Impacto de la pandemia por SARS-CoV-2 en el diagnóstico y tratamiento de la Endocarditis Infecciosa en un hospital terciario

Introducción: Desde que se declaró la alerta sanitaria el 13 de marzo del 2020, todos nuestros protocolos de actuación se han visto modificados, dando prioridad al diagnóstico y tratamiento de aquellos pacientes infectados con SARS-CoV-2;lo cual creemos ha tenido un impacto negativo en el diagnóstico y tratamiento de otras patologías infecciosas, incluida la endocarditis Infecciosa (EI). Objetivos: Evaluar el impacto de la pandemia por SARS-CoV-2 en diagnóstico y tratamiento de la endocarditis infecciosa en un hospital terciario. Material y métodos: Estudio observacional retrospectivo de una base de datos obtenidos prospectivamente. La comparación entre periodos (2019 vs. 2020) se realizo utilizando un análisis de t de Fisher para las variables cualitativas y una prueba t para muestras independientes para las variables cuantitativas. Resultados: Al comparar los periodos de estudio (tabla), hemos encontrado una reducción del 62,5% en el número de casos diagnosticados con EI durante la pandemia (48 casos en 2019 vs. 18 casos en 2020). La mayoría de los casos (55,5%) de los casos diagnosticados durante la pandemia fueron mujeres, con un significativamente menor índice de Charlson ajustado por edad (5,69 vs. 4,38 p = 0,002). Cuatro de los casos de EI durante el 2020 tuvieron una coinfección por SARS-CoV-2;dos de los cuales fueron de adquisición nosocomial. Dentro de los efectos de la pandemia en el diagnóstico de la endocarditis hemos encontrado un aumento significativo en la media de días desde el primer contacto médico hasta el ingreso hospitalario de 18,7 días en 2019 a 35,3 días en 2020;al igual que en la adquisición nosocomial (18,7 vs. 37,3% p = 0,17) y el número de casos de endocarditis infecciosa por S. aureus resistente a meticilina (4,2% vs. 16,6 p = 0,095). El tiempo desde el diagnóstico hasta la cirugía también se vio significativamente aumentado de 36,8 días en 2019 a 69,8 días en 2020 (p = 0,015). [Formula presented] Conclusiones: La pandemia por SARS-CoV-2 ha tenido un impacto negativo tanto en el diagnóstico como en el tratamiento de la endocarditis infecciosa, retrasando tanto el ingreso hospitalario como el tiempo hasta la cirugía. Aunque ninguno de estos efectos ha tenido un impacto en la mortalidad de nuestros pacientes, quizás es un buen momento para reflexionar como deberemos modificar nuestros protocolos de actuación en los próximos años.

Molecular determinants of the SARS-CoV-2 fusion peptide activity

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronaviruses 2 (SARS-CoV-2), emerged in late 2019 and quickly spread worldwide. SARS-CoV-2 is an enveloped virus and its entry into host cells is mediated by the spike glycoprotein (S-protein) [1]. The S-protein is composed of two subunits (S1 and S2) that contain essential domains for the viral entry mechanism, such as the fusion peptide (FP) which inserts into and disturbs the host cell membrane promoting the fusion between viral and host membranes. Despite its relevance for viral entry, there is still no consensus among scientists for its location on the S-protein and amino acid sequence, although two major candidate regions have been proposed [2, 3]. To shed light on this matter, we combined computational and experimental methods to characterize and compare the effect of the two putative SARS-CoV-2 FPs. We performed a systematic analysis of the SARS-CoV-2 putative FPs, using Molecular Dynamics simulations, to dissect how these peptides interact with the membrane. In parallel, we evaluated the putative FPs behavior in membrane model systems applying biophysical techniques. Since both FPs revealed modest fusogenic activity, we hypothesized that a longer FP or a cooperation among the individual FPs might be required to achieve fusion between viral and host membranes. Given the pivotal role of the FP to viral entry, our work provides relevant insights on the SARS-CoV-2 entry mechanism.

