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Institutions, organisations, and policymakers use open educational resources (OERs) to promote student equity and social inclusion. The global COVID-19 crisis highlighted the need for lifelong learning and underscored the importance of the higher education system in this endeavour. This study describes informal learning among adults through OERs, during the COVID-19 crisis, distinguishing between employed and unemployed individuals and between professional and personal development. A questionnaire distributed during the COVID-19 lockdown focused on three themes: (1) types of OERs used for learning during this period;(2) perceived OERs' usefulness;and (3) changes in OER use due to the crisis. Our findings revealed group differences in types of OERs used and in changes brought about by COVID-19, as well as within-group differences based on personal characteristics. Only a few participants reported using massive open online courses (MOOCs). Moreover, videoconferencing usage increased despite low perceived usefulness ratings, pointing to a change in informal learning modes. This exploratory research provides insights into the preferences of individual groups. These insights may be used to reduce socioeconomic disparities, especially among those who have lost their jobs, and to develop effective models for open education. Implications for practice or policy: • Enhancing the discussions about the future of open education by reflecting a wide picture of OERs use. • Redesigning OERs for the labour market by distinguishing between employed and unemployed, and professional and personal development. • OER preferences according to personal characteristics can be used to achieve better engagement with learning. © Articles published in the Australasian Journal of Educational Technology (AJET) are available under Creative Commons Attribution Non-Commercial No Derivatives Licence (CC BY-NC-ND 4.0). Authors retain copyright in their work and grant AJET right of first publication under CC BY-NC-ND 4.0.
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Introduction: CARTITUDE-2 (NCT04133636) is a phase 2, multicohort study evaluating cilta-cel, an anti-BCMA CAR-T therapy, in several multiple myeloma (MM) patient (pt) populations. Objective(s): To report updated results with longer follow-up on cohort C pts with previous exposure to a non-cellular anti- BCMA immunotherapy. Method(s): Cohort C pts had progressive MM after treatment (tx) with a proteasome inhibitor, immunomodulatory drug, anti-CD38 antibody, and non-cellular BCMA-targeting agent. A single cilta-cel infusion (target dose 0.75x106 CAR+ viable T cells/kg) was administered 5-7 days post lymphodepletion. Primary endpoint was minimal residual disease (MRD) negativity at 10-5. Secondary endpoints included overall response rate (ORR), duration of response (DOR), and adverse events (AEs). Result(s): As of June 1, 2022, 20 pts (13 ADC exposed;7 BsAb exposed) were treated with cilta-cel;4 pts did not receive cilta-cel due to either low cellular yield (n=2, 1 in each group) or death due to progressive disease (PD) prior to dosing (n=2, 1 in each group) and 6 pts received anti-BCMA tx as their last line of therapy (n=4 ADC, n=2 BsAb). During prior anti-BCMA tx, best responses included VGPR (ADC: 2 pts;BsAb: 1 pt), sCR (ADC: 1 pt), and CR (BsAb: 1 pt);the rest had best response of stable disease or PD (1 pt not evaluable). Baseline characteristics are presented in Figure 1A. Median time from last anti- BCMA agent to cilta-cel infusion was 195 d;median administered dose of cilta-cel was 0.65x106 CAR+ viable T cells/kg. At a median follow-up of 18.0 mo, 7/10 evaluable pts (70%) were MRD negative at 10-5 (ADC: 5/7 [71.4%], BsAb: 2/3 [66.7%]). ORR: full cohort, 60%;ADC, 61.5%;BsAb, 57.1% (Figure 1B). Median DOR: full cohort, 12.8 mo;ADC, 12.8 mo;BsAb, 8.2 mo. Median PFS: full cohort, 9.1 mo;ADC, 9.5 mo;BsAb, 5.3 mo. Cilta-cel responders had a shorter median duration of last anti- BCMA agent exposure (29.5 d) compared with non-responders (63.5 d). Responders also had a longer median time from last anti-BCMA tx exposure to apheresis (161.0 d) than non-responders (56.5 d). Most common AEs were hematologic. CRS: n=12 (60%;all Gr1/2), median time to onset 7.5 d, median duration 6.0 d. ICANS: n=4 (20%, 2 Gr3/4), median time to onset 9.0 d, median duration 7.0 d. No patient had movement or neurocognitive tx emergent AE/parkinsonism. There were 12 deaths (PD: 8;COVID-19 pneumonia: 2 [not tx related];subarachnoid hemorrhage: 1 [not tx related];C. difficile colitis: 1 [tx related]). (Figure Presented)(Figure Presented)Conclusions: Pts with heavily pretreated MM and previous exposure to a non-cellular anti-BCMA therapy had favorable responses to cilta-cel. However, depth and DOR appear lower than that seen in anti-BCMA-naive pts treated with cilta-cel (at 27.7 mo, median DOR was not reached in heavily pre-treated but anti-BCMA naive CARTITUDE-1 pts). These data may inform tx plans, including sequencing and washout period between BCMA-targeting agentsCopyright © 2023 American Society for Transplantation and Cellular Therapy
