Citations

Abstract Background: Young doctors have made up a substantial part of healthcare forces during the Coronavirus Disease 2019 (COVID-19) pandemic. The aim of this study was to determine the rate and level of psychological distress among young doctors during the COVID-19 outbreak. Methods: This cross-sectional cohort study, dedicated to doctors, at or below the age of 40, was conducted in 62 countries as an online survey between September – November 2020. Survey questions covered the following areas: 1. demographics 2. work environment 3.the ‘Hospital Anxiety and Depression Scale (HADS)’ and the ‘Perceived Stress Scale 10 (PSS-10)’. The primary outcome was the rate and level of anxiety/depression and stress among surveyed population defined according to adopted cut off values (HADS>13, PSS-10>14). Secondary outcomes included risk factors for increased HADS and PSS-10 scores.Results: Among 1186 respondents, median aged 32 [29–36], 675 (44.5%) females, 96% reported a high level of anxiety/depression and 97% reported a high level of stress. Factors associated with significantly higher scores for anxiety/depression were increased work hours [OR 1.61 95%CI (1.12–2.34);p=0.01] and loss of pay [OR 5.53, 95% CI (1.57–19.47);p=0.008], while reduced work hours [OR 0.68 95% CI (0.48 - 0.98);p=0.03], increased salaries [OR 0.54 95% CI (0.35–0.85);p=0.003) and good training [OR 0.99 95%CI (0.99– 1.00);p=0.002] were associated with lower scores. Higher scores for stress were associated with higher professional experience [OR 1.08 95% CI (1.02–1.14);p=0.008], reduced salaries [OR 1.74 95% CI (1.01–2.92);p=0.04] and living with a partner [OR 1.53 95% CI (1.08–2.17);p=0.01]. Conclusions: A high rate of young doctors working clinically during the COVID-19 pandemic reported a persistently high level of psychological distress more than six months after the initial outbreak. Improvements in work organization, including reduced work hours and financial security are essential to prevent further psychological suffering among young doctors worldwide.

AbstractBackgroundThe SARS‐CoV‐2 pandemic disrupted hospital operations, affected the blood supply, and challenged the health care system to develop new therapeutic options, including convalescent plasma (CCP). The aim of this study is to describe and analyze blood supply fluctuations and the use of convalescent plasma in 2020.MethodsAABB distributed a weekly and biweekly questionnaire through email to hospital‐based members (HBM).ResultsThe survey was sent to 887 HBM with 479 unique respondents, most of the hospitals served pediatric and adult patients, and all states of the country participated, except Idaho and Vermont. Fifty four percent of HBM reported increased wastage in the early phase of the pandemic (May), which decreased to 4% by the end of June and throughout the rest of the year. The majority of HBM reported receiving alerts from their blood suppliers reporting blood shortages throughout the year. During March and April, only 12% of HBM were performing elective surgical procedures. The top reasons to delay procedures were: bed availability (28%); COVID‐19 caseload (23%; and blood availability (19%). By mid‐April, 42% HBM had transfused CCP and reported >24 h delay in getting the units; the vast majority obtained CCP using the Expanded Access Protocol, and later, the Emergency Use Authorization. HBM consistently prioritized the most severe patients to receive CCP, but the proportion of severely ill recipients fell from 52% to 37% between May and October, with an increase from 5% to 21% of HBM providing CCP transfusion early in the course of the disease.DiscussionBlood utilization and availability fluctuated during the pandemic. The fluctuations appeared to be related to the number of COVID‐19 in the community. The use and regulatory landscape of CCP rapidly evolved over the first 8 months of the pandemic.

AbstractObjectiveWith COVID-19, there was a need for a rapidly scalable annotation system that facilitated real-time integration with clinical decision support systems (CDS). Current annotation systems suffer from a high-resource utilization and poor scalability limiting real-world integration with CDS. A potential solution to mitigate these issues is to use the rule-based gazetteer developed at our institution.Materials and MethodsPerformance, resource utilization, and runtime of the rule-based gazetteer were compared with five annotation systems: BioMedICUS, cTAKES, MetaMap, CLAMP, and MedTagger.ResultsThis rule-based gazetteer was the fastest, had a low resource footprint, and similar performance for weighted microaverage and macroaverage measures of precision, recall, and f1-score compared to other annotation systems.DiscussionOpportunities to increase its performance include fine-tuning lexical rules for symptom identification. Additionally, it could run on multiple compute nodes for faster runtime.ConclusionThis rule-based gazetteer overcame key technical limitations facilitating real-time symptomatology identification for COVID-19 and integration of unstructured data elements into our CDS. It is ideal for large-scale deployment across a wide variety of healthcare settings for surveillance of acute COVID-19 symptoms for integration into prognostic modeling. Such a system is currently being leveraged for monitoring of postacute sequelae of COVID-19 (PASC) progression in COVID-19 survivors. This study conducted the first in-depth analysis and developed a rule-based gazetteer for COVID-19 symptom extraction with the following key features: low processor and memory utilization, faster runtime, and similar weighted microaverage and macroaverage measures for precision, recall, and f1-score compared to industry-standard annotation systems.

