Potent and Selective Covalent Inhibition of the Papain-like Protease from SARS-CoV-2

Direct-acting antivirals are needed to combat coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The papain-like protease (PLpro) domain of Nsp3 from SARS-CoV-2 is essential for viral replication. In addition, PLpro dysregulates the host immune response by cleaving ubiquitin and interferon-stimulated gene 15 protein (ISG15) from host proteins. As a result, PLpro is a promising target for inhibition by small-molecule therapeutics. Here we have designed a series of covalent inhibitors by introducing a peptidomimetic linker and reactive electrophile onto analogs of the noncovalent PLpro inhibitor GRL0617. The most potent compound inhibited PLpro with k inact /K I = 10,000 M - 1 s - 1 , achieved sub-microM EC 50 values against three SARS-CoV-2 variants in mammalian cell lines, and did not inhibit a panel of human deubiquitinases at > 30 microM concentrations of inhibitor. An X-ray co-crystal structure of the compound bound to PLpro validated our design strategy and established the molecular basis for covalent inhibition and selectivity against structurally similar human DUBs. These findings present an opportunity for further development of covalent PLpro inhibitors.

Beyond COVID: The Value of Wastewater Based Epidemiology (WBE) Monitoring for Municipal and Industrial Systems

The goal of this paper is to demonstrate how Wastewater Based Epidemiology (WBE) can be used after COVID-19 in both Municipal and Industrial wastewater systems to proactively monitor, manage, and avoid risks that could negatively impact the business continuity and resiliency of an organization. The history of WBE will first be reviewed to show how it has been used to maximize public health protection and social well-being while minimizing economic impacts and unintended consequences in public and private settings. The design of a WBE monitoring program for Closed, Semi-Closed, and Open Municipal and Industrial wastewater systems will be evaluated through a couple of case studies. Alignment between WBE programs and an organizations' risk management programs, sustainability goals, and ethical considerations will also be explored. Copyright © 2022 Water Environment Federation.

SAPV patients in the COVID-19 crisis: An interview-based study of palliative care patients' experiences.

Background: In the outpatient setting, COVID-19 primarily affects palliative care patients who receive care as part of specialized outpatient palliative care (SAPV). To prevent infections, the implementation of new safety precautions and telemedical communication options in the SAPV participating in the study became necessary. Objective(s): This study examines the impact of the COVID-19 pandemic on palliative care patients' personal and social problems and their experiences with caregiving SAPV. Material(s) and Method(s): A total of 20 SAPV patients were interviewed about their problems in relation to the pandemic and about their experiences with care provided by SAPV in semi-structured phone interviews. Result(s): Fear of loneliness and infection weigh heavily on palliative care patients. Most patients wanted to avoid hospitalization due to increased risk of infection. Protective measures of SAPV gave them a sense of security and were accepted despite restrictions on personal contact. Modern forms of communication were useful but could not replace personal contact. Conclusion(s): The pandemic led to changes in SAPV and had an impact on the social environment of palliative care patients. Protective measures are important for the sense of security of palliative care patients under care. The quality of care provided by the SAPV structure adapted to COVID-19 is usually not perceived by patients as having deteriorated. Fears of social isolation are highly valued by palliative care patients and can be reduced by SAPV. Personal contact with SAPV cannot be replaced by modern communication options, although patients do accept telemedicine as an "emergency solution".Copyright © 2022, The Author(s).

Innovative Development of the Russian Agricultural System Based on the Principles of Food Security

The paper presents the results of a comparative assessment of Russian macroregions in terms of food security. A set of indicators allows assessing food security in three main areas: (1) food independence, (2) economic, and (3) physical availability of food. For all federal districts, we analyze the indicators of achieving food independence (self-sufficiency) with food (in the context of the main food groups), indicators of the availability of regional products following rational nutritional standards, indicators of satisfying physiological needs for food, and "poverty” ratios and the structure of household expenditures for food. The authors investigate the change in these indicators due to the import substitution policy of 2014–2018. A ranged number of Russian macroregions was built according to the level of food security. The authors conclude that the challenges to the food security of Russian regions geographically distant from the administrative center of the state (the Far Eastern Federal District in the first place) are high. The effectiveness of import substitution in these territories is low. The authors formulate proposals to improve food security in the Far Eastern Federal District. The regional Ministries of Agriculture can use the proposed methodology for analyzing the level of food security to express diagnostics of the agri-food market of the territory and formulating management decisions aimed at achieving and maintaining the level of food security that meets the goals and objectives of Russia in the context of sanctions, the COVID-19 pandemic, and other geopolitical upheavals. © 2023, The Author(s), under exclusive license to Springer Nature Switzerland AG.