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Background: COVID-19 vaccines that expand immunity against emerging variants of concern (VOC) are needed to protect against ongoing viral evolution. We investigated the impact of boosting nonhuman primates pre-immune to the original WA-1 strain with updated VOC vaccines on the breadth and magnitude of mucosal and systemic antibody (Ab) and T cell (Tc) responses. Method(s): Cynomolgus macaques were primed with 2 doses of WA-1 Spike protein encoded by either an IL-12 adjuvanted DNA vaccine administered by gene gun (GG) or a self-amplifying RNA vaccine (repRNA) delivered intramuscularly (IM) with a cationic nanocarrier (LIONTM/IM, HDT Bio) or by GG (FIG 1). A booster dose was administered at week 17 with DNA or repRNA vaccines expressing B.1.351 (Beta) and B.1.617 (Delta) Spike receptor-binding domains (RBDs) fused to influenza HA2 stem domain (SHARP, designed by AIR/ JP) followed by a final Beta + Delta + WA-1 SHARP boost at week 34. Blood and bronchoalveolar lavages (BAL) were collected before and after each dose. Binding and neutralizing Ab to VOCs, including Omicron strains, were measured by ELISA and pseudovirus neutralization assays. Tc responses to Spike protein (WA-1 peptides) were measured by ELISpot. Immune responses were compared between groups and between blood vs lung using non-parametric statistical tests. Result(s): Two doses of WA-1 DNA or repRNA vaccines induced broad Ab against all VOC with the repRNA vaccine inducing the highest titers. Boosting with VOC SHARP significantly increased mucosal and systemic Ab responses against all VOCs tested including Omicron. After final boost, all groups had comparable binding and neutralization Ab titers and Tc responses regardless of method of delivery (GG or LIONTM/IM) or formulation (DNA or repRNA). Tc responses were significantly higher in the BAL vs PBMC after WA-1 Spike doses (p=0.0420) and VOC SHARP boosters (p=0.0009). Conclusion(s): The WA-1 strain primed for broad responses against VOCs that were significantly boosted with updated SHARP vaccines including responses against Omicron, even though this strain was not included in any dose. This suggests that sequential immunization with updated vaccines may broaden mucosal and systemic immunity against future VOCs. The repRNA vaccine initially induced the strongest responses, but there were no differences between RNA and DNA following additional booster doses, a result that supports development of a more cost-effective, room temperature stable DNA vaccine for worldwide boosters. (Figure Presented).
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Background: Vaccines are highly effective in preventing severe disease and death from COVID-19, and new medications that can reduce disease severity have been approved. However, many countries are facing limited supply of vaccine doses and medications. Research question: A model estimating the probabilities for hospitalisation and mortality according to individual risk factors and vaccine doses received could help prioritise vaccination and yet scarce medications to maximise lives saved and reduce the burden on hospitalisation facilities. Method(s): Electronic health records from 101,034 individuals infected with SARS-CoV-2, since the beginning of the pandemic and until 30 November 2021, were extracted from a national healthcare organization in Israel. Logistic regression models were built to estimate the risk for subsequent hospitalization and death based on the number of BNT162b2 mRNA vaccine doses received and few major risk factors (age, sex, body mass index, hemoglobin A1C, kidney function, and presence of hypertension, pulmonary disease or malignancy). Result(s): The models built predicts the outcome of newly infected individuals with remarkable accuracy: area under the curve was 0.889 for predicting hospitalisation, and 0.967 for predicting mortality. Even when a breakthrough infection occurs, receiving three vaccination doses significantly reduces the risk of hospitalization by 66% (OR = 0.336) and death by 78% (OR = 0.220). Conclusion(s): The models enable rapid identification of individuals at high risk for hospitalisation and death when infected. These patients can be prioritised to receive booster vaccination and the yet scarce medications. A calculator based on these models is made public: http://covidest.web.app.
