Citations

Open reading frame 8 (ORF8) shows one of the highest levels of variability among accessory proteins in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Disease 2019 (COVID-19). It was previously reported that the ORF8 protein inhibits the presentation of viral antigens by the major histocompatibility complex class I (MHC-I), which interacts with host factors involved in pulmonary inflammation. The ORF8 protein assists SARS-CoV-2 in evading immunity and plays a role in SARS-CoV-2 replication. Among many contributing mutations, Q27STOP, a mutation in the ORF8 protein, defines the B.1.1.7 lineage of SARS-CoV-2, engendering the second wave of COVID-19. In the present study, 47 unique truncated ORF8 proteins (T-ORF8) with the Q27STOP mutations were identified among 49,055 available B.1.1.7 SARS-CoV-2 sequences. The results show that only one of the 47 T-ORF8 variants spread to over 57 geo-locations in North America, and other continents, which include Africa, Asia, Europe and South America. Based on various quantitative features, such as amino acid homology, polar/non-polar sequence homology, Shannon entropy conservation, and other physicochemical properties of all specific 47 T-ORF8 protein variants, nine possible T-ORF8 unique variants were defined. The question as to whether T-ORF8 variants function similarly to the wild type ORF8 is yet to be investigated. A positive response to the question could exacerbate future COVID-19 waves, necessitating severe containment measures.

AbstractHumidified rapid‐insufflation ventilatory exchange (HRIVE) is an option for maintenance of oxygenation. This technique allows for oxygenation while the patient is apnoeic due to continuous positive airway pressure and gas exchange through flow‐dependent dead space flushing. There is no study about the usage of HRIVE during rigid bronchoscopy. This retrospective study looked at rigid bronchoscopy cases utilizing HRIVE. Data points assessing adequacy of oxygenation and ventilation were recorded at time points: oxygen saturation (SpO2), partial pressure of oxygen (PaO2) and partial pressure of carbon dioxide (PaCO2). Our nine cases had an average baseline SpO2 of 99.26%, 95.56% at 10 min into HRIVE and 95.27% at the end of HRIVE. The average baseline PaO2 was 309.01 mmHg, 124.99 mmHg at 10 min into HRIVE and 128.17 mmHg at the end of HRIVE. The average baseline PaCO2 was 43.26 mmHg, 68.76 mmHg at 10 min into HRIVE and 75.52 mmHg at the end of HRIVE. The average pre‐HRIVE end‐tidal CO2 (ETCO2) was 38.56 mmHg and the average post‐HRIVE ETCO2 was 61.22 mmHg. The average baseline pH was 7.36, 7.22 at 10 min into HRIVE and 7.19 at the end of HRIVE. In this small cohort study, HRIVE was able to maintain adequate oxygenation via the rigid bronchoscope in a select group of patients. Hypercapnia and respiratory acidosis did result after 10 min, which may predispose certain patient populations to complications. HRIVE potentially offers an additional option of oxygenation via the rigid bronchoscope.

Background: When operative treatment is indicated, tibial spine fractures can be successfully managed with open or arthroscopic reduction and internal fixation (ARIF). The purpose of the study is to evaluate short-term treatment outcomes of tibial spine fractures in patients treated with both open and arthroscopic fracture reduction. Methods: We performed an Institutional Review Board (IRB)-approved retrospective cohort study of pediatric tibial spine fractures presenting between January 1, 2000 and January 31, 2019 at 10 institutions. Patients were categorized into 2 cohorts based on treatment: ARIF and open reduction and internal fixation (ORIF). Short-term surgical outcomes, the incidence of concomitant injuries, and surgeon demographics were compared between groups. Results: There were 477 patients with tibial spine fractures who met inclusion criteria, 420 of whom (88.1%) were treated with ARIF, while 57 (11.9%) were treated with ORIF. Average follow-up was 1.12 years. Patients treated with ARIF were more likely to have an identified concomitant injury (41.4%) compared with those treated with ORIF (24.6%, P=0.021). Most concomitant injuries (74.5%) were treated with intervention. The most common treatment complications included arthrofibrosis (6.9% in ARIF patients, 7.0% in ORIF patients, P=1.00) and subsequent anterior cruciate ligament injury (2.1% in ARIF patients and 3.5% in ORIF, P=0.86). The rate of short-term complications, return to the operating room, and failure to return to full range of motion were similar between treatment groups. Twenty surgeons with sports subspecialty training completed 85.0% of ARIF cases; the remaining 15.0% were performed by 12 surgeons without additional sports training. The majority (56.1%) of ORIF cases were completed by 14 surgeons without sports subspecialty training. Conclusion: This study demonstrated no difference in outcomes or nonunion following ARIF or ORIF, with a significantly higher rate of concomitant injuries identified in patients treated with ARIF. The majority of identified concomitant injuries were treated with surgical intervention. Extensive surgical evaluation or pretreatment magnetic resonance imaging should be considered in the workup of tibial spine fractures to increase concomitant injury identification. Level of Evidence: Level III.