[Platypnea-orthodeoxia syndrome secondary to pneumonia: Two cases]. / Syndrome platypnée-orthodéoxie secondaire à une pneumopathie : à propos de deux cas.

INTRODUCTION: The platypnea-orthodeoxia syndrome is a rare situation characterized by the appearance of dyspnea and/or hypoxemia during the transition to orthostatism. OBSERVATIONS: We report the case of two patients, who presented with a platypnea-orthodeoxia syndrome following pneumocystis pneumonia and COVID-19, revealing an intracardiac communication with a right-left shunt on contrast ultrasound. CONCLUSION: This syndrome can be detected easily at the bedside with positional maneuvers and the shunt demonstrated by a hyperoxia test. Non-reversible situations may require correction of the anatomical anomaly by transcatheter intervention or surgery.

External Validation of the 4C Mortality Score and the qSOFA for Different Variants of Concerns of SARS-CoV-2 Using Data of the NAPKON Cross-Sectoral Cohort Platform (SUEP)

Background. Numerous predictive clinical scores with varying discriminatory performance have been developed in the context of the current coronavirus disease 2019 (COVID-19) pandemic. To support clinical application, we test the transferability of the frequently applied 4C mortality score (4C score) to the German prospective Cross-Sectoral Platform (SUEP) of the National Pandemic Cohort Network (NAPKON) compared to the non COVID-19 specific quick sequential organ failure assessment score (qSOFA). Our project aims to externally validate these two scores, stratified for the most prevalent variants of concerns (VOCs) of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) in Germany. Methods. A total of 685 adults with polymerase chain reaction (PCR)-detected SARS-CoV-2 infection were included from NAPKON-SUEP. Patients were recruited from 11/2020 to 03/2022 at 34 university and non-university hospitals across Germany. Missing values were complemented using multiple imputation. Predictive performance for in-hospital mortality at day of baseline visit was determined by area under the curve (AUC) with 95%-confidence interval (CI) stratified by VOCs of SARS-CoV-2 (alpha, delta, omicron) (Figure 1). Figure 1: Study flow chart with inclusion criteria and methodological workflow. Results. Preliminary results suggest a high predictive performance of the 4C score for in-hospital mortality (Table 1). This applies for the overall cohort (AUC 0.813 (95%CI 0.738-0.888)) as well as the VOC-strata (alpha: AUC 0.859 (95%CI 0.748-0.970);delta: AUC 0.769 (95%CI 0.657-0.882);omicron: AUC 0.866 (95%CI 0.724-1.000)). The overall mortality rates across the defined 4C score risk groups are 0.3% (low), 3.2% (intermediate), 11.6% (high), and 49.5% (very high). The 4C score performs significantly better than the qSOFA (Chi2-test: p=0.001) and the qSOFA does not seem to be a suitable tool in this context. Table 1: Discriminatory performance of the 4C Mortality Score and the qSOFA score within the validation cohort NAPKON-SUEP stratified by the Variant of Concerns of SARS-CoV- 2. Conclusion. Despite its development in the early phase of the pandemic and improved treatment, external validation of the 4C score in NAPKON-SUEP indicates a high predictive performance for in-hospital mortality across all VOCs. However, since the qSOFA was not specifically designed for this predictive issue, it shows low discriminatory performance, as in other validation studies. Any interpretations regarding the omicron stratum are limited due to the sample size.

