[Interinstitutional Command Mexico: organizational decision-making in the face of COVID-19]

Background: The third wave of COVID-19 in Mexico produced a high demand for hospital care, which is why it was created a multidisciplinary group to optimize decision-making: the Interinstitutional Command for the Health Sector (COISS, according to its initials in Spanish). So far, there is no scientific evidence of the COISS processes or their effect on the behavior of epidemiological indicators and the hospital care needs of the population in the context of COVID-19 in the entities involved. Objectives: To analyze the trend on epidemic risk indicators throughout the COISS group's management in the third wave of COVID-19 in Mexico. Material and methods: Mixed study: 1) non-systematic review of information from technical documents issued by COISS, 2) secondary analysis of open-access institutional databases through the description of healthcare needs of cases notified with COVID-19 symptoms, and an ecological analysis by each Mexican state on the behavior of hospital occupancy, RT-PCR positivity, and COVID-19 mortality in two-time points. Results: The COISS activity in identifying states with epidemic risk generated actions aimed at a reduction in hospital occupancy of beds, positivity by RT-PCR, and mortality from COVID-19. Conclusions : The decisions of the COISS group reduced the indicators of epidemic risk. Continuing the work of the COISS group is an urgent need. Conclusions: The decisions of the COISS group reduced the indicators of epidemic risk. Continuing the work of the COISS group is an urgent need. Copyright © 2023 Revista Medica del Instituto Mexicano del Seguro Social.

Analysis of the university teaching influenced by the COVID-19 context: some lessons learned

The health crisis caused by the SARS-COV-2 virus produced a drastic change in teaching in March 2020, when face-to-face teaching was forced to become online teaching. It led to changes in teaching methodologies, teaching materials and evaluation methods. The objective of this study is to determine which of these changes in the on-site university have been positive and should be sustained over time. To this end, a survey has been carried out among the students of different courses of the degrees taught at the E.T.S.I. Minas y Energía (E.T.S.I.M.E) of Universidad Politécnica de Madrid that allows us to know how the pandemic has influenced the use of didactic materials, what type of teaching modalities students prefer, and what resources they use the most during the study. Although class notes and slides remain the preferred resources among students, they showed great interest in class recordings. Other traditional materials, such as bibliography or tutoring, are less used by students. As for teaching methodologies, opinion is polarized. Therefore, it is necessary to make an effort to efficiently combine tele-teaching methodologies and didactic resources to face-to-face teaching, generating asynchronous resources without detriment to traditional face-to-face activities. Copyright © 2021 for this paper by its authors. Use permitted under Creative Commons License Attribution 4.0 International (CC BY 4.0).

Subcutaneous (SC) Administration of Mosunetuzumab with Cycle 1 Step-up Dosing Is Tolerable and Active in Patients with Relapsed/Refractory B-Cell Non-Hodgkin Lymphomas (R/R B-NHL): Initial Results from a Phase I/II Study