INTRODUCTION: Several scoring systems predict mortality in alcohol-associated hepatitis (AH), including the Maddrey discriminant function (mDF) and model for end-stage liver disease (MELD) score developed in the United States, Glasgow alcoholic hepatitis score in the United Kingdom, and age, bilirubin, international normalized ratio, and creatinine score in Spain. To date, no global studies have examined the utility of these scores, nor has the MELD-sodium been evaluated for outcome prediction in AH. In this study, we assessed the accuracy of different scores to predict short-term mortality in AH and investigated additional factors to improve mortality prediction. METHODS: Patients admitted to hospital with a definite or probable AH were recruited by 85 tertiary centers in 11 countries and across 3 continents. Baseline demographic and laboratory variables were obtained. The primary outcome was all-cause mortality at 28 and 90 days. RESULTS: In total, 3,101 patients were eligible for inclusion. After exclusions (n = 520), 2,581 patients were enrolled (74.4% male, median age 48 years, interquartile range 40.9–55.0 years). The median MELD score was 23.5 (interquartile range 20.5–27.8). Mortality at 28 and 90 days was 20% and 30.9%, respectively. The area under the receiver operating characteristic curve for 28-day mortality ranged from 0.776 for MELD-sodium to 0.701 for mDF, and for 90-day mortality, it ranged from 0.773 for MELD to 0.709 for mDF. The area under the receiver operating characteristic curve for mDF to predict death was significantly lower than all other scores. Age added to MELD obtained only a small improvement of AUC. DISCUSSION: These results suggest that the mDF score should no longer be used to assess AH's prognosis. The MELD score has the best performance in predicting short-term mortality.

Abstract Objective To study maternal anxiety in pregnant women without comorbidities in the context of the COVID-19 outbreak in Brazil and to study maternal knowledge and concerns about the pandemic. Methods This is a secondary analysis from a national multicenter cross-sectional study performed in 10 cities, from June to August, 2020, in Brazil. Interviewed postpartum women, without medical or obstetrical comorbidities, were included in the present subanalysis. A structured questionnaire and the Beck Anxiety Inventory (BAI) were applied. Results Out of the 1,662 women, 763 (45.9%) met the criteria for the current analysis and 16.1% presented with moderate and 11.5% with severe maternal anxiety. Moderate or severe maternal anxiety was associated with high school education (odds ratio [OR]:1.58; 95% confidence interval [CI]:1.04–2.40). The protective factor was cohabiting with a partner (OR: 0.46; 95%CI: 0.29–0.73). There was a positive correlation between the total BAI score and receiving information about care in the pandemic (rpartial 0.15; p < 0.001); concern about vertical transmission of COVID-19 (rpartial 0.10; p = 0.01); receiving information about breastfeeding (rpartial 0.08; p = 0.03); concerns about prenatal care (rpartial 0.10; p = 0.01), and concerns about the baby contracting COVID-19 (rpartial 0.11; p = 0.004). The correlation was negative in the following aspects: self-confidence in protecting from COVID-19 (rpartial 0.08; p = 0.04), having learned (rpartial 0.09; p = 0.01) and self-confidence in breastfeeding (rpartial 0.22; p < 0.001) in the context of the pandemic. Conclusion The anxiety of pregnant women without medical or obstetrical comorbidities was associated to high school educational level and not living with a partner during the COVID-19 pandemic. Self-confidence in protecting against COVID-19 and knowledge about breastfeeding care during the pandemic reduced maternal anxiety.