SARS-CoV-2 variants impact RBD conformational dynamics and ACE2 accessibility

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has killed over 5 million people and is causing a devastating social and economic impact all over the world. The rise of new variants represents a difficult challenge due to the loss of vaccine and natural immunity, and increased transmissibility. These variants contain mutations in the spike glycoprotein, which mediates fusion between the viral and host cell membranes, via its receptor binding domain (RBD) that binds to angiotensin-converting enzyme 2 (ACE2). To understand the effect of RBD mutations, a lot of attention has been given to the RBD-ACE2 interaction. However, this type of analysis is limited since it ignores the conformational dynamics of the RBD itself. Observing that some variants mutations occur in residues that are not in direct contact with ACE2, we hypothesized that they could affect RBD conformational dynamics. To test this, we performed long atomistic molecular dynamics simulations to investigate the structural dynamics of wt RBD, and that of three variants (alpha, beta and delta). Our results show that in solution, wt RBD presents two distinct conformations: an 'open' conformation where it is free to bind ACE2;and a 'closed' conformation, where the RBM ridge blocks the binding surface. The alpha and beta variants significantly impact the open/closed equilibrium, shifting it towards the open conformation by roughly 20%. This shift likely increases ACE2 binding affinity. In the delta variant RBD simulations, the closed conformation was never observed. Instead, the system alternated between the before mentioned open conformation and an alternative 'reversed' one, with a significantly changed orientation of the RBMridge flanking the RBD. These results support the hypothesis that variants impact RBD conformational dynamics in a direction that simultaneously promotes efficient binding to ACE2 and antibody escape.

The impact of SARS-CoV-2 Omicron variant on the human ACE2 binding: a computational study

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the COVID-19 pandemic, which escalated into a global pandemic in early 2020, accounting for more than 400 million infections and more than 6 million confirmed deaths worldwide (as of 2022/03/10). The SARS-CoV-2 mechanism of transmission and infection involves the binding of the virus to the angiotensin-converting enzyme 2 (ACE2) host receptor through the receptor-binding domain (RBD) of the spike (S) protein. The RBD is a privileged target of our immune system and antiviral therapies. Throughout last year multiple vaccines and new therapeutics against SARS-CoV-2 have been developed. However, their effectiveness is challenged by the continuous evolution of SARS-CoV-2, accompanying the origin and spread of new variants of concern (VOC): Alpha, Beta, Gamma, Delta, and recently, Omicron. Among the reported mutations in the VOC S proteins, several are specific to the RBD, which are associated with higher transmissibility or the ability to escape the immune response of previously infected patients. (Previously published in: Greaney, A.J. et al. (2021) Cell Host Microbe 29,44- 57). In late 2021, the newly SARS-CoV-2 Omicron VOC raised considerable global concern due to the presence of more than 30 mutations in the S protein, 15 of which occur in the RBD (Previously published in: Mannar D et al. (2022) Science 375,760-764). Here we investigated the impact of the VOC RBD mutations on its interaction with ACE2, with a major focus on the Omicron RBD, by performing microsecond molecular dynamics (MD) simulations of this complex. Our analysis of the binding and structural dynamics of these mutations provided a detailed characterization of the binding mode between the VOC RBDs and the receptor. This allowed us to understand the role of key residues in the VOC RBD-ACE2 interface and the effect of specific substitutions on the binding affinity via the establishment of new inter-protein contacts.

Design, production and characterization of antiviral proteins targeting SARS-CoV-2

The virus responsible for the current COVID -19 pandemic is SARS-CoV-2, which has caused >400 million infections and >5 million deaths (as of February 2022). Despite vaccination efforts, there is still an urgent need to develop strategies to control infection and treat patients. One of the proteins bound to the viral membrane is the spike (S) protein, which consists of two subunits: S1, which contains a receptor-binding domain (RBD) responsible for binding to the host cell receptor, and S2, which facilitates membrane fusion between the viral and host cell membranes, previously published in: Jackson CB et al. (2018) Nat Rev Mol Cell Biol 23, 3-20. Thus, this protein is primarily responsible for the ability of the virus to enter host cells, making it one of the most promising therapeutic targets of coronavirus, previously published in: Cao L et al. (2020) Science 6515, 426- 431. The aim of this work was to design and produce antiviral proteins that could prevent the interaction between the two proteins and thus block infection by binding to the RBD region and blocking its interaction with the host receptor, angiotensin converting enzyme-2 (ACE2) protein. First, several antiviral proteins were computationally designed using the Rosetta program based on the interactions between ACE2 and the RBD. Next, six molecular dynamics simulations (MD) of 1 ls of three candidates were performed to test their interaction with the RBD. This was followed by experimental validation after expression and purification of the three candidates. The secondary structure and thermostability of these proteins were tested by far-UV circular dichroism spectropolarimetry. Surface plasmon resonance was used to evaluate the affinity of each candidate for RBD. Neutralization assays were performed to investigate the neutralization ability of the proteins. The experimental results show that one of the developed proteins is a promising therapeutic approach that will be further improved in the future.

The impact of COVID-19 upon student radiographers and clinical training in Latin America.