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Background: Long COVID-19 is a multisystem syndrome that may start 12 weeks after the acute illness. About 10% of the recoverees will have at least one symptom during this period. We lack information about the rate of various symptoms and persistence beyond six months, especially after mild disease without hospitalisation. Research question: Characterisation of the long-term symptoms of COVID-19 patients in Israel. Method(s): A nationwide telephone survey was conducted using a structured questionnaire on 714 post COVID-19 participants aged 18 or over, 12 weeks or more after virological defined recovery. Patients were randomly selected from approximately 80,000 COVID-19-recovered patients at Leumit Health Service in Israel. Result(s): About 14% of convalescents had at least one symptom 12 weeks or more from recovery. The most common symptoms were memory or concentration disturbances (10%), muscle aches (8.5%), muscle weakness (7.6%), loss of taste or smell (5.9%) and headaches (3.8%). Six months after recovery, the incidence of most symptoms decreased, but memory or concentration problems (9.2%), muscle pain (7.8%) and muscle weakness (6.6%) remained common. In patients with fever or muscle aches at the time of COVID-19 and in patients with chronic diseases, the rate of prolonged symptoms (>6 months) was higher. Older age and hospitalisation during the course of the disease were not predictive of prolonged symptoms. Conclusion(s): In a large sample of recovering patients, most of them with mild, community-managed, the most common long-term complaints were disturbances in memory and concentration and muscle pain.
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The inflammaging concept was introduced in 2000 by Prof. Franceschi. This was an evolutionary or rather a revolutionary conceptualization of the immune changes in response to a lifelong stress. This conceptualization permitted to consider the lifelong proinflammatory process as an adaptation which could eventually lead to either beneficial or detrimental consequences. This dichotomy is influenced by both the genetics and the environment. Depending on which way prevails in an individual, the outcome may be healthy longevity or pathological aging burdened with aging-related diseases. The concept of inflammaging has also revealed the complex, systemic nature of aging. Thus, this conceptualization opens the way to consider age-related processes in their complexity, meaning that not only the process but also all counter-processes should be considered. It has also opened the way to add new concepts to the original one, leading to better understanding of the nature of inflammaging and of aging itself. Finally, it showed the way towards potential multimodal interventions involving a holistic approach to optimize the aging process towards a healthy longevity.
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The COVID-19 pandemic revealed ways in which communities take care of themselves in deeply unequal times. Tracing a pandemic-year evolution of community-based organizations (CBOs) in the San Francisco Bay Area through twenty-seven semi-structured interviews with CBO staff, we argue that, through diverse approaches that we characterize as a politics of care, Bay Area CBOs are reshaping their work in ways that could address social and structural determinants of health inequities in the long term. Their approaches call for rethinking the crisis framework around public health challenges such as pandemics. Our research confirms that, rather than an exceptional, short-term challenge, the pandemic crisis is a product of a longer trajectory of structurally produced inequities endemic to racial capitalism.
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INTRODUCTION: Many first wave COVID ARDS patients who were intubated spent a prolonged time on non-conventional ventilators (NCV) (e.g. transport devices, BiPAP machines) that are not intended for long-term use. The impact of prolonged NCV use on mortality is unknown. We hypothesized that time spent on NCV, compared to conventional ventilators (CV), is associated with higher mortality among COVID ARDS patients. METHOD(S): This is a retrospective multicenter study of our health system's COVID ARDS database from 03/01/20 - 04/30/20. We included intubated adults with COVID ARDS, mechanically ventilated on either NCV or CV. We excluded patients who switched between ventilator types, palliative extubations, and deaths within 24 hours of intubation. Baseline demographics and confounders were recorded. The primary outcome was 90 day mortality, and secondary outcomes were 3 and 28 day mortality. The effect of time spent on a NCV on 90 day mortality was modeled using logistic regression while controlling for confounders. The effect of time on NCV on 90 day mortality was quantified as an odds ratio (OR) and compared to the null using the Wald test. This was repeated for 3 and 28 day mortality. RESULT(S): Of 2094 patients who met inclusion criteria, we excluded 113 deaths within 24 hours, 500 ventilator switches, and 426 missing data points, for n=1055. Mean age was 65 years, 317 (30%) female, and 384 (36%) Caucasian. NCVs were used in 345 (33%) cases. Median time intubated was 9.8 days for NCV and 11 days for CV groups. Mean adjusted tidal volumes (ATV) were 6.8 for NCV and 6.6 ml/kg for CV. Overall unadjusted 90, 3 and 28 day mortality were 68%, 9% and 62%, respectively. Charlson Comorbidity Index (CCI), BMI, respiratory compliance (RC), ATV, P/F ratio, time averaged PEEP, time on vasopressors, and steroid use were controlled for. CCI and vasopressors correlated with higher mortality (p< 0.05). RC, P/F and PEEP correlated with lower mortality (p< 0.05). Time on NCV did not correlate with 90 day (OR=1.27, p=0.12) or 3 day mortality (OR=1.28, p=0.31) and correlated with increased 28 day mortality (OR = 1.5, p = 0.006). CONCLUSION(S): Among patients with COVID ARDS in early 2020, mechanical ventilation with NCVs was associated with increased adjusted mortality at 28 days but not at 3 and 90 days compared with CVs.