Abstract Background Allogeneic (off the shelf) chimeric antigen receptor (CAR) T-cell therapy addresses the logistical challenges, availability (including insufficient T-cell yields from low baseline absolute lymphocyte count), and variable product quality of autologous CAR T therapy. ALLO-715 is a genetically modified anti-BCMA AlloCAR T™ cell which uses Cellectis TALEN ® technology to disrupt the T-cell receptor alpha constant gene (TRAC) and the CD52 gene to reduce the risk of graft-versus-host disease (GvHD) and permit the use of ALLO-647, an anti-CD52 monoclonal antibody (mAb), for selective and transitory host lymphodepletion (LD). Methods UNIVERSAL is an open-label, Phase 1 trial (NCT04093596) in adults with relapsed/refractory (R/R) multiple myeloma who have received ≥3 prior lines of therapy including a proteasome inhibitor, immunomodulator, and anti-CD38 mAb. Patients (pts) must be refractory to their last treatment line. Pts receive LD followed by ALLO-715 at 1 of 4 dose levels (DLs) in a 3+3 dose escalation design: 40, 160, 320, and 480 x 10 6 CAR+ T cells. Several LD regimens are being evaluated: FCA39; FCA60; FCA90; and CA39; with fludarabine [F] 90 mg/m 2, cyclophosphamide [C] 900 mg/m 2, and ALLO-647 [A] 39, 60, or 90 mg divided over 3 days. Results As of June 21, 2021 data-cut, 47 subjects were enrolled; 42 were treated with ALLO-715; 5 progressed prior to treatment. Median time from enrollment to LD was 5 days and no treated pts required bridging therapy. Pts were heavily pretreated with a range of 3-11 prior lines of therapy; 42.9% were penta refractory. There were 19% ISS Stage III at screening, 34% had high risk cytogenetics, and 19% had extramedullary disease. The most common Grade (Gr) 3+ adverse events (AEs) included anemia, neutropenia, lymphopenia, and thrombocytopenia. Cytokine release syndrome (CRS) occurred in 52.4%, all Gr 1/2 except 1 pt with Gr 3. CRS was treated with tocilizumab (21.3%) and corticosteroids (12.8%). One pt (with Gr 2 CRS) experienced Gr 1 neurotoxicity that resolved. Gr 3+ infections occurred in 12.8% of pts, including 2 previously reported Gr 5 events (fungal pneumonia and adenovirus hepatitis). Early results from this trial have been presented previously (ASH 2020) and therefore the efficacy analysis on pts (n=26) treated at DL3 and DL4 with FCA LD, which are considered a more relevant cell dose and LD, is presented here (Table). In pts who received DL3 or DL4 (320 or 480 x 10 6 CAR T cells) (n=26), the ORR was 61.5% (95% CI: 40.6, 79.8); very good partial response or better (VGPR+) rate was 38.5% (95% CI: 20.2, 59.4). Median time to 1 st response was 16 days. The median follow-up for the DL3/DL4 pts was 7.4 months (95% CI: 3.6, 9.9) with a median duration of response of 8.3 months (95% CI: 1.5, not reached). Of the 10 pts with a best response of VGPR+, 8 were found to be negative by minimal residual disease (MRD) analysis. Conclusions UNIVERSAL demonstrates proof of concept for allogeneic CAR T therapy in multiple myeloma. ALLO-715 showed CAR T cell dose response relationship with higher doses (DL3/DL4) leading to clinically meaningful efficacy, including high VGPR+ rate of 38.5% and high MRD negativity without requiring leukapheresis or bridging therapy. ALLO-715 following LD with FCA has a tolerable safety profile. FCA induces a deep and durable window of lymphocyte depletion allowing CAR T cell expansion and persistence. A study using the next generation anti-BCMA CAR (ALLO-605) which supplies cytokine signaling to the CAR bearing cells is ongoing (IGNITE). The current UNIVERSAL trial continues to enroll, including a cohort with consolidation, and updated data will be presented at the meeting. Figure 1 Figure 1. Disclosures Mailankody: Allogene Therapeutics: Research Funding; Plexus Communications: Honoraria; Fate Therapeutics: Research Funding; Physician Education Resource: Honoraria; Bristol Myers Squibb/Juno: Research Funding; Jansen Oncology: Research Funding; Legend Biotech: Consultancy; Evicore: Consultancy; Takeda Oncology: Research Funding. Liedtke: Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Sidana: BMS: Consultancy; Magenta Therapeutics: Consultancy, Research Funding; Allogene: Research Funding; Janssen: Consultancy, Research Funding. Chhabra: GSK: Honoraria. Oluwole: Janssen: Consultancy; Pfizer: Consultancy; Curio Science: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Kumar: Oncopeptides: Consultancy; Antengene: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Roche-Genentech: Consultancy, Research Funding; Merck: Research Funding; Carsgen: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Beigene: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Sanofi: Research Funding. Nath: Actinium: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Anwer: Janssen pharmaceutical: Honoraria, Research Funding; Allogene Therapeutics: Research Funding; GlaxoSmithKline: Research Funding; BMS / Celgene: Honoraria, Research Funding. Raje: Caribou: Other; Janssen: Other; bluebird bio: Other; Amgen: Other; Celgene: Other; BMS: Other. Siegel: Bristol Myers Squibb: Honoraria, Speakers Bureau; Takeda: Honoraria; GlaxoSmithKline: Honoraria, Speakers Bureau; Celularity: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria; Amgen Inc.: Honoraria; Janssen: Honoraria, Speakers Bureau. Karski: Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company; Crispr Therapeutics: Current equity holder in publicly-traded company; Nektar Therapeutics: Current equity holder in publicly-traded company. Lovelace: Allogene Therapeutics, Inc.: Current Employment. Lourbakos: Allogene Therapeutics, Inc.: Current Employment. Hari: Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Karyopharm: Consultancy; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau.