Glycemic control is associated with lower odds of mortality and successful extubation in severe COVID-19

Context Corticosteroids, specifically dexamethasone, have become the mainstay of treatment for moderate to severe COVID-19. Although the RECOVERY trial did not report adverse effects of corticosteroids, the METCOVID (Methylprednisolone as Adjunctive Therapy for Patients Hospitalized with COVID-19) study reported a higher blood glucose level in patients receiving methylprednisolone. Objectives This study aims to analyze the association between corticosteroids and COVID-19–related outcomes in patients admitted to the medical ICU (MICU) for COVID-19 pneumonia. Methods This is an observational study of 141 patients admitted to the MICU between March 18 and June 7, 2020. Data on demographics, laboratory and imaging studies, and clinical course were obtained, including data on corticosteroid use. Bivariate analyses and logistic regression were performed between patient characteristics and mortality and successful extubation. Results Of the 141 patients, 86 required mechanical ventilation, 50 received steroids, and 71 died. Regarding demographics, patients had a median age of 58 (interquartile range [IQR] 48, 65), Hispanic (57.4%, n=81), and non-Hispanic Black (37.5%, n=53). The most prevalent comorbidities were hypertension (49.6%, n=70) and diabetes (48.2%, n=68). Lower blood glucose levels on admission (125.5 vs. 148 mg/dL, p=0.025) and lower peak blood glucose levels on corticosteroids (215.5 vs. 361 mg/dL, p=0.0021) were associated with lower prevalence of mortality. Patients who were successfully extubated had a lower admission blood glucose (126.5 vs. 149 mg/dL, p=0.0074) and lower peak blood glucose on corticosteroids (217 vs. 361 mg/dL, p=0.0023). Conclusions Lower blood glucose on admission and lower maximum blood glucose on corticosteroids were associated with lower odds of mortality and successful extubation, regardless of preexisting diabetes. Hyperglycemia may be negating any potential benefit of corticosteroid therapy. These findings suggest that glucose control could be a parameter that impacts the outcome of patients receiving corticosteroids for COVID-19 pneumonia.

P-O08 Effect of socioeconomic deprivation on clinical characteristics and outcomes of patients undergoing an emergency appendectomy

Background Appendicectomy is one of the commonest emergency general surgical operations performed. Previous studies have shown that socioeconomic status (SES) impact outcomes in a number of diseases. Currently, there is no study analysing the impact of SES on the outcome of appendectomy. Our aim was to compare the clinical characteristics and outcomes of adults having an emergency appendectomy between deprived and less deprived SES groups. Methods A multicentre retrospective observational study of all adult patients who had an emergency appendectomy across four hospitals (two district general and two tertiary care hospitals) between August 2018 and November 2020 was performed. Patients were identified through pathology records. Data was extracted from electronic records for demographics, pre-operative (peak) blood results, pre and post-operative imaging, operative details and the clinical outcomes. Patient’s residential address was used to calculate Scottish Index of Multiple Deprivation (SIMD). The patients were grouped by SIMD into a more deprived SES group (SIMD 1-5) and a less deprived SES group (SIMD 6-10) and results compared. Results A total of 1,105 patients (57.5% male) were included. Median age was lower in the more deprived group (35 vs 40 years, p < 0.001). The less deprived group were more likely to be fitter: ASA-1 grade 51.6% vs 43.5%, p = 0.008. There were fewer appendectomies in most deprived decile compared to the least deprived decile (5.2 vs 11.3 per 10,000 population per year, p < 0.001). There was no difference in inflammatory markers, pre-operative imaging, surgical approach, severity of appendicitis and the median length of stay (3 days). However, there were more surgical site infection in the more deprived group (3.4% vs 0.9%, p = 0.006). Conclusions This study demonstrates that SES does impact on the age of presentation and incidence of appendectomy. Surgical site infection were seen more frequently in the more deprived patients undergoing emergency appendectomy. This may be a reflection of the underlying comorbidities.

Acute Metabolic Responses to Glucose and Fructose Supplementation in Healthy Individuals: A Double-Blind Randomized Crossover Placebo-Controlled Trial

The aim of this study was to investigate the impact of glucose (Glu), fructose (Fru), glucose and fructose (GluFru) and sucralose on blood glucose response in healthy individuals. Fifteen healthy individuals (five females, age of 25.4 ± 2.5 years, BMI of 23.7 ± 1.7 kg/m2 with a body mass (BM) of 76.3 ± 12.3 kg) participated in this double-blind randomized crossover placebo-controlled trial. Participants received a mixture of 300 mL of water with 1 g/kg BM of Glu, 1 g/kg BM of Fru, 0.5 g/kg BM of GluFru (each), and 0.2 g sucralose as a placebo. Peak BG values Glu were reached after 40 ± 13 min (peak BG: 141 ± 20 mg/dL), for Fru after 36 ± 22 min (peak BG: 98 ± 7 mg/dL), for GluFru after 29 ± 8 min (BG 128 ± 18 mg/dL), and sucralose after 34 ± 27 min (peak BG: 83 ± 5 mg/dL). Significant differences regarding the time until peak BG were found only between Glu and GluFru supplementation (p = 0.02). Peak blood glucose levels were significantly lower following the ingestion of Fru compared to the supplementation of Glu and GluFru (p < 0.0001) while Glu and GluFru supplementation showed no difference in peak values (p = 0.23). All conditions led to a significantly higher peak BG value compared to sucralose (p < 0.0001). Blood lactate increased in Glu (p = 0.002), Fru and GluFru (both p < 0.0001), whereas sucralose did not increase compared to the baseline (p = 0.051). Insulin levels were significantly higher in all conditions at peak compared to sucralose (p < 0.0001). The findings of this study prove the feasibility of combined carbohydrate supplementations for many applications in diabetic or healthy exercise cohorts.