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Background: Severe coronavirus disease 2019 (COVID-19) is associated with inflammatory cytokine burst and coagulopathy. Platelets may contribute to microthrombosis development and be a target in COVID-19 therapy. Aim(s): To determine the significance of platelet activation and antiplatelet agents (APAs) treatment in COVID-19 pathophysiology and mortality in two cohorts of patients with COVID-19. Method(s): We explored two cohorts of COVID-19 patients: Cohort A (NCT04624997) included 208 ambulatory and hospitalized patients of different clinical severity with evaluation of soluble CD40 ligand (sCD40L) and P-selectin (sP-sel) plasma levels of within the first 48 hours following admission. Cohort B included 2878 patients initially admitted in medical ward with collection of clinical characteristics and outcomes (NCT04344327). In both cohorts, the primary outcome was in-hospital mortality. Result(s): In cohort A, circulating median levels of sCD40L and sP-sel were significantly increased solely in critical patients with COVID-19 (sP-sel: 40059 pg/ml, IQR 26876-54678;sCD40L: 1914 pg/ml IQR 1410-2367;p < 0.001 for both), signaling platelet hyper-activation. However, pre-hospitalization APAs did not significantly modified sCD40L and sP-sel levels. Admission sP-sel levels were predictive in-hospital mortality (Kaplan-Meier log-rank p = 0.004), even after adjustment on CRP, while adjustment on D-dimer abolished this relationship, suggesting that platelet activation is highly interrelated with coagulopathy. We confirmed this finding in a Cox model adjusted for age, sex, CRP and D-dimer levels (Odds ratio 1.78, 95% CI 0.63-4.50). We confirmed in cohort B (2878 patients) that, among patients receiving APA before hospitalization, there was no significant difference in the proportion of death in a Cox model (Hazard ratio 1.0, IQR0.77-1.30) adjusted for demographic comorbidities. Conclusion(s): Our findings highlight the critical role of coagulopathy, in contrast to platelet activation, in discriminating COVID-19 severity and increased risk of in-hospital mortality. We also confirm that APAs before hospitalization do not influence neither mortality nor platelet activation. (Table Presented).
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Context: CARTITUDE-2 (NCT04133636) Cohort A is assessing cilta-cel in lenalidomide-refractory patients with progressive MM after 1-3 prior LOT. Objective(s): To present updated results from CARTITUDE-2 Cohort A. Design(s): Phase 2, multicohort study. Patient(s): Lenalidomide-refractory patients with progressive MM after 1-3 prior LOT (PI and IMiD included) and no previous exposure to BCMA-targeting agents. Intervention(s): Single cilta-cel infusion (target dose 0.75x106 CAR+ viable T-cells/kg) after lymphodepletion Main Outcome Measure(s): Primary endpoint was minimal residual disease (MRD) negativity at 10-5. Management strategies were used to reduce risk of movement/neurocognitive adverse events (MNTs). Pharmacokinetics (PK) (Cmax/Tmax of CAR+T-cell transgene levels), cytokine release syndrome (CRS)-related cytokines over time, peak cytokine levels by response/CRS, association of cytokine levels with immune effector cell-associated neurotoxicity syndrome (ICANS), and CAR+T-cell CD4/CD8 ratio by response/CRS/ICANS are being evaluated. Result(s): As of January 2022 (median follow-up [MFU] 17.1 months), 20 patients (65% male;median age 60 years;median 2 prior LOT;95% refractory to last LOT) received cilta-cel. Overall response rate was 95% (90% >=complete response;95% >=very good partial response). Median times to first and best response were 1.0 month and 2.6 months, respectively. All 16 MRD-evaluable patients achieved MRD negativity at 10-5. Median duration of response was not reached. At 12 months, event-free rate was 79% and progression-free survival rate was 75%. 95% of patients had CRS (gr3/4 10%);median time to onset was 7 days and median duration was 3 days. Neurotoxicity was reported in 30% of patients (5 gr1/2;1 gr3/4) and ICANS in 15% (all 3 gr1/2);1 patient had gr2 facial paralysis. No MNTs were observed. 1 death occurred due to COVID-19 (treatment-related), 2 due to progressive disease, and 1 due to sepsis (not treatment-related). Preliminary PK analyses showed peak CAR-T cell expansion at day 10.5;median persistence was 153.5 days. Conclusion(s): At MFU of 17.1 months, a single cilta-cel infusion resulted in deep and durable responses in lenalidomide-refractory MM patients with 1-3 prior LOT. We will present updated PK/cytokine/CAR-T subset analyses and clinical correlation to provide novel insights into biological correlates of efficacy/safety in this population. Copyright © 2022 Elsevier Inc.