SummaryZUMA‐1 (NCT02348216) examined the safety and efficacy of axicabtagene ciloleucel (axi‐cel), an autologous CD19‐directed chimaeric antigen receptor (CAR)‐T cell therapy, in refractory large B‐cell lymphoma. To reduce treatment‐related toxicity, several exploratory safety management cohorts were added to ZUMA‐1. Specifically, cohort 6 investigated management of cytokine release syndrome (CRS) and neurologic events (NEs) with prophylactic corticosteroids and earlier corticosteroid and tocilizumab intervention. CRS and NE incidence and severity were primary end‐points. Following leukapheresis, patients could receive optional bridging therapy per investigator discretion. All patients received conditioning chemotherapy (days −5 through −3), 2 × 106 CAR‐T cells/kg (day 0) and once‐daily oral dexamethasone [10 mg, day 0 (before axi‐cel) through day 2]. Forty patients received axi‐cel. CRS occurred in 80% of patients (all grade ≤2). Any grade and grade 3 or higher NEs occurred in 58% and 13% of patients respectively. Sixty‐eight per cent of patients did not experience CRS or NEs within 72 h of axi‐cel. With a median follow‐up of 8·9 months, objective and complete response rates were 95% and 80% respectively. Overall, prophylactic corticosteroids and earlier corticosteroid and/or tocilizumab intervention resulted in no grade 3 or higher CRS, a low rate of grade 3 or higher NEs and high response rates in this study population.

Abstract Background Interval duration measurements (IDMs) were compared between standard 12‐lead electrocardiograms (ECGs) and 6‐lead ECGs recorded with AliveCor's KardiaMobile 6L, a hand‐held mobile device designed for use by patients at home. Methods Electrocardiograms were recorded within, on average, 15 min from 705 patients in Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic. Interpretable 12‐lead and 6‐lead recordings were available for 685 out of 705 (97%) eligible patients. The most common diagnosis was congenital long QT syndrome (LQTS, 343/685 [50%]), followed by unaffected relatives and patients (146/685 [21%]), and patients with other genetic heart diseases, including hypertrophic cardiomyopathy (36 [5.2%]), arrhythmogenic cardiomyopathy (23 [3.4%]), and idiopathic ventricular fibrillation (14 [2.0%]). IDMs were performed by a central ECG laboratory using lead II with a semi‐automated technique. Results Despite differences in patient position (supine for 12‐lead ECGs and sitting for 6‐lead ECGs), mean IDMs were comparable, with mean values for the 12‐lead and 6‐lead ECGs for QTcF, heart rate, PR, and QRS differing by 2.6 ms, −5.5 beats per minute, 1.0 and 1.2 ms, respectively. Despite a modest difference in heart rate, intervals were close enough to allow a detection of clinically meaningful abnormalities. Conclusions The 6‐lead hand‐held device is potentially useful for a clinical follow‐up of remote patients, and for a safety follow‐up of patients participating in clinical trials who cannot visit the investigational site. This technology may extend the use of 12‐lead ECG recordings during the current COVID‐19 pandemic as remote patient monitoring becomes more common in virtual or hybrid‐design clinical studies.