Corimmuno19-BEVA : essai ouvert controle randomise evaluant l'efficacite et l'innocuite du bevacizumab (BEV) (Zirabev) en addition du traitement standard (STD) chez les patients atteints de pneumonie COVID-19 hypoxemique severe (ClinicalTrials.gov, NCT04822818)

Declaration de liens d'interets: Les auteurs declarent ne pas avoir de liens d'interets. Copyright © 2022

Troubles mnésiques persistants post-COVID-19 : intérêt de la recherche des anti-SARS-CoV-2 dans le LCR couplée à la spectro-IRM cérébrale ?

La maladie post-COVID-19 se développe quelle que soit la gravité de l'infection à SARS-CoV-2 initiale et comporte un large éventail de manifestations cliniques parmi lesquelles figurent de nombreux troubles neurologiques tels que les céphalées, l'anosmie, des troubles de la mémoire.... Nous rapportons le cas d'une patiente âgée de 68 ans adressée en consultation de médecine interne pour asthénie, troubles de la concentration et de la mémoire dans les suites d'une infection à SARS-CoV-2. Ses antécédents sont marqués par une HTA, un asthme, une thrombose veineuse profonde, une cholécystectomie, un œdème de Quincke avec choc anaphylactique aux AINS et une hypogammaglobulinémie modérée. On note une absence d'intoxication alcoolo-tabagique. La patiente a présenté en janvier 2021 une infection à SARS-CoV-2 avec fièvre et céphalées. La recherche de virus par PCR était négative lors de cet épisode avec secondairement une sérologie positive confirmant l'infection. Progressivement sont apparus des troubles de la mémoire et de la concentration. Son MMS était à 27/30. L'IRM cérébrale en juin 2021 montrait de multiples hypersignaux de la substance blanche. Un bilan a été réalisé en hôpital de jour avec réalisation d'une ponction lombaire. Le LCR retrouvait l'absence de leucocytes (< 1 élément/mm3), des hématies à 24 éléments/mm3 et une protéinorachie à 0,45 g/L. Les anticorps anti-rNMDA, anti-CASPR2, anti-rGABAb, anti-DPPX, anti-LGI1 et anti-AMPAr dans le LCR étaient négatifs. Absence de bande surnuméraire à l'isofocalisation. Les anticorps anti-SARS-CoV-2 dans le LCR étaient positifs à 108,7 UA/mL, la recherche de virus par PCR étant négative. Le rapport de Delpech était normal à 0,52 mais n'excluant pas une synthèse intrathécale d'IgG. Par ailleurs, l'index albumine LCR/albumine sérum était normal. Une polysomnographie ne retrouvait pas de syndrome d'apnées du sommeil. Une spectroscopie par IRM cérébrale en mai 2022 a mis en évidence une réaction gliale ainsi qu'une dysfonction neuronale au niveau de l'hippocampe et de la protubérance. Les séquelles neuropsychologiques post-COVID-19 témoignent d'une neuro-inflammation liée à l'activation de la microglie et à une réaction auto-immune [1]. La persistance de troubles cognitifs associée à la présence d'anticorps anti-SARS-CoV-2 dans le LCR 6 mois après COVID-19 a été rapportée chez une patiente de 57 ans [2]. Dans notre observation, la présence de ces anticorps peut témoigner d'une neuro-inflammation constatée sur la spectroscopie par IRM cérébrale. Une exploration biologique plus approfondie du LCR ainsi qu'une exploration par spectroscopie par IRM cérébrale pourraient être suggérées chez les patients présentant des troubles cognitifs plusieurs mois après une infection à SARS-CoV-2. D'autres études seront nécessaires afin de mieux définir la place de la recherche des anticorps anti-SARS-CoV-2 dans le LCR chez les patients ayant des séquelles neurologiques majeures liées au COVID-19. (French) [ FROM AUTHOR]

Syndrome inflammatoire inexpliqué révélant une thyroïdite de De Quervain : à propos de 2 cas

