Vaccine hesitancy is considered as one of the greatest challenges to control the ongoing coronavirus disease 2019 (COVID-19) pandemic. A related challenge is the unwillingness of the general public to pay for vaccination. The objective of this study was to determine willingness-to-pay (WTP) for COVID-19 vaccine among individuals from ten low-middle-income countries (LMICs) in Asia, Africa, and South America. Data were collected using an online questionnaire distributed during February - May 2021 in ten LMICs (Bangladesh, Brazil, Chile, Egypt, India, Iran, Nigeria, Pakistan, Sudan, and Tunisia). The major response variable of in this study was WTP for a COVID-19 vaccine. The assessment of COVID-19 vaccine hesitancy was based on items adopted from the World Health Organization (WHO) Strategic Advisory Group of Experts (SAGE) vaccine hesitancy scale constructs. In this study, 1337 respondents included in the final analysis where the highest number of respondents was from India, while the lowest number was from Egypt. A total of 88.9% (1188/1337) respondents were willing to pay for the COVID-19 vaccination, and 11.1% (149/1337) were not. The average WTP for COVID-19 vaccination was 87.9 US dollars ($), (range: $5-$200). The multivariate model analysis showed that the country, monthly household income, having a history of respiratory disease, the agreement that routine vaccines recommended by health workers are beneficial and having received the flu vaccination within the previous 12 months were strongly associated with the WTP. Based on the country of origin, the highest mean WTP for COVID-19 vaccine was reported in Chile, while the lowest mean WTP for the vaccine was seen among the respondents from Sudan. The availability of free COVID-19 vaccination services appears as a top priority in the LMICs for successful control of the ongoing pandemic. This is particularly important for individuals of a lower socio-economic status. The effects of complacency regarding COVID-19 extends beyond vaccine hesitancy to involve less willingness to pay for COVID-19 vaccine and a lower value of WTP for the vaccine.
Background:The Green-Anderson (GA) leg-length data remain the gold standard for the age-based assessment of leg lengths in children despite their methodologic weaknesses. We aimed to summarize current growth trends among a cross-sectional cohort of modern U.S. children using quantile regression methods and to compare the median femoral and tibial lengths of the modern U.S. children with those of the GA cohort.Methods:A retrospective review of scanograms and upright slot-scanning radiographs obtained in otherwise healthy children between 2008 and 2020 was completed. A search of a radiology registry revealed 3,508 unique patients between the ages of 2 and 18 years for whom a standard-of-care scanogram or slot-scanning radiograph had been made. All patients with systemic illness, genetic conditions, or generalized diseases that may affect height were excluded. Measurements from a single leg at a single time point per subject were included, and the latest available time point was used for children who had multiple scanograms made. Quantile regression analysis was used to fit the lengths of the tibia and femur and overall leg length separately for male patients and female patients.Results:Seven hundred patients (328 female and 372 male) met the inclusion criteria. On average, the reported 50th percentile tibial lengths from the GA study at each time point were shorter than the lengths in this study by 2.2 cm (range, 1.4 to 3.3 cm) for boys and 2 cm (range, 1.1 to 3.1 cm) for girls. The reported 50th percentile femoral lengths from the GA study at each time point were shorter than the lengths in this study by 1.8 cm (range, 1.1 to 2.5 cm) for boys and 1.7 cm (range, 0.8 to 2.3 cm) shorter for girls.Conclusions:This study developed new growth charts for femoral and tibial lengths in a modern U.S. population of children. The new femoral and tibial lengths at nearly all time points are 1 to 3 cm longer than traditional GA data. The use of GA data for epiphysiodesis could result in underestimation of expected childhood growth.Level of Evidence:Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.