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The COVID-19 crisis emphasizes the importance of Self-Regulated Learning (SRL), one of today’s most valuable skills, with which learners set their learning goals, monitor and control their cognition, motivation, and behavior, and reflect upon them. In the current experimental study, an intervention program based on short online interactive videos was developed to promote SRL skills. This paper presents the impact of the intervention on students’ use of SRL skills and grades. It also explores four key pedagogical processes (teacher-student relationships, collaboration, autonomy, and feedback) as mediators for SRL strategies use and grades. The experimental and control groups were randomly assigned (N = 290 students, 18 classes, grades 7–12). Each teacher taught the same subject in two classes for a month, an amount of time that allows intervention to take effect. One of the classes participated in the video-based intervention program (experimental group), whereas the other performed all activities but did not have access to the videos (control group). Data was collected through an SRL and pedagogies usage questionnaire, SRL video prompts, and knowledge tests and was analyzed using the quantitative method. In addition to the theoretical contribution, a practical tool has been developed for educators who wish to employ online SRL training. © 2022, The Author(s), under exclusive license to Springer Nature Switzerland AG.
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Background: Fluid boluses are amongst the strongest recommendations for the management of septic patients, and they are generally administered with the goal increasing cardiac output and improving tissue perfusion. Early identification of volume responsiveness is challenging and dependent on many patient factors, but it may prevent the harmful consequences of hypervolemia. Left ventricular outflow tract (LVOT) velocity time integral (VTI) has been used as a predictor of volume responsiveness. Study Objectives: The purpose of this study was to determine whether lack of volume responsiveness, defined as =15% change in LVOT VTI, is associated with increased risk of mortality, admission to an intensive care unit (ICU), or rapid response team activation within 24 hours of hospital arrival (composite outcome measure). We hypothesize that septic patients who are not volume responders will be more critically ill and therefore at greater risk of experiencing the composite outcome.
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Background: Cohort A of the multicohort phase 2 CARTITUDE-2 (NCT04133636) study is assessing ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR-T) therapy, in patients with multiple myeloma (MM) who received 1-3 prior lines of therapy (LOT) and were refractory to lenalidomide (len). This population is difficult to treat and has poor prognosis. Aims: To present updated results from CARTITUDE-2 Cohort A. Methods: All patients provided informed consent. Eligible patients had progressive MM after 1-3 prior LOT that included a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD). Patients were len-refractory and had no prior exposure to BCMA-targeting agents. Patients received a single cilta-cel infusion (target dose: 0.75×106 CAR+ viable T cells/kg) after lymphodepletion. Cilta-cel safety and efficacy were assessed. The primary endpoint was minimal residual disease (MRD) negativity at 10-5 by next generation sequencing. Patient management strategies were used to reduce the risk of movement and neurocognitive adverse events (MNTs). Other assessments included pharmacokinetic (PK) analyses (Cmax and Tmax of CAR+ T-cell transgene levels in blood), levels of cytokine release syndrome (CRS)-related cytokines (e.g., IL-6) over time, peak levels of cytokines by response and CRS, association of cytokine levels with immune effector cell-associated neurotoxicity syndrome (ICANS), and CAR+ T cell CD4/CD8 ratio by response, CRS, and ICANS. Results: As of January 2022 (median follow-up: 17.1 months [range: 3.3-23.1]), cilta-cel was administered to 20 patients (male: 65%;median age: 60 years [range: 38-75]). Median number of prior LOT was 2 (range: 1-3);median time since MM diagnosis was 3.5 years (range: 0.7-8.0). 95% of patients were refractory to their last LOT;40% were triple-class refractory. Overall response rate was 95%, with 90% of patients achieving ≥complete response and 95% achieving ≥very good partial response. Median time to first response was 1.0 month (range: 0.7-3.3);median time to best response was 2.6 months (range: 0.9-13.6). All MRD-evaluable patients (n=16) achieved MRD negativity at 10-5. Median duration of response was not reached. The 12-month progression-free survival rate was 75% and the 12-month event-free rate was 79%. CRS occurred in 95% of patients (grade 3/4: 10%), with a median time to onset of 7 days (range: 5-9) and median duration of 3 days (range: 2-12). 30% of patients had neurotoxicity (5 grade 1/2 and 1 grade 3/4). ICANS occurred in 3 patients (15%;all grade 1/2);1 patient had facial paralysis (grade 2). No MNTs were observed. 1 death due to COVID-19 occurred and was assessed as treatment-related by the investigator;2 deaths due to progressive disease and 1 due to sepsis (not related to treatment) also occurred. Based on preliminary PK analyses of CAR transgene by qPCR, peak expansion of CAR-T cells occurred at day 10.5 (range: 8.7-42.9);median persistence was 153.5 days (range: 57.1-336.8). Summary/Conclusion: A single cilta-cel infusion led to deepening and durable responses at this longer follow-up (median 17.1 months) in patients with MM who had 1-3 prior LOT and were len-refractory. Follow-up is ongoing. We will present updated and detailed PK, cytokine, and CAR-T subset analyses as well as clinical correlation to provide novel insights into biological correlates of efficacy and safety in this difficult-to-treat patient population, which is being further evaluated in the CARTITUDE-4 study (NCT04181827;enrollment concluded).
