AUTOPHAGY AND Acyl-CoA-BINDING PROTEIN INFLUENCE COVID-19 SEVERITY

Background: Autophagy, a cytosolic-structure degradation pathway, allows production of IL21 by CD4 T-cells and efficient cytolytic responses by CD8 T-cells. Autophagy is in part regulated by acyl-CoA-binding protein (ACBP) which has two functions. Intracellular ACBP favors autophagy, whereas secreted extracellular ACBP inhibits autophagy. Herein, we assessed whether autophagy and the ACBP pathway were associated with COVID-19 severity. Method(s): Through the BQC-19 Quebec biobank, somalogic proteomic analysis was performed on 5200 proteins in plasma samples collected between March 2020 and December 2021. Plasma from 903 patients (all data available) during the acute phase of COVID-19 were assessed. COVID-19 severity was stratified using WHO criteria. In vitro, ACBP intracellular levels, autophagy levels (LC3II) and IL21 production were assessed by flow in PBMCs after a 24h stimulation with IL6, phorbol myristate acetate (PMA)+ionomycin or lipopolysaccharide (LPS). Plasma levels of anti-SARS-CoV-2 (full spike protein or RBD) IgG were assessed by ELISA. Result(s): Median age of the cohort was 62 yo, 48% were female, 55% had comorbidities (see table). Increasing plasma levels of ACBP were found with severity (mild, moderate, severe and fatal groups having 5.3, 7.3, 9.5 and 10.6 RFU/50muL of plasma, respectively, p< 0.001 for all comparisons). Patients with comorbidities had higher plasma ACBP levels (7.4 vs 6.4 RFU/50muL, p< 0.001). Plasma ACBP levels were higher during the delta and omicron-variant periods (8.4 vs 6.8 RFU/50muL;p< 0.001). Plasma ACBP levels correlated with LC3II levels (r=0.51, P< 0.001) and IL6 (r=0.41, p< 0.001), but neither with markers IL1beta nor IL8. ACBP levels negatively correlated with IL21 levels (r=-0.27, p< 0.001), independently of age, sex, and severity. ACBP levels were not associated with levels of anti-SARS-CoV-2 IgG levels. In vitro, IL6 stimulation of healthy control PBMC induced extracellular ACBP release. Moreover, adding recombinant ACBP: 1) reduced autophagy in lymphocytes and monocytes upon polyclonal stimulation with PMA/ionomycin or LPS;2) reduced intracellular production of IL21 in T-cells after PMA/ ionomycin stimulation. Conclusion(s): Plasma ACBP levels were inversely linked with IL21 levels, suggesting that autophagy and IL21 allow control of SARS-CoV-2 infection, independently of the level of SARS-CoV-2 antibody secretion. ACBP is a targetable autophagy checkpoint and its extracellular inhibition may improve SARS-CoV-2 immune control. (Table Presented).

Hygienic fundamentals or environmental resilience? Waste management in Covid crisis

Since the end of the 19th century, urban management priorities have evolved from hygienic imperatives to more environmentalist logics (Barraque, 2014). The global spread of the pandemic in 2020 and the sudden implementation of initially strict containment measures have led waste management stakeholders to review their overall strategy. The objective of this article is to understand how waste management services, which are socially not very visible, but nevertheless essential, have been reorganised by the stakeholders since March 2020. The aim is to put these adaptations into perspective with regard to the various waste management issues, in particular by comparing health and environmental considerations.

Low T Cell Responsiveness in the Early Phase Of COVID-19 Associates with Progression to Severe Pneumonia in Kidney Transplant Recipients

Purpose: Kidney transplant (KT) recipients are more prone to developing lifethreatening forms of COVID-19 than the general population. Little is known about the immunological mechanisms underlying disease severity in these patients receiving T-cell targeting immunosuppressive drugs. We investigated the relationship between T cell responsiveness at the beginning of the infection and the risk to subsequently progress to respiratory failure. Method(s): We performed a multicentric prospective study in 45 KT recipients with a positive RT-PCR COVID-19 test and only mild symptoms at inclusion. Blood samples were collected at baseline directly in a cell culture system containing T cell stimuli. We assessed T cell responsiveness by computing the ratio between the levels of Th1, Th2, Th17 and Treg cytokines produced after polyclonal stimulation and the number of blood lymphocytes. We then used an unsupervised classification approach to stratify patients into low and high T cell responders and a penalized logistic regression to identify variables independently associated with progression to severe COVID-19. Result(s): Forty-five kidney transplant patients were included. Unsupervised clusterization identified 31 low and 14 high T cell responders. Patients who progressed to severe pneumonia were all low T cell responders (p=0.01). In multivariate analysis, we found that low T cell responsiveness at baseline was the main risk factor for subsequent progression to severe pneumonia. Conclusion(s): Low T cell reactivity in the early phase of COVID-19 is strongly associated with progression to severe pneumonia. This study provides new insights into the mechanisms underlying COVID-19 severity in organ transplant recipients and data of interest to clinicians managing immunosuppressive drugs in these patients.

DIMENSIONALITY REDUCTION for STEPWISE ANALYSIS of IMMUNE RESPONSE DYNAMICS in COVID19

Background: COVID-19 is highly heterogeneous in clinical severity and outcome. Considerable advances have uncovered biomolecular traits associated with fatal outcome. However, novel analytical tools are needed to rapidly and accurately delineate patient subgroups with various immunovirological profiles, analyze diverging disease trajectories and prioritize in-depth molecular studies. Methods: To find how immunovirological features are interrelated, we profiled 12 plasma analytes (SARS-CoV-2 vRNA, SARS-CoV-2-specifc antibodies, cytokine and tissue injury markers) in 500 acute longitudinal plasma samples collected from 214 hospitalized COVID-19 patients. We analyzed them simultaneously using PHATE algorithm (potential of heat diffusion for affinity-based transition embedding, Moon et al, Nature Biotech 2019), which can reduce multiple input variables to two salient features for visualization. We performed whole blood transcriptomic analyses to identify molecular signatures associated with survival vs death in a patient cluster identified as being at extreme mortality risk. Results: PHATE analysis of samples collected 11 days after symptom onset (DSO11) revealed four distinct k-means clusters of patients, which aligned with disease severity and outcome. Two groups were highly enriched in critical patients requiring mechanical ventilation: a high-fatality critical cluster 1 accounted for 59% of fatal outcomes (16/27) by DSO60, while critical cluster 2 had good prognosis. Clusters 3 and 4 consisted almost entirely of non-critical survivors delineated respectively by low and high antibody responses. Averaged trajectories between DSO3 to DSO30 diverged between clusters. All patients of the high-fatality cluster had detectable plasma vRNA, which lingered unlike the critical survivor cluster. Their antibody response had a 4-day delay, while their cytokine profile diverged from the other clusters by DSO8, remaining distinct until DSO22. Transcriptome profiles differed between deceased and survivors of the high-fatality cluster 1, with differential expression of GO terms associated with metabolic processes, protein regulation, cell signaling and immune pathways. Conclusion: This unbiased approach gives an integrated view of dysregulated immune response components in fatal COVID-19, which may be explained through differences in molecular pathways. This approach allows to efficiently target detailed investigations on very high-risk patient subgroups who may most likely benefit from new therapeutic interventions.

Chirurgie en période COVID, étude observationnelle☆

But Cette étude vise à évaluer la stratégie, adoptée en matière de programmation opératoire, dans un service d’otorhinolaryngologie et de chirurgie cervicofaciale adulte généraliste, dans une zone fortement touchée, pendant le pic épidémique du COVID-19. L’objectif principal était d’analyser les motifs du maintien des opérations et le devenir des patients opérés. L’objectif secondaire était d’évaluer le devenir des patients reportés. Matériel et méthode Observationnelle monocentrique réalisée pendant la période du COVID-19 en France. Elle inclut 124 patients programmés pour une intervention chirurgicale durant la période du 21 mars au 20 mai 2020. Le nombre et la nature de ces interventions, effectuées ou reportées, ont été recueillis. Résultats Au total, 54,0 % patients ont été opérés et 46,0 % ont été reportés après la période étudiée. Les interventions étaient maintenues lorsqu’il s’agissait de gestes urgents ou semi-urgents. Les patients opérés n’ont pas déclaré d’infection au cours de leur hospitalisation. Parmi les patients reportés, 29,8 % ont été perdus de vus et 49,1 % ont été reprogrammés. Conclusion L’application des recommandations nationales et internationales a permis de minimiser le risque de perte de chance pour les patients avec des pathologies urgentes sans augmenter le risque de contamination. Le report des patients annulés a entraîné de nombreux perdus de vus. Le suivi intensifié de ces patients semble nécessaire.

Shared decision-making interventions: An overview and a meta-analysis of their impact on vaccine uptake.

BACKGROUND: The interest in shared decision making (SDM) and the use of patient decision aids have increased significantly. Research indicates that this approach has benefits, and yet, implementation remains a challenge. To illustrate this development, we focus on vaccine hesitancy which has become a serious public health challenge during the COVID-19 pandemic. Various strategies have been used in healthcare, with limited success, to help patients overcome vaccine hesitancy. It is unclear whether SDM interventions can increase vaccination rates. AIMS: Our aim was two-fold: to provide an overview of SDM and the use of patient decision aids and to determine the effect of SDM interventions on vaccine uptake. METHODS: To provide an overview, we drew on our knowledge of the field and summarized the most recent systematic reviews. We examined the impact on vaccine hesitancy by searching for randomized controlled trials (RCTs) of SDM interventions, conducted a meta-analysis and calculated a pooled odds ratio. Additional outcomes were reported in a narrative synthesis. RESULTS: SDM is viewed as the pinnacle of patient-centred care, supported by an ethical imperative and by empirical evidence of benefits. We found 10 RCTs that met our inclusion criteria. SDM interventions significantly increased vaccine uptake compared to control groups (odds ratio = 1.45; 95% confidence interval [1.17-1.80]; p < 0.01). Some RCTs also reported significantly decreased decisional conflict and increased decision confidence. CONCLUSION: Future healthcare delivery systems will need to consider how to support the implementation of SDM. Interventions designed to facilitate this approach can represent a helpful, ethically defensible, strategy to increase vaccination rates.

Outcomes following the triage of patients for urological cancer and non-cancer surgery during covid-19 pandemic peak

INTRODUCTION AND OBJECTIVE: To assess clinical characteristics and surgical outcomes of triaged patients undergoing oncological and non-oncological surgery during the first wave of Covid-19 crisis. METHODS: We conducted a cohort-controled, nonrandomized, study in a Covid-19 reference centre in south-eastern France. Participants were consecutive surgical patients after triage and application to prevent from Covid-19 (Tab1). Data were collected prospectively during the propagation period from March 15th to May1st and compared with control data from outside the Covid-19 period. Primary endpoint was intensive care unit (ICU) admissions for surgery-related complications. Rates of surgery-specific death, postponed operations, positive PCR testing and Clavien-Dindo complications were assessed. Cancer and non-cancer subgroups during Covid-19 were also compared. RESULTS: After triage, 96 of 142 elective surgeries were postponed. Altogether, 71 patients, median age 68 yo [56-75], sex ratio M/F of 4/1, had surgery, among whom, 48 (68%) had uro-oncological surgery (Tab 2). No patients developed Covid-19 pneumonia in the post-surgery period. Three (4%) were admitted to the ICU, one of whom died from multi-organ failure due to septic shock caused by klebsiella pneumonia following a delay in treatment. Three Covid-19 RT-PCR were done and all were negative. There was no difference in mortality rates or ICU admission rates between control and Covid-era patients (Tab 3). CONCLUSIONS: Surgery after triage during the Covid-19 pandemic was not associated with worse short-term outcomes. Urological cancers could be operated on safely in our context but delays in care for aggressive genitourinary diseases could be lifethreatening. Altogether, two-thirds of elective surgeries were postponed and now need to be rescheduled, thus increasing the work-load in our centre.

Surgery under COVID: An observational study.

AIM: To evaluate the surgery program strategy adopted in an adult otorhinolaryngology and head and neck surgery department in an area badly affected by the Covid-19 epidemic peak. The main objective was to analyze the reasons for not cancelling surgeries and the postoperative course of operated patients. The secondary objective was to assess the situation of postponed patients. MATERIAL AND METHODS: A single-center observational study carried out during the COVID-19 period in France included 124 patients scheduled for surgery during the period March 21-May 20, 2020. The number and nature of operations, both performed and postponed, were reviewed. RESULTS: A total of 54.0% patients were operated on during the COVID period and 46.0% were postponed. Operations were maintained in urgent or semi-urgent cases. The operated patients did not show any signs of infection during their hospital stay. A total of 29.8% of postponed patients were lost to follow-up and 49.1% were rescheduled. CONCLUSION: The application of national and international recommendations minimized the risk of loss of chance for operated patients without increasing the risk of contamination. The postponement of canceled operations resulted in considerable loss to follow-up. Intensified follow-up is necessary for these patients.

The Anti-inflammatory Effect of the Tricyclic Antidepressant Clomipramine and Its High Penetration in the Brain Might Be Useful to Prevent the Psychiatric Consequences of SARS-CoV-2 Infection.

At the time of writing (December 2020), coronavirus disease 2019 (COVID-19) has already caused more than one million deaths worldwide, and therefore, it is imperative to find effective treatments. The "cytokine storm" induced by Severe Acute Respiratory Syndrome-Coronavirus type 2 (SARS-CoV-2) is a good target to prevent disease worsening, as indicated by the results obtained with tocilizumab and dexamethasone. SARS-CoV-2 can also invade the brain and cause neuro-inflammation with dramatic neurological manifestations, such as viral encephalitis. This could lead to potentially incapacitating long-term consequences, such as the development of psychiatric disorders, as previously observed with SARS-CoV. Several pathways/mechanisms could explain the link between viral infection and development of psychiatric diseases, especially neuro-inflammation induced by SARS-CoV-2. Therefore, it is important to find molecules with anti-inflammatory properties that penetrate easily into the brain. For instance, some antidepressants have anti-inflammatory action and pass easily through the blood brain barrier. Among them, clomipramine has shown very strong anti-inflammatory properties in vitro, in vivo (animal models) and human studies, especially in the brain. The aim of this review is to discuss the potential application of clomipramine to prevent post-infectious mental complications. Repositioning and testing antidepressants for COVID-19 management could help to reduce peripheral and especially central inflammation and to prevent the acute and particularly the long-term consequences of SARS-CoV-2 infection.

[Outcomes following the triage of patients for urological cancer and non-cancer surgery during Covid-19 pandemic peak]. / Évaluation des mesures de triages de la première vague pandémique Covid-19 pour sélectionner les patients à opérer pour cancers et urgences urologiques.

INTRODUCTION: Faced with the first wave of Covid-19 pandemic, guidelines for surgical triage were developed to free up healthcare resources. The aim of our study was to assess clinical characteristics and surgical outcomes of triaged patients during the first Covid-19 crisis. METHOD: We conducted a cohort-controlled, non-randomized, study in a University Hospital of south-eastern France. Data were collected prospectively from consecutive patients after triage during the period from March 15th to May 1st and compared with control data from outside pandemic period. Primary endpoint was intensive care unit (ICU) admissions for surgery-related complications. Rates of surgery-specific death, postponed operations, positive PCR testing and Clavien-Dindo complications and data from cancer and non- cancer subgroups were assessed. RESULTS: After triage, 96 of 142 elective surgeries were postponed. Altogether, 71 patients, median age 68 y.o (IQR: 56-75 y.o), sex ratio M/F of 4/1, had surgery, among whom, 48 (68%) had uro-oncological surgery. No patients developed Covid-19 pneumonia in the post-surgery period. Three (4%) were admitted to the ICU, one of whom died from multi-organ failure due to septic shock caused by klebsiella pneumonia following a delay in treatment. Three Covid-19 RT-PCR were done and all were negative. There was no difference in mortality rates or ICU admission rates between control and Covid- era patients. CONCLUSIONS: Surgery after triage during the first Covid-19 pandemic was not associated with worse short-term outcomes. Urological cancers could be operated on safely in our context but delays in care for aggressive genitourinary diseases could be life threatening. LEVEL OF EVIDENCE: 3.