Treatment of Patients with T Cells Expressing a Fully-Human Anti-BCMA CAR with a Heavy-Chain Antigen-Recognition Domain Caused High Rates of Sustained Complete Responses and Relatively Mild Toxicity

Multiple myeloma (MM) is a malignancy of plasma cells that is nearly always incurable. T cells expressing chimeric antigen receptors (CAR) that target B-cell maturation antigen (BCMA) can recognize and eliminate MM. The murine or other non-human sequences in the single-chain variable fragments (scFv) of many anti-BCMA CARs can elicit recipient immune responses against CAR T cells. We constructed a CAR incorporating an anti-BCMA fully-human heavy-chain variable domain designated FHVH33. FHVH33 lacks the light chain, the artificial linker sequence, and the 2 linker-associated junctions of a scFv, so FHVH33 is smaller than a scFv and is likely to be less immunogenic. The FHVH33-containing CAR utilized in this clinical trial also incorporated a CD8a hinge and transmembrane domain, a 4-1BB domain, and a CD3z domain. The CAR was designated FHVH33-CD8BBZ and was encoded by a gamma-retroviral vector. T cells expressing FHVH33-CD8BBZ were designated FHVH33-T. The FHVH33-T production process was initiated with unsorted peripheral blood mononuclear cells and took 7 days. The treatment protocol was 300 mg/m 2 of cyclophosphamide and 30 mg/m 2 of fludarabine on days -5 to -3 followed by infusion of FHVH33-T on day 0. Twenty-five patients received FHVH33-T infusions. Median age of the treated patients was 62 (range 39-73). Patients received a median of 6 prior lines of therapy (range 3-10). Five dose levels were assessed (Table). Dose level 4, 6x10 6 CAR + T cells/kg was identified as the maximum feasible dose after considering efficacy and manufacturing factors. Twenty-three of 25 patients (92%) obtained objective responses (OR) of partial response (PR) or better. Seventeen patients (68%) attained a best response of stringent complete response (sCR) or very good partial response (VGPR). Thirteen patients have ongoing responses. To date, the median duration of response is 50 weeks for the highest two dose levels. At present, the overall median progression free survival (PFS) is 78 weeks; as responses are ongoing in 13 patients (52%), PFS will likely improve. Nine of 25 patients had extramedullary plasmacytomas at baseline; patients with extramedullary plasmacytomas at baseline were less likely to achieve sCR (P=0.011). All 25 treated patients were evaluable for toxicity. Eighteen patients had grade 1 or 2 cytokine-release syndrome (CRS), and 6 patients had grade 3 CRS. One patient had no CRS. No patients had grade 4 CRS. Five patients received tocilizumab and 4 patients received corticosteroids for CRS. Two of twenty-five patients had grade 3 neurological toxicity possibly attributable to FHVH33-T. No patient had grade 4 neurologic toxicity attributable to CAR T cells. One patient died of influenza pneumonia. We assessed blood CAR+ cells by quantitative PCR. The median peak blood CAR+ cell level was 126.5 cells/µl (range 3-1071 cells/µl), and the median time post-infusion of peak blood CAR + cell levels was 10.5 days (range 7-14). Peak CAR T-cell level was not associated with obtaining a sCR. In contrast, blood CAR+ T cell levels at both 1 and 2 months after infusion were statistically higher for patients obtaining sCR. For the 1-month time-point, blood CAR+ cell levels in cells/mL were 20 for sCR patients and 4 for not sCR patients (P=0.04). Pretreatment serum BCMA was not statistically different when patients obtaining or not obtaining sCR were compared (median serum BCMA in pg/mL: sCR patients 86,243; not sCR patients 261,675, P=0.20). We assessed cell-surface BCMA expression level on MM cells by antibody binding capacity (ABC) flow cytometry. Cell-surface BCMA expression level was not statistically different in sCR versus not sCR patients (median ABC in sites/cell: sCR patients 844; not sCR patients 535, P=0.29). Patients with MM expressing low levels of BCMA obtained durable responses of greater than 2 years duration, which suggests that FHVH33-T can recognize low levels of cell-surface BCMA. Eight patients had extramedullary plasmacytomas at relapse; 4 patients had plasmacytomas biopsied. Two of the biopsied plasmacytomas were BCMA+, and two were BCMA-negative by immunohistochemistry. FHVH33-CD8BBZ CAR T cells caused relatively mild toxicity and a high rate of sCRs in patients with relapsed MM including MM with low cell-surface BCMA expression. Figure 1 Figure 1. Disclosures Brudno: Kyverna Therapeutics: Membership on an entity's Board of Directors or advisory committees. Lam: Kite, a Gilead Company: Patents & Royalties. Kochenderfer: Kite, a Gilead Company: Patents & Royalties: on anti-CD19 CARs, Research Funding; Bristol Myers Squibb: Research Funding.

Safety assessment and potential risks of the glucagon stimulation test in the diagnosis of secondary adrenal insufficiency

Background: Although it takes more time, the glucagon stimulation test (GST) is a reliable measure for assessing growth hormone (GH) and adrenocorticotropic hormone (ACTH) secretion. The GST is considered to be a safe test, however, it still has mild side effects and potential risks. Objective : The objective of this study was to analyze the side effects of the GST while testing adrenal insufficient patients. Methods: This was a prospective study in which GST was performed in eighty-one patients (44 men, 37 women, mean age: 35.83±19.62 years) with pituitary disorder. The GST consisted in an intramuscular injection of 1 mg of glucagon. Blood samples were collected at baseline, and 30, 60, 90, 120, 150, 180 and 210 min after glucagon injection for cortisol measurements. All patients were asked to report side-effects associated with this test. Results: The mean peak blood glucose level under GST was 9.01±2.03 mmol/L and the mean glycemic nadir was 4.34±1.75 mmol/L was found most frequently during the 30th minute (p <10-3). During the test, 35 subjects (43.2%) had side effects with a mean age of 42.89 ± 19.75 years. Frequent side effects included: nausea (29.62%), vomiting (27.16%), abdominal cramps (18.51%) and hunger (13.58%). All patients tolerated the test until the end. Adverse effects were significantly more prevalent in patients older than 50 years (p=0.012). Conclusions: The GST is a reliable alternative to assess hypothalamic pituitary adrenal axis but should be cautiously used especially in the elderly although its minor side effects.

Apixaban concentration variability and relation to clinical outcomes in real-life patients with atrial fibrillation

In some clinical situations, measurements of anticoagulant effect of apixaban may be needed. We investigated the inter- and intra-individual apixaban variability in patients with atrial fibrillation and correlated these results with clinical outcome. We included 62 patients receiving either 5 mg (A5, n = 32) or 2.5 mg (A2.5, n = 30) apixaban twice-daily. We collected three trough and three peak blood samples 6–8 weeks apart. Apixaban concentration was measured by liquid chromatography-tandem mass-spectrometry (LC–MS/MS) and by anti-Xa. Patients on A2.5 were older, had lower creatinine clearance, higher CHA2DS2VASc (4.7 ± 1.0 vs. 3.4 ± 1.7) and lower trough (85 ± 39 vs. 117 ± 53 ng/mL) and peak (170 ± 56 vs. 256 ± 91 ng/mL) apixaban concentrations than patients on A5 (all p < 0.01). In patients on A5, LC–MS/MS showed a significant difference between through levels and between peak levels (p < 0.01). During apixaban treatment, 21 patients suffered bleeding (2 major). There was no association between bleeding and apixaban concentrations or variability. Four patients who suffered thromboembolic event had lower peak apixaban concentrations than patients without it (159 ± 13 vs. 238 ± 88 ng/mL, p = 0.05). We concluded, that there was a significant intra- and inter-individual variability in apixaban trough and peak concentrations. Neither variability nor apixaban concentrations were associated with clinical outcomes.

The time to peak blood bicarbonate (HCO3–), pH, and the strong ion difference (SID) following sodium bicarbonate (NaHCO3) ingestion in highly trained adolescent swimmers

The timing of sodium bicarbonate (NaHCO3) supplementation has been suggested to be most optimal when coincided with a personal time that bicarbonate (HCO3–) or pH peaks in the blood following ingestion. However, the ergogenic mechanisms supporting this ingestion strategy are strongly contested. It is therefore plausible that NaHCO3 may be ergogenic by causing beneficial shifts in the strong ion difference (SID), though the time course of this blood acid base balance variable is yet to be investigated. Twelve highly trained, adolescent swimmers (age: 15.9 ± 1.0 years, body mass: 65.3 ± 9.6 kg) consumed their typical pre-competition nutrition 1–3 hours before ingesting 0.3 g∙kg BM-1 NaHCO3 in gelatine capsules. Capillary blood samples were then taken during seated rest on nine occasions (0, 60, 75, 90, 105, 120, 135, 150, 165 min post-ingestion) to identify the time course changes in HCO3–, pH, and the SID. No significant differences were found in the time to peak of each blood measure (HCO3–: 130 ± 35 min, pH: 120 ± 38 min, SID: 98 ± 37 min; p = 0.08); however, a large effect size was calculated between time to peak HCO3– and the SID (g = 0.88). Considering that a difference between time to peak blood HCO3– and the SID was identified in adolescents, future research should compare the ergogenic effects of these two individualized NaHCO3 ingestion strategies compared to a traditional, standardized approach.