Treating actinic keratosis (AK) and photodamaged skin is critical to reduce the risk of progression to skin cancer. Laser resurfacing for AK treatment is available as either lesion-directed or field therapy. Laser resurfacing removes the superficial epidermis and dermis containing actinic damage, promoting re-epithelialization of healthy skin. Although laser resurfacing has been explored as a modality for AK treatment in the literature, studies summarizing its efficacy in the treatment of AK are lacking. This review summarizes existing research on laser resurfacing as a monotherapy for AK treatment, highlighting the various laser resurfacing modalities available for AK treatment as well as their complications and efficacy in comparison to other therapies. Despite longer healing time, fully ablative laser resurfacing, including carbon dioxide and erbium-doped yttrium aluminum garnet were found to be more effective for AK treatment than fractional ablative techniques. Although some studies suggest laser resurfacing monotherapy as less efficacious than photodynamic therapy, and equally effective to 5-fluorouracil and 30% trichloroacetic acid, clinical trials of larger sample size are required to establish stronger evidence-based conclusions. Moreover, laser resurfacing used as lesion-directed therapy, as opposed to the usual field-therapy, requires further investigation.

Background: Limited studies have described long-term outcomes in pathology confirmed multiple sclerosis (MS). Objectives: To describe long-term clinical–radiographic–cognitive outcomes in a prospectively followed cohort of patients with pathologically confirmed CNS demyelinating disease, consistent with MS. Methods: Subjects underwent clinical assessment, standardized 3T-MRI brain, and cognitive battery. Results: Seventy-five patients were included. Biopsied lesion size was ⩾ 2 cm in 62/75. At follow-up, median duration since biopsy was 11 years. Median EDSS was 3 and lesion burden was large (median 10 cm 3 ). At follow-up, 57/75 met MS criteria, 17/75 had clinically isolated syndrome, and 1 radiographic changes only. Disability scores were comparable to a prevalence cohort in Olmsted County ( p < 0.001, n = 218). Cognitive outcomes below age-normed standards included psychomotor, attention, working memory, and executive function domains. Total lesion volume and index lesion-related severity correlated with EDSS and cognitive performance. Volumetric cortical/subcortical GM correlated less than lesion metrics to cognitive outcomes. Conclusion: Despite early aggressive course in pathologically confirmed MS, its long-term course was comparable to typical MS in our study. Cognitive impairment in this group seemed to correlate strongest to index lesion severity and total lesion volume. It remains to be established how the aggressive nature of the lesion, biopsy, and treatment affect clinical/cognitive outcomes.

Abstract Background: Conventional prognostic factors for LBCL were not associated with outcomes in the pivotal ZUMA-1 study of axi-cel in relapsed LBCL (Neelapu et al. NEJM. 2017); however, other attributes like chimeric antigen receptor (CAR) T-cell fitness and composition (CCR7+CD45RA+ T cells), reduced preTx tumor burden, and immune tumor microenvironment (TME) with presence of activated CD8+PD-1+LAG-3+/-TIM-3- T cells were associated with efficacy (Locke et al. Blood Adv. 2020; Galon et al. ASCO 2020. #3022). Here, we evaluated preTx immune cell phenotypes in premanufacturing apheresis (premfg aph) material, comprising peripheral blood mononuclear cells, to determine associations with product attributes, immune TME features, and clinical efficacy in ZUMA-1. Methods: Evaluable samples from patients (pts) in Phase (Ph) 1 and Ph2 Cohorts (C) 1-3 were analyzed (NCT02348216; Ph1 and Ph2 C1+2, ≥2-y follow-up; C3, ≥6-mo follow-up). Memory T, myeloid, NK, NKT, and B cells in premfg aph material (n=101, excluding C3) were characterized by flow cytometry (FC). PreTx immune TME was analyzed by multiplex IHC (n=18) and gene expression analysis (n=30) as previously described (Rossi et al. AACR 2018. #LB-016; Galon et al. ASCO 2020. #3022). CAR T-cell fitness was analyzed by doubling time, viability during manufacturing, and product T-cell phenotypes by FC (n=145). Associations between these covariates, and with routine hematology tests, were performed by Spearman rank correlation or Wilcoxon tests. Effects on survival were assessed by Kaplan-Meier with optimized cutpoint selection. Results: The percentage (%) of naive (CCR7+CD45RA+) T helper (Th; CD4+CD127+CD25low) cells coexpressing CD27 and CD28 (median, 1%; range, 0.01%-15.8%; IQR, 0.3%-3.8%) in aph associated positively with axi-cel efficacy. The % of intermediate monocytes (IMs; CD14+CD16+; median, 1.8%; range, 0.003%-16.7%; IQR, 1%-3%) in aph associated negatively with efficacy. The % of circulating CD27+CD28+ naive Th cells associated positively with an enriched preTx immune TME T-cell signature, % CCR7+CD45RA+ product T cells, objective response rate, PFS, and OS. An increased % of IMs associated directly with negative predictive markers (preTx serum levels of LDH, IL-6, and CRP) and inversely with TME T-cell signature, PFS, and OS. The premfg ratio of CD27+CD28+ naive Th cells/IMs associated directly with CAR T-cell expansion and efficacy. Conclusions: This work points to a link between the pre-existing state of the immune system, reflected in premfg aph, and immune TME, as well as product attributes influencing axi-cel efficacy in LBCL. These data bear practical implications towards the development of predictive biomarkers for axi-cel efficacy. [JB and JC contributed equally.] Citation Format: Justin Budka, Justin Chou, Vicki Plaks, Francesca Milletti, Zixing Wang, Frederick L. Locke, Sattva S. Neelapu, David B. Miklos, Caron A. Jacobson, Lazaros J. Lekakis, Yi Lin, Armin Ghobadi, Zahid Bashir, Nathalie Scholler, Jérôme Galon, John M. Rossi, Adrian Bot. Pretreatment (PreTx) immune cell phenotypes in peripheral blood associated with the tumor immune contexture, product attributes, and durable clinical efficacy in patients with large B-cell lymphoma (LBCL) treated with axicabtagene ciloleucel (axi-cel) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT166.