INTRODUCTION: This study aimed to identify the impact of the COVID-19 pandemic upon radiography education across Latin American countries. METHODS: A survey containing 20 questions was circulated to radiography students, across 13 universities in 11 countries of Latin America using Google Forms. The survey contained open and closed questions. Answers were analysed with descriptive statistics and the methodology of interpretative phenomenological analysis for the open answers. RESULTS: Of the 1310 responses only 23.9% (n = 313) of students reported attending clinical placements and from this cohort only 8.9% (n = 28) became infected with COVID-19. In response to how the pandemic had impacted upon the students' academic progression, the most common topic in the open answers was "Concerns about the lack of clinical training", mentioned by 629 students. Students in middle and later years of their radiography education expressed the greatest concern about future clinical placements. Almost all radiography students (95.2%/n = 1247) indicated that their main concerns regarding COVID-19 infection while undertaking clinical placements was in relation to the risk of infecting their families as most students stated they cohabited with relatives (86.6%/n = 1134). CONCLUSION: Compared to European findings co-habitation trends increased anxiety related to infection and impacted their mental health. Students expressed concern about the quality of education they were receiving during the pandemic and access to resources to facilitate on-line learning was inadequate. Socio-economic and internet connectivity factors specific to Latin America were identified and these issues need to be addressed if on-line education is required in the future. IMPLICATIONS FOR PRACTICE: The COVID-19 pandemic has impacted Latin America and this study identifies the implications for radiography students related to their clinical and academic training and highlights factors which require consideration to support radiography students as the pandemic continues.

Virtual multi-institutional tumor board: Feasibility and physicians acceptance, a GSTU foundation project in Sicily

Introduction & Objectives: Multidisciplinary tumor boards (MTBs) play a pivotal role in patients’ clinical management and decision-making process. Main barriers to achieve efficient MTBs, are lack of time and geographical distance. COVID-19 pandemic represented an exceptionalobstacle. Telehealth practice has recently expanded including live video conferences and remote patient visit. The elaboration of an efficient virtual(v)MTB during COVID-19 pandemic is a need and a key-point to realize a successful oncology team and to increase a network among healthprofessionals and institutions. Objective of the study was to assess the mode of operating of our vTMB and to evaluate satisfaction and concernsof participating physicians through a dedicated survey.Materials & Methods: A project for a virtual multi-institutional uro-oncological MTB was activated in Sicily. The vMTB was structured according to aBowen framework method, employing a cloud-based virtual platform (Navify®). A 5-point Likert scale measured acceptability, appropriateness, andfeasibility of the instrument. Consensus on patients’management was voted electronically and approved if at least 75% of consensus was reached.Decisions were matched to recent medical literature and verified as adhering to the guidelines. After the first 3 months of activity a structured surveywas carried out among the members of the vMTB to investigate their satisfaction, adherence and concerns.Results: The vMTB started in September 2020. Up to the end of December 2020, 13 virtual meetings (60-90 min each) were holded and 77cases of urological tumors were discussed. Overall, 18 hospital units and 48 specialists joined the meetings. The survey conducted among the 48participating physicians, positively highlighted the impact of the project: 48 (100%) preferred virtual to in-person MTB, 44 (91%) were satisfied ofthe quality of clinical information;46 (96%) on equity of care;42 (88%) on collaboration among specialists;42 (88%) on method standardizationand 37 (77%) on data security, tracking, storage, and availability.Conclusions: vMTB represents a unique opportunity to optimize multidisciplinary patient management. Our experience shows a rapid adaptation of physicians to vMTB. However, legal and technical issues remain fields of concern and must be carefully checked. Acknowledgments: Thanks to the GSTU foundation for Technical and Editing support

