A Reflection of Metabolic Syndrome through the Window of COVID-19.

COVID-19 and metabolic syndrome, though seemingly different disorders, appear to share certain common pathogenic components, especially in the development of COVID-19-associated diabetes mellitus. The similarities include impairment in immunoendothelial, gastrointestinal, pancreatic, adipose and mitochondrial functions, with several critical micronutrients undergirding the intricate interactions among these dysfunctions. This discussion aims to highlight the parallels between COVID-19 and metabolic syndrome and to propose the possibility of SARS-CoV-2 being a prototype of an acquired etiological agent which can eventually lead to the development of classical metabolic syndrome. Based on the proposed model, the discussion will include the implication for early management of COVID-19 and metabolic syndrome.

Dendritic cell therapy with CD137L-DC-EBV-VAX in locally recurrent or metastatic nasopharyngeal carcinoma is safe and confers clinical benefit.

INTRODUCTION: Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC), and provides a target for a dendritic cell (DC) vaccine. CD137 ligand (CD137L) expressed on antigen presenting cells, costimulates CD137-expressing T cells, and reverse CD137L signaling differentiates monocytes to CD137L-DC, a type of DC, which is more potent than classical DC in stimulating T cells. METHODS: In this phase I study, patients with locally recurrent or metastatic NPC were administered CD137L-DC pulsed with EBV antigens (CD137L-DC-EBV-VAX). RESULTS: Of the 12 patients treated, 9 received full 7 vaccine doses with a mean administered cell count of 23.9 × 106 per dose. Treatment was well tolerated with only 4 cases of grade 1 related adverse events. A partial response was obtained in 1 patient, and 4 patients are still benefitting from a progression free survival (PFS) of currently 2-3 years. The mean pre-treatment neutrophil: lymphocyte ratio was 3.4 and a value of less than 3 was associated with prolonged median PFS. Progressors were characterized by a high frequency of naïve T cells but a low frequency of CD8+ effector T cells while patients with a clinical benefit (CB) had a high frequency of memory T cells. Patients with CB had lower plasma EBV DNA levels, and a reduction after vaccination. CONCLUSION: CD137L-DC-EBV-VAX was well tolerated. The use of CD137L-DC-EBV-VAX is demonstrated to be safe. Consistent results were obtained from all 12 patients, indicating that CD137L-DC-EBV-VAX induces an anti-EBV and anti-NPC immune response, and warranting further studies in patients post effective chemotherapy. PRECIS: The first clinical testing of CD137L-DC, a new type of monocyte-derived DC, finds that CD137L-DC are safe, and that they can induce an immune response against Epstein-Barr virus-associated nasopharyngeal carcinoma that leads to tumor regression or prevents tumor progression.

Cohort study to evaluate the effect of vitamin D, magnesium, and vitamin B12 in combination on progression to severe outcomes in older patients with coronavirus (COVID-19).

OBJECTIVES: The aim of this study was to determine clinical outcomes of older patients with coronavirus (COVID-19) who received a combination of vitamin D, magnesium, and vitamin B12 (DMB) compared with those who did not. We hypothesized that fewer patients administered this combination would require oxygen therapy, intensive care support, or a combination of both than those who did not. METHODS: This was a cohort observational study of all consecutive hospitalized patients ≥50 y of age with COVID-19 in a tertiary academic hospital. Before April 6, 2020, no patients received the (DMB) combination. After this date, patients were administered 1000 IU/d oral vitamin D3, 150 mg/d oral magnesium, and 500 mcg/d oral vitamin B12 upon admission if they did not require oxygen therapy. Primary outcome was deterioration leading to any form of oxygen therapy, intensive care support, or both. RESULTS: Between January 15 and April 15, 2020, we identified 43 consecutive patients ≥50 y of age with COVID-19. Seventeen patients received DMB before onset of primary outcome and 26 patients did not. Baseline demographic characteristics between the two groups were significantly different by age. In univariate analysis, age and hypertension had a significant influence on outcome. After adjusting for age or hypertension separately in a multivariate analysis, the intervention group retained protective significance. Fewer treated patients than controls required initiation of oxygen therapy during hospitalization (17.6 vs 61.5%, P = 0.006). DMB exposure was associated with odds ratios of 0.13 (95% confidence interval [CI], 0.03-0.59) and 0.20 (95% CI, 0.04-0.93) for oxygen therapy, intensive care support, or both on univariate and multivariate analyses, respectively. CONCLUSIONS: A vitamin D / magnesium / vitamin B12 combination in older COVID-19 patients was associated with a significant reduction in the proportion of patients with clinical deterioration requiring oxygen support, intensive care support, or both. This study supports further larger randomized controlled trials to ascertain the full benefit of this combination in ameliorating the severity of COVID-19.