Le syndrome inflammatoire d'origine inexpliqué est une situation fréquente en médecine. Nous rapportons le cas de deux patients chez qui les investigations devant ce syndrome ont permis de conclure à une thyroïdite subaiguë de De Quervain. Cas numéro 1 : une femme de 61 ans consultait pour une fébricule vespérale depuis 3 semaines, accompagnée de sueurs nocturnes et de vagues cervicalgies droites difficiles à caractériser. L'examen clinique ne retrouvait que deux adénopathies sensibles cervicales droites centimétriques. On notait une bronchite aiguë quelques semaines avant, totalement guérie. La biologie retrouvait une CRP oscillant autour de 150 mg/L et un hémogramme normal. Le scanner corps entier était décrit normal. La persistance de l'inflammation la 4e semaine (CRP 200 mg/L, fibrinogène 12 g/L) se sanctionna d'une hospitalisation à visée diagnostique. Les prélèvements infectieux étaient stériles et l'endoscopie ORL, l'échographie cardiaque et la biopsie temporale normales. Finalement, le TEP scanner rapportait un hypermétabolisme intense et diffus de la thyroïde (SUV 10). Un contrôle échographique retrouvait une glande de taille normale franchement hypo-échogène et sans hyper-vascularisation au doppler. Le bilan thyroïdien était dans les normes (TSH 0,86 mUi/L [0,27–4,2], T4 libre 17,4 pmol/L [11,4–22,6], T3 libre 6,93 pmol/L [3,54–6,47]). Les anticorps anti-thyroïdes n'étaient pas détectés. La fièvre et le syndrome inflammatoire s'amendaient à la 6e semaine pour laisser apparaître une hypothyroïdie d'allure périphérique (TSH 6,7 mUi/L, T4 libre 11 pmol/L), qui sera surveillée jusqu'à la totale rémission biologique quelques mois plus tard. Cas numéro 2 : un technicien EDF de 56 ans était adressé d'un centre périphérique pour une fièvre quotidienne, une tachycardie et syndrome inflammatoire depuis deux semaines. Un large bilan de fièvre inexpliquée réalisé en amont de l'admission était resté non contributif. La réévaluation clinique retrouvait une odynophagie (sans pharyngite), un lobe thyroïdien droit sensible à la palpation, une adénopathie cervicale droite. Dans un second temps, on objectivait un rash urticarien généralisé le matin et rapidement réversible. La biologie retrouvait un syndrome inflammatoire majeur en plateau (CRP 130 mg/L, fibrinogène 9 g/L). Le bilan thyroïdien retrouvait une hyperthyroïdie d'allure périphérique (TSH < 0,01 mUi/L, T4 libre 44 pm/L, T3 libre 11,8 pm/L). Les anticorps anti-récepteur de la TSH n'étaient pas détectés mais les anti-thyroglobulines l'étaient. L'échographie retrouvait un parenchyme de taille normal hétérogène et anormalement avasculaire avec deux adénopathies centrimétriques non supectes. Le TEP scanner retrouvait un hypermétabolisme diffus, intense (SUV 24) et isolé de la glande thyroïde. L'évolution était spectaculairement favorable en 48 h d'une corticothérapie à 0,5 mg/kg. La thyroïdite subaiguë (de De Quervain) est une thyroïdite douloureuse granulomateuse qui fait souvent suite à une virose ORL (infection à SARS-CoV-2 comprise) [1] chez des patients génétiquement prédisposés (HLA-Bw35, HLA-B67, HLA-Drw8) [2]. Elle semble plus fréquente chez les femmes entre 40 et 50 ans. Les signes généraux ou pseudo-grippaux peuvent être au premier plan, parfois associés de signes de thyrotoxicose. Les cervicalgies plutôt antérieures, peuvent irradier dans la mâchoire ou les oreilles (simulant une pharyngite). La palpation de la thyroïdite peut être sensible. La biologie retrouve un syndrome inflammatoire, une TSH basse, une augmentation de la T4 libre (pouvant entraîner une thyréotoxicose) et l'absence d'anticorps anti-thyroïde (hormis les anti-thyroglobulines). L'échographie peut montrer un goitre hétérogène, hypoéchogène, sans hypervascularisation avec des adénopathies. La scintigraphie montre que la fixation du radio-isotope dans la glande thyroïde est nettement réduite ou absente. L'hypothyroïdie peut succéder transitoirement (ou définitive ent) à l'hyperthyroïdie. Les traitements anti-inflammatoires (AINS, corticothérapie) avec décroissance sur quelques semaines sont suffisants pour contrôler les symptômes. À long terme, il y a un surrisque d'hypothyroïdie auto-immune [3]. La thyroïdite subaiguë (de De Quervain) est une cause de syndrome inflammatoire inexpliqué. Elle peut compliquer les infections à SARS-Cov-2. (French) [ FROM AUTHOR]

