is to continue getting feedback from the client as well as continuing to adapt and modify Joomla as needed to fit our needs.Deliverables for IPRO 328: Development of Play for Peace Website for the Spring 2006 semester

Development of Play for Peace Website (semester?), IPRO 328: Play for Peace IPRO 328 Final Report Sp06

At this point, most of the requirements from the client have been obtained (in table below). Based off of this, we have selected the Joomla Client Management System to develop the web-site. The decision was made between Joomla, Mambo, and PHP-Nuke. All three are CMS systems with varying capabilities and weaknesses. The description for each of the CMS systems is provided below. What is left is to continue getting feedback from the client as well as continuing to adapt and modify Joomla as needed to fit our needs.Deliverables for IPRO 328: Development of Play for Peace Website for the Spring 2006 semester

Development of Play for Peace Website (semester?), IPRO 328

At this point, most of the requirements from the client have been obtained (in table below). Based off of this, we have selected the Joomla Client Management System to develop the web-site. The decision was made between Joomla, Mambo, and PHP-Nuke. All three are CMS systems with varying capabilities and weaknesses. The description for each of the CMS systems is provided below. What is left is to continue getting feedback from the client as well as continuing to adapt and modify Joomla as needed to fit our needs.Deliverables for IPRO 328: Development of Play for Peace Website for the Spring 2006 semester