Urgent Delivery - Validation and Operational Implementation of Urgent Blood Delivery by Modern High Speed Hospital Pneumatic Tube System to Support Bleeding Emergencies Within a Hospital Massive Transfusion Protocol.

BACKGROUND: Timely blood delivery to patients with critical bleeding poses logistic challenges. A modern, high speed hospital pneumatic tube system (PTS) is one solution, but blood units may be subjected to high-speed torque and acceleration/deceleration forces. OBJECTIVE: To validate a new PTS system for potential use at our 1,400-bed hospital in Singapore. METHOD: Our validation included red blood cells, platelets, thawed plasma, and cryoprecipitate units transported from the blood bank for a distance of 820 meters (PTS track), at a velocity of 3-6 meters per second. Transit time, temperature, bag integrity, and blood quality were assessed visually and through analytical testing on pre- and post-PTS specimens. RESULTS: Blood units arrived physically intact in less than 8 minutes. The temperature for each was within the acceptable range. Comparative testing of pre-PTS and post-PTS specimens showed no significant difference in physical quality and analyzed parameters (P> .05). CONCLUSIONS: High speed PTS transportation of blood components has satisfactory fidelity and speed, without significant impact on quality. As a result, we incorporated PTS blood delivery into the hospital massive-transfusion protocol and successfully operationalized that new system.

Tumor infiltrating lymphocytes from acute myeloid leukemia marrow can be reverted to CD45RA+ central memory state by reactivation in SIP (Simulated Infective Protocol).

Simulated Infective Protocol (SIP) is an ex-vivo culture system modeled after the temporal changes of essential cytokines in an acute infection, and previously proven successful in converting T lymphocytes harvested and activated from peripheral blood of normal donors, to revertant CD45RA + Central Memory T lymphocytes (Tcmra) demonstrating properties akin to T Memory Stem Cells (Tscm). In this study, we applied similar SIP on tumor infiltrating lymphocytes (TIL) from bone marrow of patients diagnosed with acute myeloid leukemia (AML), and replicated the feasibility to convert activated TILs into Tcmra phenotype. These revertant Tcmra lymphocytes re-expressed CD45RA+, CCR7+, CD62L + and CD127+, shown improved survivability with longer telomere length, expressed memory properties including higher Eomes to Tbet ratio, and exhibited cytotoxicity against autologous AML blast cells.

Large-scale Isolation of Highly Pure "Untouched" Regulatory T Cells in a GMP Environment for Adoptive Cell Therapy.

Adoptive cell therapy is an emerging treatment strategy for a number of serious diseases. Regulatory T (Treg) cells represent 1 cell type of particular interest for therapy of inflammatory conditions, as they are responsible for controlling unwanted immune responses. Initial clinical trials of adoptive transfer of Treg cells in patients with graft-versus-host disease were shown to be safe. However, obtaining sufficient numbers of highly pure and functional Treg cells with minimal contamination remains a challenge. We developed a novel approach to isolate "untouched" human Treg cells from healthy donors on the basis of negative selection using the surface markers CD49d and CD127. This procedure, which uses an antibody cocktail and magnetic beads for separation in an automated system (RoboSep), was scaled up and adapted to be compatible with good manufacturing practice conditions. With this setup we performed 9 Treg isolations from large-scale leukapheresis samples in a good manufacturing practice facility. These runs yielded sufficient numbers of "untouched" Treg cells for immediate use in clinical applications. The cell preparations consisted of viable highly pure FoxP3-positive Treg cells that were functional in suppressing the proliferation of effector T cells. Contamination with CD4 effector T cells was <10%. All other cell types did not exceed 2% in the final product. Remaining isolation reagents were reduced to levels that are considered safe. Treg cells isolated with this procedure will be used in a phase I clinical trial of adoptive transfer into leukemia patients developing graft-versus-host disease after stem cell transplantation.