Abstract Background: Engineered toxin bodies (ETBs), composed of an engineered Shiga-like Toxin A subunit genetically fused to an antibody-binding domain, can force receptor internalization, induce potent cell-kill via enzymatic and permanent inactivation of ribosomes, and may not be subject to resistance mechanisms of other targeted agents. MT-5111, a de-immunized 55 kD ETB targeting HER2 in solid tumors, also binds to an epitope distinct from trastuzumab and pertuzumab, which may permit combination strategies with other HER2 targeting agents. Methods: The primary objective is to determine maximum tolerated dose (MTD) of MT-5111 monotherapy in adult patients (pts) with advanced HER2+ solid tumors. Secondary objectives are PK, efficacy, and immunogenicity. Using a modified 3+3 design, the dose-escalation part of the study includes the following 7 cohorts: 0.5, 1, 2, 3, 4.5, 6.75, and 10 µg/kg. Three dose-expansion cohorts will follow for HER2+ breast cancer, gastro-esophageal cancer, and any other HER2+ tumors. All pts will receive MT-5111 weekly as a 30-min IV infusion in each 21-d treatment (tx) cycle (C) until disease progression (PD), unacceptable toxicity, death, or withdrawn consent (NCT04029922). Results: As of the data cut in December 2020, 16 pts were treated; cancer types included breast (n=6), gastric (n=1), colon (n=1), gallbladder (n=5), and other solid tumors (n=3). Mean age was 64 years (range, 34-78); 37.5% were male. Pts received a median of 4 prior lines of systemic therapies (range, 1-8). No G4 or G5 TEAEs occurred. Six pts had 11 G3 TEAEs; the most common were increased AST and dyspnea (both n=2). Three pts had tx-emergent serious adverse events (abdominal distension [n=1]; dyspnea [n=2]). Tx-related TEAEs occurred in 8 (50%) pts; the most common was fatigue (n=5, 31.3%) and all were ≤ grade 2 in nature, except for one grade 3 event of dyspnea. No cardiac TEAEs, clinically significant changes in cardiac biomarkers (troponin, electrocardiogram, left ventricular ejection fraction), or cases of capillary leak syndrome were observed. Fifteen pts discontinued with PD; 1 pt in cohort 5 (4.5 µg/kg) is on tx with stable disease. To date, no DLTs have been observed and the MTD has not been reached. One pt in cohort 2 (1 µg/kg) had resolution of all hepatic lesions (sub-centimeter lesions pre-tx) at the end of C8; however, the pt came off study due to clinical progression at the end of C10. PK data for the first 5 cohorts matched simulations based on non-human primate studies. Conclusions: MT-5111 was well tolerated with no clinically significant cardiotoxicity. Continued dose escalations are ongoing. Citation Format: Zev A. Wainberg, Monica M. Mita, Minal A. Barve, Erika P. Hamilton, Andrew J. Brenner, Frances Valdes, Daniel Ahn, Joleen Hubbard, Jason Starr, Christine Burnett, Joshua Pelham, Eric T. Williams, Banmeet S. Anand, Thomas Strack, Andrés Machado Sandri, Brian A. Van Tine. Phase 1 study of the novel immunotoxin MT-5111 in patients with HER-2+tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT130.