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Background: The COVID-19 pandemic sparked increased utilization of telemedicine services, as telemedicine offers care at a safe distance. Dermatology is well-suited for telemedicine due to its visual nature;however, concerns regarding diagnostic accuracy limit its widespread use. Visits for certain types of concerns may be more conducive to virtual visits than others. Further study of teledermatology may reveal trends in visit types and influence future integration into practice. Methods: Thomas Jefferson University analyzed aggregated, de-identified data from FAIR Health’s FH NPIC repository of privately insured medical claims, for telehealth services performed by dermatologists between 2019 and 2020 at urban and rural levels. Calculations were performed to determine the percentage of teledermatology visits that used specific diagnosis codes relative to all teledermatology visits. Visits were also assessed for the following parameters: demographics, diagnosis codes, and procedure codes. Results: Diagnosis codes L70.0 and L71.0, which primarily pertain to acne and rosacea, comprised 61% and 75% of Disorders of Skin Appendages teledermatology claims in 2019 and 2020 respectively. In 2019, teledermatology visits most often used diagnosis codes L60-75 in both urban and rural locations (33.7% and 31.9%, respectively). Moreover, from 2019 to 2020, the percentage of teledermatology visits that used codes L60-75 was 1.35 times greater in urban locations and 1.48 times greater in rural locations. Conclusions: Teledermatology visits favored specific diagnoses, specifically pertaining to acne and rosacea. This suggests that these diagnoses may be more conducive to virtual visits relative to other diagnoses such as skin neoplasms or papulosquamous disorders, including psoriasis.
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Background: Cohort A of the multicohort phase 2 CARTITUDE-2 (NCT04133636) study is evaluating cilta-cel safety and efficacy in pts with MM who received 1-3 prior LOT and were len-refractory - a difficult- to-treat population with poor prognosis. We present updated results. Methods: Pts had progressive MM after 1-3 prior LOT, including a PI and IMiD, were len-refractory, and had no prior exposure to BCMA-targeting agents. A single cilta-cel infusion (target dose 0.75×106 CAR+ viable T cells/kg) was given post lymphodepletion. Safety and efficacy were assessed, and the primary endpoint was MRD negativity at 10-5. Management strategies were implemented to minimize risk of movement/neurocognitive AEs (MNTs). Pharmacokinetic (PK) analyses (Cmax and Tmax of CAR+ T-cell transgene levels in blood) are being conducted, as well as analyses of levels of CRS-related cytokines (eg, IL-6) over time, peak levels of cytokines by response and CRS, association of cytokine levels with ICANS, and CAR+ T cell CD4/CD8 ratio by response, CRS, and ICANS. Results: As of January 2022 (median follow- up [MFU] 17.1 mo [range 3.3-23.1]), 20 pts (65% male;median age 60 y [range 38-75]) received cilta-cel. Pts received a median of 2 (range 1-3) prior LOT, and a median of 3.5 y (range 0.7-8.0) since MM diagnosis. 95% were refractory to last LOT, and 40% were triple-class refractory. ORR was 95%, 90% achieved CR or better, and 95% had ≥VGPR. Median times to first and best response were 1.0 mo (range 0.7-3.3) and 2.6 mo (range 0.9-13.6), respectively. 16 pts were MRDevaluable, all of whom achieved MRD negativity at 10-5. Median DOR was not reached and 12-mo event-free rate was 79%. The 12-mo PFS rate was 75%. Median time to onset of CRS was 7 d (range 5-9) and occurred in 95% of pts (gr 3/4: 10%), with median duration of 3 d (range 2-12). Neurotoxicity occurred in 30% of pts (5 gr 1/2;1 gr 3/4). 3 pts (15%) had ICANS (all gr 1/2);1 pt had gr 2 facial paralysis. No MNTs were seen. 1 death occurred due to COVID-19 (assessed as tx-related by the investigator), 2 due to progressive disease, and 1 due to sepsis (not related to tx). Preliminary PK analyses indicate that peak expansion of CAR-T cells occurred at d 10.5 (range 8.7-42.9) and median persistence was 153.5 d (range 57.1-336.8). Conclusions: At a longer MFU of 17.1 mo, a single cilta-cel infusion led to deepening and durable responses in pts with MM who had 1-3 prior LOT and were lenrefractory. Follow-up is ongoing. Updated and in-depth PK, cytokine, and CAR-T subset analyses and clinical correlation will be presented and provide novel insights into biological correlates of efficacy and safety in this pt population. This pt population is being further evaluated in the CARTITUDE-4 study (NCT04181827), which has concluded enrollment.