Background: Cytokine release syndrome (CRS) is a potentially serious complication of T-cell engaging immunotherapy. Effective measures are needed to reduce the rate and severity. In a multicenter Phase I/II study (NCT02500407), the CD20xCD3 bispecific antibody mosunetuzumab (Mosun) showed durable complete responses (CR) and had manageable safety in patients (pts) with late-line R/R B-NHL (Schuster et al. ASH 2019). IV administration with Cycle (C) 1 step-up dosing was an effective strategy for mitigating CRS during C1 (Bartlett et al. ASCO 2019). Fixed-dose SC administration was also a viable strategy for CRS mitigation, owing to the slower rate of Mosun absorption compared with IV (Matasar et al. ASH 2020). A combination of both strategies could further improve the CRS profile. We present safety and efficacy data from the initial cohorts investigating SC Mosun administration with C1 step-up dosing in the Phase I/II study. Methods: All pts had R/R B-NHL with ≥1 prior line of systemic therapy and ECOG PS ≤1. SC Mosun was given in 21-day cycles using two step-up dosing schedules (C1 day [D]1/C1D8/C1D15 and D1 of subsequent cycles: 5/15/45mg or 5/45/45mg). Mosun was discontinued after C8 in pts who achieved a CR, while pts with a partial response or stable disease continued Mosun for a total of 17 cycles, unless progressive disease or unacceptable toxicity occurred. Primary objectives included evaluation of safety, tolerability, and pharmacokinetics (PK). Responses were evaluated by investigator-assessment of PET/CT scans using Cheson 2007 criteria. CRS is reported using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Results: As of June 21, 2021, 74 pts had been enrolled (5/15/45mg: 38 pts;5/45/45mg: 36 pts). Median age was 67.0 years (range: 41-88). The most common NHL subtypes were DLBCL (31 pts), FL (21), transformed (tr) FL (10), and MCL (3). 70.0% of pts had Ann Arbor stage III or IV disease. Median number of prior lines of therapy was 3 (range: 1-9). 79.5% of pts were refractory to prior anti-CD20 therapy and 82.4% were refractory to their last prior therapy. Median follow-up for safety was 2.5 months (range: 0.2-7.2). No dose-limiting toxicities were observed during dose-escalation. Common all-Grade (Gr) adverse events (AEs;≥10% of pts) were injection site reaction (52.7%;Gr 1: 47.3%;Gr 2: 5.4%), CRS (24.3%), fatigue (21.6%), headache (17.6%), rash (13.5%), and pyrexia (10.8%). CRS mostly occurred in C1 and was low Gr in all pts (Gr 1: 17.6%;Gr 2: 6.8%);no Gr ≥3 CRS occurred. Gr 2 CRS occurred with a similar frequency in the 5/15/45mg and 5/45/45mg cohorts (7.9% vs 5.6% of pts, respectively). In the 5/15/45mg cohort, the 3 Gr 2 CRS events occurred after each of the C1 doses, while in the 5/45/45mg cohort, the 2 Gr 2 CRS events occurred after the first 45mg dose. Median duration of CRS was 2 days (range: 1-6) and all events resolved without sequelae. Neutropenia occurred in 12.2% of pts (Gr 2: 2.7%;Gr 3: 6.8%;Gr 4: 2.7%). Febrile neutropenia occurred in only 1 pt (Gr 3). Serious infections occurred in 3 pts (2 pneumonia, both resolved;1 COVID-19, fatal outcome). No Mosun-related Gr 5 (fatal) AEs or Mosun-related AEs leading to Mosun discontinuation occurred. The PK profile of SC Mosun was consistent with that previously reported, with high bioavailability (>85%), a slow absorption rate, and a blunted C max. IL-6 and IFN-y kinetics in plasma were similar in both SC cohorts, with modest and delayed increases observed after the initial dose, contrasting with the more marked and rapid increases observed with IV dosing, and consistent with the low frequency and severity of CRS observed. At data cut-off, 38 pts were efficacy evaluable. Responses were observed in 19 pts across all histologies, including 8/10 (80%) pts with R/R FL and 6/17 (35.3%) pts with R/R DLBCL/trFL. Conclusions: SC Mosun administration with C1 step-up dosing has a favorable safety profile in pts with late-line and highly refractory B-NHL, enabling an outpatient treatment schedule without mandatory hospitalizations. Encouragingly, the 5/45/45mg schedule had a low rate of CRS that was similar to the 5/15/45mg schedule, allowing the target dose to be reached earlier. Early response data suggest that the efficacy of Mosun is not compromised by SC dosing. Compared with IV, SC Mosun is likely to improve convenience for pts and efficiency for healthcare providers. Updated efficacy data with longer follow up and depth of response will be presented. Disclosures: Bartlett: Affimed: Research Funding;Autolus: Research Funding;Bristol-Myers Squibb: Research Funding;Celgene: Research Funding;Forty Seven: Research Funding;Janssen: Research Funding;Kite Pharma: Research Funding;Merck: Research Funding;Millennium: Research Funding;Pharmacyclics: Research Funding;Genentech, Inc./F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding;Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding;ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding;Washington University School of Medicine: Current Employment. Giri: Royal Adelaide Hospital: Current Employment. Budde: Genentech, Inc.: Consultancy;Merck, Inc: Research Funding;Amgen: Research Funding;AstraZeneca: Research Funding;Mustang Bio: Research Funding;Novartis: Consultancy;Gilead: Consultancy;Roche: Consultancy;Beigene: Consultancy. Schuster: Celgene: Consultancy, Honoraria, Research Funding;Nordic Nanovector: Consultancy;Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding;Abbvie: Consultancy, Research Funding;Acerta Pharma/AstraZeneca: Consultancy;Alimera Sciences: Consultancy;BeiGene: Consultancy;Juno Theraputics: Consultancy, Research Funding;Loxo Oncology: Consultancy;Tessa Theraputics: Consultancy;Genentech/Roche: Consultancy, Research Funding;Pharmaclyclics: Research Funding;Adaptive Biotechnologies: Research Funding;Merck: Research Funding;Incyte: Research Funding;TG Theraputics: Research Funding;DTRM: Research Funding. Assouline: Johnson&Johnson: Current equity holder in publicly-traded company;Gilead: Speakers Bureau;Amgen: Current equity holder in publicly-traded company, Research Funding;Novartis: Honoraria, Research Funding;Eli Lilly: Research Funding;Roche/Genentech: Research Funding;Jewish General Hospital, Montreal, Quebec: Current Employment;Takeda: Research Funding;BeiGene: Consultancy, Honoraria, Research Funding;F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding;AstraZeneca: Consultancy, Honoraria;AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau;Janssen: Consultancy, Honoraria;Pfizer: Consultancy, Honoraria. Matasar: Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company;Juno Therapeutics: Consultancy;Janssen: Honoraria, Research Funding;Daiichi Sankyo: Consultancy;Genentech, Inc.: Consultancy, Honoraria, Research Funding;Bayer: Consultancy, Honoraria, Research Funding;Merck: Consultancy;Teva: Consultancy;TG Therapeutics: Consultancy, Honoraria;F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding;Takeda: Consultancy, Honoraria;GlaxoSmithKline: Honoraria, Research Funding;Seattle Genetics: Consultancy, Honoraria, Research Funding;Memorial Sloan Kettering Cancer Center: Current Employment;IGM Biosciences: Research Funding;Pharmacyclics: Honoraria, Research Funding;Rocket Medical: Consultancy, Research Funding;ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding. Canales: Takeda: Consultancy, Honoraria, Speakers Bureau;Incyte: Consultancy;Sandoz: Honoraria, Speakers Bureau;iQone: Honoraria;Sanofi: Consultancy;Novartis: Consultancy, Honoraria;Karyopharm: Consultancy, Honoraria;Eusa Pharma: Consultancy, Honoraria;Celgene/Bristol-Myers Squibb: Consultancy, Honoraria;Gilead/Kite: Consultancy, Honoraria;F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Speakers Bureau;Janssen: Consultancy, Honoraria, Speakers Bureau. Fay: St Vincent's Hosptial, Sydney, ustralia: Current Employment. Cheah: BMS: Consultancy, Research Funding;Abbvie: Research Funding;Janssen: Consultancy, Honoraria;MSD: Consultancy, Honoraria;Gilead: Consultancy, Honoraria;Ascentage Pharma: Consultancy, Honoraria;AstraZeneca: Consultancy, Honoraria;Lilly: Consultancy, Honoraria;TG therapeutics: Consultancy, Honoraria;Beigene: Consultancy, Honoraria;Novartis: Consultancy, Honoraria;Roche: Consultancy, Honoraria, Other: travel, Research Funding. Marlton: BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees;F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees;Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees;Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees;AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees;AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees;Queensland Health: Current Employment;Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wiebking: Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company;F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Yin: Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. To: Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Li: Genentech, Inc.: Current Employment, Current holder of individual stocks in a privately-held company. Huang:F. Hoffmann-La Roche Ltd: Current Employment. Zhou: Fibrogen China: Ended employment in the past 24 months;Roche Pharma Product Development: Current Employment. Penuel: Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. O'Hear: Genentech, Inc.: Current Employment;F. Hoffmann-La Roche Ltd: Current holder of individual stocks in a privately-held company. Sehn: Novartis: Consultancy;Debiopharm: Consultancy;Genmab: Consultancy. OffLabel Disclosure: Mosunetuzumab is a CD20xCD3 bispecific antibody that redirects T cells to engage and eliminate malignant B cells. Mosunetuzumab is an investigational agent.

