Despite unprecedented efficacy, 1 the use of axicabtagene ciloleucel (axi-cel) for the treatment of patients with relapsed or refractory large B-cell lymphoma (LBCL) remains associated with acute toxicity, such as grade $3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), occurring in 11% and 32% of patients, respectively. 2 Analysis of 44 different analytes in the serum of patients with relapsed or refractory LBCL treated with axi-cel showed that an increase in IL-6 or IL-1 may be associated with such toxicity. 3 However, in 2 murine models, whereas IL-6 blockade (typically achieved in clinical practice with the use of tocilizumab) prevented CRS only, only IL-1 blockade prevented both CRS and/or ICANS. 4,5 IL-1 blockade can be clinically achieved with the use of anakinra, an IL-1 receptor antagonist, currently approved by the US Food and Drug Administration for the treatment of patients with rheumatoid arthritis and neonatal-onset multisystem inflammatory disease. 6,7 Anakinra is also used off label for the treatment of secondary hemophagocytic lymphohistiocytosis (HLH), a condition in the spectrum of CRS potentially associated with chimeric antigen receptor (CAR) T-cell therapy. 8,9 Data regarding the clinical use of anakinra for the mitigation of axi-cel-associated toxicity have not been published.Patients with relapsed or refractory LBCL treated with standard axi-cel therapy, who received anakinra for mitigation of CAR T-cell therapy-associated toxicity at The University of Texas MD Anderson Cancer Center from September 2018 through September 2019, were eligible for this study. During this time, 100 patients with relapsed or refractory LBCL were treated with standard-of-care axi-cel, 41 developed grade $3 ICANS, 9 had grade $3 CRS, and 5 had HLH. Among these, 8 patients with LBCL (6 with diffuse LBCL and 2 with transformed follicular lymphoma) were treated with anakinra. CRS and ICANS were prospectively graded according to the CAR toxicity (CARTOX) grading system. 10 An unpaired Student t test was used for area-under-the-curve comparisons.

Today, the world is facing the challenge of a major pandemic due to COVID-19, which has caused more than 6.1 million cases of infection and nearly 370,000 deaths so far. Most of the deaths from the disease are clustered in the older population, but the young and children are not spared. In this context, there is a critical need to revisit the formula for calculating potential years of life lost (PYLL). Data on age-specific deaths due to COVID-19 in three countries, including the United States (US), Italy, and Germany, were evaluated. New York State, as a significant outlier within the US, was also included. PYLLs in the US were five times as high as those of Italy. Compared with Germany, PYLLs in Italy were 4 times higher, and the rates in the US were 23, 25, and 18 times higher when using upper age limits of 70, 75, and 80, respectively. Standardized PYLLs in New York were 2 times as high as the rates in Italy, and 7 to 9 times as high as PYLLs in Germany. The revised formula of PYLL, using an upper limit of age 80, is recommended to accurately measure premature deaths due to a major disastrous disease such as COVID-19.

Nucleotide sequences of the long terminal repeats (LTRs) of four murine intracisternal A-particle (IAP) genes IAP62, 19, 81 and 14 were determined. Each IAP LTR contains three sequence domains, 5'-U3-R-U5-3', and each is bound by 4 bp imperfect inverted repeats. The transcriptional regulatory sequences, CAAT and TATA, as well as the enhancer core sequence GTGGTAA are conserved and precisely positioned within the U3 region. In the R region, the sequence AATAAA is located twenty base pairs preceding the dinucleotide CA, the polyadenylation site. In IAP19 and IAP81, the 5' and 3' LTRs are flanked by a six nucleotide direct repeat of cellular sequences representing the possible integration sites for these IAP proviruses. Both the size and sequences of different IAP LTRs vary considerably, with the majority of the variation localized within the R regions. The size of R varies from 66 bp in IAP14 to 222 bp in IAP62; in contrast, the U3 and U5 regions are all similar in size. These extra sequences within the R region of large LTRs consist of several unusual directly repeating sequences which account for this variability.

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Objectives: The objectives of this study were to: 1) determine the association between vasopressor dosing intensity during the first 6 hours and first 24 hours after the onset of septic shock and 30-day in-hospital mortality; 2) determine whether the effect of vasopressor dosing intensity varies by fluid resuscitation volume; and 3) determine whether the effect of vasopressor dosing intensity varies by dosing titration pattern. Design: Multicenter prospective cohort study between September 2017 and February 2018. Vasopressor dosing intensity was defined as the total vasopressor dose infused across all vasopressors in norepinephrine equivalents. Setting: Thirty-three hospital sites in the United States (n = 32) and Jordan (n = 1). Patients: Consecutive adults requiring admission to the ICU with septic shock treated with greater than or equal to 1 vasopressor within 24 hours of shock onset. Interventions: None. Measurements and Main Results: Out of 1,639 patients screened, 616 were included. Norepinephrine (93%) was the most common vasopressor. Patients received a median of 3,400 mL (interquartile range, 1,851–5,338 mL) during the 24 hours after shock diagnosis. The median vasopressor dosing intensity during the first 24 hours of shock onset was 8.5 μg/min norepinephrine equivalents (3.4–18.1 μg/min norepinephrine equivalents). In the first 6 hours, increasing vasopressor dosing intensity was associated with increased odds ratio of 30-day in-hospital mortality, with the strength of association dependent on concomitant fluid administration. Over the entire 24 hour period, every 10 μg/min increase in vasopressor dosing intensity was associated with an increased risk of 30-day mortality (adjusted odds ratio, 1.33; 95% CI, 1.16–1.53), and this association did not vary with the amount of fluid administration. Compared to an early high/late low vasopressor dosing strategy, an early low/late high or sustained high vasopressor dosing strategy was associated with higher mortality. Conclusions: Increasing vasopressor dosing intensity during the first 24 hours after septic shock was associated with increased mortality. This association varied with the amount of early fluid administration and the timing of vasopressor titration.