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Classifying moral values in user-generated text from social media is critical in understanding community cultures and interpreting user behaviors of social movements. Moral values and language usage can change across the social movements;however, text classifiers are usually trained in source domains of existing social movements and tested in target domains of new social issues without considering the variations. In this study, we examine domain shifts of moral values and language usage, quantify the effects of domain shifts on the morality classification task, and propose a neural adaptation framework via instance weighting to improve cross-domain classification tasks. The quantification analysis suggests a strong correlation between morality shifts, language usage, and classification performance. We evaluate the neural adaptation framework on a public Twitter data across 7 social movements and gain classification improvements up to 12.1%. Finally, we release a new data of the COVID-19 vaccine labeled with moral values and evaluate our approach on the new target domain. For the case study of the COVID-19 vaccine, our adaptation framework achieves up to 5.26% improvements over neural baselines. This is the first study to quantify impacts of moral shifts, propose adaptive framework to model the shifts, and conduct a case study to model COVID-19 vaccine-related behaviors from moral values. © 2022 ACM.
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Rationale: Although mortality from COVID-19 increases with advanced age, most older adults survive a COVID hospitalization. Disability, or dependence in functional activities, is known to increase after a serious illness among older adults, with adverse consequences for patients, families, and society. Little is known about disability, and the factors associated with disability, after a COVID hospitalization among older adults. Methods: We enrolled 341 older (≥60 years) adults during their index COVID-19 hospitalization between 7/6/2020-6/24/2021 from five hospitals in the Yale-New Haven Health System. Upon enrollment, participants underwent an assessment of baseline (prehospitalization) disability, frailty, general health, social support, hearing, vision, mental health, and assessments of current (in-hospital) symptom burden and cognitive function. These assessments were linked to EMR data including demographics, SOFA score, comorbidities, biomarkers, respiratory support, pressors, length of stay, and COVIDspecific treatments. Disability was assessed at baseline and 1, 3, and 6 months by asking about dependence in 15 basic, instrumental, and mobility activities. The primary outcome was the disability count (0-15) over the 6 months after the COVID hospitalization. The analytic sample included 304 participants who survived their hospitalization and had at least one post-discharge follow-up. We determined the mean (SD) number of disabilities over the 6 months after discharge and evaluated 27 factors for their association with the 6-month disability count using backwards selection based on minimization of the Bayesian Information Criterion with a zero-inflated negative binomial distribution and adjustment for baseline disability count and months of follow-up. Results: The mean age was 71.2 years (SD 8.5), 158 (51.8%) were women, and 108 (35.5%) were of nonwhite race or Hispanic ethnicity (Table). The mean prehospitalization disability count was 2.2 (SD 3.4), and the mean disability count over the 6 months after the COVID hospitalization was 2.9 (SD 3.7). In the multivariable model, greater baseline disability, older age, higher BMI, higher comorbidity count, cognitive dysfunction, greater symptom burden during the hospitalization, and the need for advanced respiratory support were all associated with greater disability over the 6 months after a COVID hospitalization. Conclusions: Other than the need for advanced respiratory support, factors associated with disability after a COVID hospitalization among older adults reflect vulnerability at baseline (comorbidities, baseline disability, age, BMI) or during the hospitalization (symptom burden, cognitive dysfunction), rather than biomarkers or severity of illness. These factors may identify older adults for referral to Post-COVID clinic programs to improve the likelihood of functional recovery after discharge. (Table Presented).
ABSTRACT
In this paper, we report on research findings from a cross-sectional survey with 143 primarily Mexican migrant agricultural worker respondents in British Columbia (BC), Canada. Participants reported high rates of experiences of threats and violence by employers, limited faith in the follow-through of both Canadian and country-of-origin authorities when reporting concerns, and a unanimous lack of knowledge in how to file a claim of a legal matter (e.g., housing, human rights violation). Most participants also reported that they believed they would receive poorer health care in relation to their Canadian counterparts and that their privacy would not be protected. While certain indicators, such as knowledge of resources for transportation, translation, and legal advocacy were higher than previous research would suggest, most participants did not feel confident that more serious issues would be addressed if they sought help. Our results suggest migrant workers in BC report similar, or even higher, rates of experiences and expectations of poor social support, legal protection, and health care in comparison to prior research in this region and elsewhere. While further research would be required to confirm this hypothesis, the impact of COVID-19 on this population is undeniable. Our findings highlight the need for greater regional and provincial commitments to fund targeted services for migrant agricultural workers that address the unique barriers they face. Additionally, greater attention and funding must be dedicated to supporting this population to navigate and access services that already exist. Together, dedicated initiatives could make a major difference for this workforce. Federal investments in support services of this nature would ensure the sustainability of such efforts. In addition, reforms to temporary migrant agricultural programs, such as open work permits and immediate access to permanent residence, would better afford workers opportunities to access the rights and protections that are currently out of reach for many.
ABSTRACT
Introduction: Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell (CAR-T) therapy expressing two B-cell maturation antigen (BCMA)-targeting, single-domain antibodies. The multicohort, open-label, phase 2 CARTITUDE-2 study (NCT04133636) is assessing cilta-cel in patients (pts) with multiple myeloma (MM) under various clinical settings and evaluating the suitability of outpatient administration. Updated results of CARTITUDE-2 cohort A are presented here. Methods: Cohort A pts had progressive MM after 1-3 prior lines of therapy (LOT;included proteasome inhibitor [PI] and immunomodulatory drug [IMiD]), were lenalidomide-refractory, and had no previous exposure to BCMA-targeting agents. A single cilta-cel infusion at a target dose of 0.75×106 CAR+ viable T cells/kg was given 5-7 d after start of lymphodepletion (cyclophosphamide [300 mg/m2] and fludarabine [30 mg/m2] for 3 d). The primary endpoint was minimal residual disease (MRD) negativity at 10-5 at any time point. Secondary endpoints were overall response rate (ORR), duration of response (DOR), time and duration of MRD negativity, and incidence and severity of adverse events (AEs). Response was assessed per International Myeloma Working Group criteria and AEs were graded by Common Terminology Criteria for Adverse Events version 5.0 (cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS] by American Society for Transplantation and Cellular Therapy). Results: As of April 15, 2021 (median follow-up of 9.7 mo), 20 pts (65% men;median age 60 y [range 38-75]) received cilta-cel, with 1 pt treated in an outpatient setting. Pts had a median of 2 prior LOT (range 1-3);60% had 1-2 prior LOT and 40% had 3 prior LOT. All pts were exposed to a PI, IMiD, and dexamethasone;95% were exposed to alkylating agents and 65% to daratumumab. 95% of pts were refractory to last LOT;40% were triple-class refractory. ORR was 95% (95% CI 75.1-99.9);85% (95% CI 62.1-96.8) had ≥complete response (CR), and 95% (95% CI 75.1-99.9) had ≥very good partial response (Figure). Median time to first response was 1.0 mo (range 0.7-3.3) and median time to ≥CR was 2.6 mo (range 0.9-7.9). Median DOR was not reached;progression-free survival (PFS) at 6 mo was 90% (95% CI 65.6-97.4). Of 13 MRD-evaluable pts, 92.3% (95% CI 64.0-99.8) were MRD-negative at 10-5. Hematologic AEs (≥20% of pts) were neutropenia (95%;grade [gr] 3/4: 95%), thrombocytopenia (80%;gr 3/4: 35%), anemia (75%;gr 3/4: 45%), lymphopenia (65%;gr 3/4: 60%) and leukopenia (55%;gr 3/4: 55%). 95% of pts had CRS (gr 3/4: 10%);median time to onset was 7 d (range 5-9) and median duration was 4 d (range 2-11). Four pts (20%) had CAR-T neurotoxicity (all gr 1/2). Three pts (15%) had ICANS (all gr 1/2);median time to onset was 8 d (range 7-10) and median duration was 3 d (range 1-3). One pt had facial paralysis (gr 2) with time to onset of 29 d and duration of 51 d. No movement and neurocognitive treatment-emergent adverse events (TEAEs) were reported. One death due to COVID-19 was assessed as treatment-related. Safety was manageable in the pt treated in an outpatient setting. Conclusions: A single cilta-cel infusion led to early and deep responses in pts with MM who had 1-3 prior LOT and were lenalidomide-refractory. No movement and neurocognitive TEAEs occurred, suggesting successful implementation of monitoring and pt management strategies across phase 2/3 studies in the CARTITUDE program.