Functional CD8+ T cell-specificImmune response alterations under ocrelizumab treatment

Objective: To investigate the viral CD8+ T cell cellular immune response under ocrelizumab. Background: Administration of higher efficacy disease modifying drugs in multiple sclerosis patients is not without concern during the SARS-CoV-2 pandemic. Under ocrelizumab, an antiCD20 antibody that causes depletion of circulating B cells with minor alleged effect on T cells, infections are generally mild, although the risk of both viral and bacterial infection is slightly increased. Design/Methods: We performed repeated enzyme linked immunospot assays (ELISPOT) in a cohort of 37 ocrelizumab-treated MS patients, before treatment initiation (T0), and at 6 months (T6) and one year into treatment (T12). Viral antigens consisted in a pool of immunodominant 8-10 mer epitope peptides including epitopes of EBV, CMV, and Influenza. Further characterization of CD8+ T cell subtypes was done using mass cytometry. We corrected all data for age and total CD8+ T cell count using linear regression models. Results: Of the 37 patients tested, 27 had positive ELISPOT assays at T0 while only 21 remained positive at T12. Although the total number of CD8+ T cells remained stable (p=0.117), the frequency of IFN-gamma secreting CD8+ T cells, among the responders, was significantly reduced in 51.5% of patients at T6 (p=0.002) and 55.2% at T12 (p<0.001). Furthermore, at T6 and T12, subpopulation analysis revealed a 22.7% reduction in memory CD8+ T cell numbers as compared to T0 (p=0.003), mostly due to a depletion of CD8/CD20 double positive T cells (frequency reduced by 68.8%, p<0.001) and an increase in numbers of naïve CD8+ T cells (23.4%, p=0.004). No correlation was noted with age at disease onset (p=0.366) or with age at ocrelizumab onset (p=0.174). Conclusions: Although a minor component of the total pool of CD8+ T cells, the double positive CD8/CD20 T cells may play an important role in virus-specific cellular immune response.