Effect of the Seraph 100 Biomimetic Pathogen Adsorbing Device on Inflammatory Biomarkers in 42 COVID-19 Patients

Background: Lack of pharmacological treatment options in severely ill hospitalized COVID-19 patients prompted explorations of extracorporeal treatments. The Seraph 100 Microbind Affinity filter, remove viruses, including SARS-CoV-2 from the blood. Data from an international registry, from a multicenter evaluation in the US, as well as from several case reports suggest that Seraph 100 can not only be safely used but it may have an impact on patient centered outcome parameters. As it is unknown whether the effect of the Seraph 100 in COVID-19 patients is solely based on the removal of the virus or, as suggest by a recent observation, by additionally modulating inflammation, we set out to perform a biomarker study. Method(s): We performed this prospective multicenter observational trial at three tertiary care hospitals in patients being treated with Seraph 100 for severe COVID-19 between June 2020 and April 2021. Biomarkers were obtained before the tretment as well as 2-4 hours after the treatment. as well as 4 days after the Seraph 100 treatment. Routine clinical chemistry parameters were performed in the respective clinical chemistry labs using certified methods. For the assessment of the inflammatory markers a Bio-Plex Pro Human Cytokine Screening Panel, 48-Plex #12007283 (Bio-Rad) was used. Result(s): From June 1st 2020 to April 1st 2021, 42 patients with COVID-19 treated with the Seraph 100 in our hospitals could be included in the study. Hemoperfusion treatment was initiated in median 3 days after hospital admission. At beginning of the treatment 41/42 (98%) of patients were in the ICU;8/42 (19%) needed mechanical ventilation, 3/42 (7%) were on additional ECMO support;27/42 (64%) needed pressors. Seraph 100 treatment significantly reduced d-dimer comparing pre-treatment data with data obtained 2-4 hours after treatment Four days after treatment hemoglobin, LDH, D-dimer, troponin and ferritin were significant reduced. From the interleukin assay IL-1b, IL8, IL-10, IL-13, IL-15, Eotaxin, G-CSF and IP-10 were significantly reduced 2-4 hours after treatment, but not 4 days later. The median hospital stay was 20 days. After 3 months 20/42 (48%) of patients had died. Conclusion(s): In conclusion, our data show that Seraph 100 leads to a significant reduction of biomarkers that are either predictive of adverse outcome or the severity COVID-19.

Psychosomatic rehabilitation in pandemic times: A multi-perspective assessment of COVID-related measures and their associations with key outcome parameters, rehabilitation satisfaction, and rehabilitation success