Chimeric antigen receptor T (CAR-T) cell therapy has been a breakthrough in personalized cancer therapy, with US Food and Drug Administration approved CD19 CAR-T products available now for the treatment of relapsed/refractory aggressive B-cell non-Hodgkin's lymphoma (r/r NHL) for close to 4 years. 1 The rate of durable response after CAR-T has been reported to be 30%-40% across various registration studies. 2,3 CAR-T expansion has been consistently correlated with clinical response. [2][3][4] The median time to peak CAR-T expansion can vary based on the CAR construct, but generally occurs in the first 2 weeks of infusion. 2-4 CAR T-cell expansion kinetics is monitored by lab-based assays like polymerase chain reaction or flow cytometry for research purposes. Currently, there is no clinically available test to assess CAR-T expansion in SOC practice.We hypothesize that since patients are lympho-depleted from chemotherapy prior to CAR-T infusion, the lymphocyte expansion in the first 2 weeks post-CAR-T infusion is due primarily to CAR-T expansion. Thus, peak absolute lymphocyte count (ALCpeak), readily accessible by clinical complete blood count (CBC) with differential, can be a surrogate for CAR-T expansion. In this study, we examined the ALC levels in the first 2 weeks after CAR-T infusion and the correlation between CAR-T levels and clinical outcomes for NHL patients who received CAR-T at our institution.We conducted a retrospective review of electronic medical records of patients who received anti CD19 CAR-T for treatment of aggressive, r/r NHL between 6/2016 and 1/2021 at Mayo Clinic, Rochester. ALC was collected daily from serial complete blood cell counts with differentials. The maximum ALC value in the first 15 days of CAR-T infusion was identified as ALCpeak.CAR-T outcomes were obtained from the prospectively collected and validated immune effector cell program clinical database. A durable response was defined as complete remission (CR) at month 6 and beyond.Sixteen patients consented to participate in the biomarker study.Research blood samples were analyzed by flow cytometry (Cytoflex and Cytoflex LX) for CAR-T quantification. CAR-T quantification was done at 2 h post infusion, day 1, day 7, and day 14 post infusion. The highest value on day 7 or day 14 was taken as the peak CART number, which is within the range of published axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) expansion time frame.Immunophenotyping was performed for CAR-T cells using canonical antibodies for T cell lineage and FMC63-PE antibody for CAR expression according to the manufacturer's recommendations. Flow data were analyzed using Kaluza software, version 2.2.The receiver operating characteristic (ROC) curve was used to determine the best cut-off of ALCpeak in predicting CR as the best response. Event-free survival (EFS) was defined as the time from CAR-T infusion to the time of PD, next therapy, or death. Overall survival (OS) was measured from the date of CAR-T infusion to the date of death or last follow-up. EFS ...
Introduction: Despite recent successes with CAR T-cell therapy against CD19 in patients with B-celllymphomas, only ~30%-40% of DLBCL and FL patients maintain a durable complete long-term remission, and over half of the patients will ultimately relapse. Several factors contribute to the lack of response or relapse, including tumor cell-intrinsic factors, an immunosuppressive tumor microenvironment (TME), and CAR T-cell dysfunction. DLBCL and FL depend on EZH2 for their proliferation and survival. Somatic gain-offunction mutations of EZH2 (EZH2 Y641X , found in 20%-30% FL and GCB-DLBCL) drive lymphomagenesis at least in part through generating immune evasive phenotypes. Of note, EZH2 inhibitors have potent activity against both wild type and mutated EZH2 FL and DLBCL patients. EZH2 also modulates the TME by increasing Tregs and repressing memory-related transcription factors in CD8 T-cells. Methods: To explore the effects of EZH2 inhibition and immunotherapy in a relevant physiological context, we developed and exhaustively characterized a genetically engineered mouse model (GEMM)-designed for conditional expression of EZH2Y641F and overexpression of BCL2 ("EZB") in germinal center (GC) B-cells-, that recapitulates low-grade human FL with their immune microenvironment. We further generated murine GC B lymphoma cell lines from these GEMM, which develop immune-depleted aggressive DLBCL when adoptively transferred into immunocompetent mice. To investigate CAR T-cell-mediated tumor killing in human cells in combination with EZH2i tazemetostat, we used the GCB-DLBCL cell lines SUDHL4 (EZH2 Y641F ), OCI-Ly18 and Toledo (WT EZH2). Results: In vivo tazemetostat treatment of EZB GEMM significantly reduced EZB lymphoma B-cells (p < 0.05) and increased of CD4 + and CD8 + cells (p < 0.05), while reducing Tregs (p < 0.01). We found that EZH2i not only directly affected T-cells, but also increased the immunogenicity of EZB lymphoma cells. Pre-treatment of GEMMderived EZB murine cell line with tazemetostat significantly increased murine CD19 CAR T-cells ability to kill lymphoma B-cells both in vitro and in vivo. Furthermore, tazemetostat pre-treatment of human GCB-DLBCL cell lines increased CAR T tumor killing and avidity, reflecting a superior CAR T-cell efficiency in binding to cancer cells. Strikingly, exposure of murine CAR T-cells to EZH2i enhanced in vivo CAR T tumor killing by increasing memory CAR T and inhibiting exhaustion. In summary, we show that EZH2i enhances CAR T antitumor effect by inhibiting lymphoma cells growth, inducing lymphoma immunogenicity and ability to synapse with T-cells, modulating the TME and enhancing T-cell function. Conclusions: We have elucidated a novel strategy to improve CAR T immunotherapy by combining with epigenetic therapy to modulate lymphoma B-cells, CAR T and the TME, that can significantly improve the clinical outcomes of DLBCL and FL patients.
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