CSF of SARS-CoV-2 patients with neurological syndromes does not display evidence ofstrong immune response butreveals hintsto understand neurologic pathophysiology

Objective: In this study we aimed to analyse if viral particles or pro-inflammatory mediators may cause neurological symptoms of SARS-CoV-2 infection. Background: Coronavirus disease (COVID-19) has been associated with a large variety of neurological disorders. However the mechanisms underlying these neurological complications remain elusive. Design/Methods: We checked for SARS-CoV-2 mRNA by qPCR, SARS-CoV-2-specific antibodies and for 49 cytokines/chemokines/growth factors (by Luminex) in the cerebrospinal fluid (CSF) +/-serum of a cohort of 17 COVID-19 patients with neurological presentation and 55 neurological controls (inflammatory, non inflammatory, multiple sclerosis). Results: We found SARS-CoV-2 mRNA and antibodies specific for this virus in the CSF of 0/17 and 8/16 COVID-19 patients, respectively. The presence of SARS-CoV-2 antibodies was explained by a rupture of the blood brain barrier (passive transfer) in 6/16 (37,5%), but an intrathecal synthesis of SARS-CoV2-specific antibodies was present in 2/17. As compared to SARS-CoV-2-negative NIND patients, the CSF of IND patients exhibited the highest level of chemokines (CCL4, CCL5, CXCL8, CXCL10, CXCL12, and CXCL13), followed the CSF of MS patients (CXCL12, and CXCL13). There was no difference between COVID-19 patients with neurological diseases compared to NIND even if some chemokines (CCL4, CCL5, CXCL8, andCXCL10) tended to be higher than NIND. Interestingly, among COVD-19 patients, the CSF of those with a severe disease (encephalitis/encephalopathy) contained higher levels CXCL8 and CXCL10 than those with other neurological presentations. Conclusions: Our results confirm the absence of obvious SARS-CoV-2 infection of the central nervous system and point to a mild inflammatory reaction reflecting an astrocytic reaction.

Multiparametric analysis reveal no intrathecal inflammation in COVID-19 associated neurological syndromes

Background and aims: Coronavirus disease (COVID-19) has been associated with a large variety of neurological disorders. However the mechanisms underlying these neurological complications remain elusive. In this study we aimed at determining whether neurological symptoms were caused by SARS-CoV-2 direct infection of by proinflammatory mediators. Methods: We checked for SARS-CoV-2 RNA by RT-qPCR, SARS-CoV-2-specific antibodies and for 48 cytokines/ chemokines/growth factors (by Luminex) in the cerebrospinal fluids (CSF) ± sera of a cohort of 17 COVID- 19 patients with neurological presentation and 55 neurological control patients (inflammatory [IND], non inflammatory [NIND], multiple sclerosis [MS]). Results: We found SARS-CoV-2 RNA and antibodies specific for this virus in the CSF of 0/17 and 8/16 COVID- 19 patients, respectively. The presence of SARS-CoV-2 antibodies was explained by a rupture of the blood brain barrier (passive transfer) in 6/16 (38%). An intrathecal synthesis of SARS-CoV2-specific antibodies was present in 2/16 patients. Of the four categories of tested patients, the CSF of IND exhibited the highest level of chemokines (CCL4, CCL5, CXCL8, CXCL10, CXCL12, and CXCL13), followed by the CSF of MS patients (CXCL12, and CXCL13). There was no significant difference between COVID-19 and NIND patients, even if some chemokines (CCL4, CCL5, CXCL8, andCXCL10) tended to be higher in the former. Interestingly, among COVD-19 patients, the CSF of those with a severe disease (encephalitis/ encephalopathy) contained higher levels CXCL8 and CXCL10 than those with other neurological presentations. Conclusion: Our results do not show obvious SARS-CoV-2 infection of the central nervous system, but point to a mild inflammatory reaction reflecting an astrocytic reaction.