Background: The SARS-CoV-2 pandemic is a global crisis with massive effects on all areas of society, such as the labor market, social security systems, and healthcare. It represents a complex stress situation that hardly leaves anyone unscathed. As a result, a significant increase in mental stress and ill- ness has been observed since the beginning of the pandemic. The coronavirus pandemic almost paralyzed rehabilitation in the spring of 2020. When comparing the 1st quarter of 2019 with that of 2021 (cumulative), a decrease of –32.8% is recorded for 2021 in the applications for services for medical rehabilitation (total 2020 to 2019: –14.2%). For the rehabilitation centers, the central and vital question is under which conditions rehabilitation measures can be carried out safely and successfully even in times of a pandemic. This also includes the confi-dence of potential rehabilitation patients, referring physicians, and employees in the structural and procedural measures taken by the centers. Materials and methods: The study aims to shed light on the effects and coping attempts of the pandemic in medical rehabilitation from different perspectives and to provide indications for routine care in “COVID normal operation”. The focus is on a comparative analysis of the results of the routine survey in the period October 2019 to June 2020, interviews with the management level of the center as well as a cat-amnestic follow-up survey of rehabilitation patients who completed a psychosomatic rehabilitation measure in the center in the period January to September 2020. Results: The interviews at the management level and the analysis of the safety concept show that a crisis team was installed at a very early stage in the center and a safety concept was established, which met with a high level of acceptance among all participants and contributed to a feeling of safety. The comparison of the routine survey shows that, with the exception of individual cases, the rehabilitation measures were carried out and completed according to plan. In most areas, the ratings have even improved in the 1st half of 2020 compared to the 4th quarter of 2019. The results of the catamnestic survey confirm the results of the routine survey. The rehabilitation patients who were treat-ed at the Rehazentrum Bad Bocklet during the COVID pandemic showed pronounced psychosomatic and participation-related limitations in the period before or at admis-sion. Regarding concerns and fears about the COVID situation, almost half of all respondents stated strong or very strong fears about the effects of the COVID pandemic on personal or close persons. In the foreground are fears that a close person could become infected or die. The hospital’s safety measures in terms of hygiene and adapted struc-tures and processes were rated positively by around three quarters of respondents. This is also confirmed by the results of the outcome parameters examined. The personal therapy goals were achieved for about three quarters of the respondents. Positive chang-es were seen in terms of health, health com-plaints, anxiety and depression symptoms, global health and the development of the ability to work, among other things. The RTW rates are 71% (time point method) and 81% (cumulative time course). The benefit of the rehabilitation measure is rated as high by 73% of the respondents is the treatment satisfaction. Substantial influences of rehab motivation, admission periods, and percep-tion and evaluation of COVID measures at the center on key outcome parameters are shown. These results emphasize the role of appropriate safety and hygiene measures adapted to the current hazard situation in the context of rehabilitation measures. The results indicate that the hospital succeeded in implementing suitable measures right at the beginning of the pandemic, and in com-municating and living these measures ac-cordingly. In addition, they allow the conclu-sion that under suitable safety and hygiene conditions, rehabilitation measures can also be carried out safely in times of pandem c and still show stable effects in essential tar-get criteria of medical rehabilitation after one year.

"Sustainability Make-It-Yourself" - the Environmental-Make@thon as an innovative science communication format

With regard to the Corona pandemic in the early 2020s, education (not only) in the natural sciences required a methodological and didactic rethink. For this reason, the Environmental-Make@thon was designed, carried out and evaluated. The participants spent a week intensively dealing with plastic waste and microplastics and designed innovative campaigns to solve the plastic waste problem. As a digital and innovative science communication format, the Environmental-Make@thon not only represents a creativity-enhancing, learning- and action-oriented setting, but also does justice to the social relevance of sustainability education.

Disruptions and exception handling in Food Supply Chains

The COVID-19 pandemic and resulting non-pharmaceutical interventions aspiring to reduce the spread of the virus, e.g., full or partial lockdowns, as well as social distancing measures, lead to increasing at-home consumption and panic buying. The resulting demand peaks for non-cooled perishable items hit the distribution systems of traditional brick-and-mortar retailers and have led to various out-of-stock situations on the shelves of ''urope's retailers. If the impact of demand peaks during the COVID-19 pandemic on grocery retail warehouses are unaware, this can result in out-of-stock situations in the supermarkets. In this paper, we use a process-based discrete-event simulation model to develop and apply a simulation approach to shed light on the underlying mechanisms of grocery retail warehouses in order to predict the future behavior of the examined system and prepare for such external demand shocks. Our results show that both investigated scenarios of volume peaks have a great impact on waiting times for truck drivers and the time-depending utilization level of the warehouse dispatch area. We then derived optimal shift distributions by developing a supply chain resilience strategy varying the output quantities for order picking. Moreover, by that, we could reduce the utilization level in the warehouse dispatch area by nearly 20 percent. Our model can inform managers about the consequences of demand peaks on grocery retail warehouses. Furthermore, our methodology can be transferred to one-time disruptions, as well as to multi-wave disruptions besides COVID-19. © 2021 Proceedings of the Hamburg International Conference of Logistics. All rights reserved.