IMPACT OF COVID-19 OUTBREAK ON GASTRO-INTESTINAL CANCER BURDEN

Background and aim: Italy was the first European country to face the outbreak of COVID-19. The aim of this study was to show its impact on the activity of a tertiary care Endoscopy Unit with more than 18,000 procedures/year. Materials and methods: This is a single-center study performed at Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy. Our Institution was converted to COVID-19 Hospital from January to April 2020 and only emergency and oncologic procedures were maintained to preserve both patients’ and operators’ health. Data about outpatients visits and endoscopic examinations performed from January to April 2020 were compared to those of the same period of the previous year. Results: A dramatic drop of all activities was shown. All outpatient visits decreased of 45,89% (1100 vs 2033), including -39.5% (227 vs 375) of Inflammatory Bowel Disease and -28.6% (30 vs 42) of biliopancreatic visits. All endoscopic examinations diminished of 74.1% (562 vs 2173). In detail, colonoscopies were reduced of 78.8% (266 vs 1256), including -85.5% (29 vs 200) of screening procedures, EGDS of 70.4% (241 vs 814), EUS of 44.8% (32 vs 58) and ERCP of 48.9% (23 vs 45). Overall, -64.6% of Gastro-Intestinal (GI) cancers were detected (17 vs 48). A reduction of 77.8% and 80% were obtained in terms of advanced adenomas (i.e., high grade dysplasia and villous histology) and adenocarcinomas detected during colonoscopy (22 vs 100 and 6 vs 30, respectively). These absolute reductions were not compensated by significative increase of relative diagnostic yields which were 3.3% vs 2.3% (17/507 vs 48/2070;Odd Ratio [OR] 0.94), 8.3% vs 7.9% (22/266 vs 100/1256;OR 1.05) and 2.3% vs 2.4% (6/266 vs 30/1256;OR 0.94) for all GI cancers, advanced adenomas, and colorectal cancer in 2020 and 2019, respectively. Although a reduction of 35.3%, a significant improvement was showed comparing diagnostic yield of gastric adenocarcinoma in 2020 and 2019, being 4.6% vs 2.1% (11/241 vs 17/814;OR 0.44), respectively. Conclusions: The COVID-19 outbreak caused a notably decrease of all activities, including colorectal screening colonoscopy. This produced a reduction of the total amount of neoplasia detected compared to the same period of the previous year. The consequences of this delay are still to be shown.

Increase in the frequency of catheter-related bloodstream infections during the COVID-19 pandemic: a plea for control.

BACKGROUND: The incidence of nosocomial infections including ventilator-associated pneumonia and bacteraemia has been described during the COVID-19 pandemic. However, information regarding the impact of COVID-19 on the incidence of catheter-related bloodstream infections (CR-BSIs) is very limited. AIM: To evaluate the impact of the COVID-19 pandemic in the evolution of CR-BSIs in a large hospital. METHODS: This was a retrospective study comparing the incidence, aetiology and outcome of CR-BSIs during the months of March to May 2019 (pre-pandemic) and 2020 (during the pandemic). FINDINGS: The number of patients with one or more CR-BSIs in 2019 and 2020 were 23 and 58, respectively (1.89 vs 5.53/1000 admissions); P<0.001. Median time from catheter implantation to demonstration of CR-BSI was 27.5 days (range 11.75-126.00 days) in the 2019 cases and 16.0 days (range 11.00-23.50 days) in the 2020 population (P=0.032). CONCLUSIONS: A dramatic increase of CR-BSIs was found during the COVID-19 pandemic. Reinforcement of classic and new preventive measures is necessary.

Impact of COVID-19 outbreak on gastro-intestinal cancer burden

Aims Italy was the first European country to experience COVID-19 outbreak. The aim of this study was to show its impacton the activity of a tertiary care Endoscopy Unit with >18,000 procedures/year. Methods This is a single-center study performed at Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy. OurInstitution was converted to COVID-19 Hospital from January to April 2020 and only emergency and oncologic procedureswere maintained to preserve both patients' and operators' health. Data about outpatients visits and endoscopicexaminations performed from January to April 2020 were compared to the same period of 2019. Results A dramatic drop of all activities was shown. In details, overall outpatient visits decreased of-45,89 % (1100 vs2033), including-39.5 % (227 vs 375) of IBD and-28.6 % (30 vs 42) biliopancreatic visits. Endoscopic examinations alsodiminished considerably as shown in table 1. Overall,-64.6 % of gastro-intestinal cancers were detected (17 vs 48). Areduction of-77.8 % and-80 % were obtained in terms of advanced neoplasia (i.e. high-grade dysplasia and villoushistology) and adenocarcinomas detected during colonoscopy between the two years (22 vs 100 and 6 vs 30, respectively).Such absolute reduction was not compensated by an increase of relative diagnostic yield, being 8.3 % vs 7.9 % (22/266 vs100/1256;Odd Ratio [OR] 1.05) and 2.3 % vs 2.4 % (6/266 vs 30/1256;OR 0.94) for advanced neoplasia and colorectalcancer, respectively. Although a reduction of-35.3 %, a significant improvement was showed comparing diagnostic yield ofgastric adenocarcinomas, being 2.1 % vs 4.6 % (17/814 vs 11/241;OR 0.44), respectively. Conclusions COVID-19 caused a notably decrease of all activities, including screening colonoscopy. This produced areduction of the total amount of neoplasia detected during endoscopy compared to the same period of the previous year.The consequences of this delay are still to be shown. (Table Presented).

The first 100 cases of COVID-19 in a Hospital in Madrid with a 2-month follow-up.

OBJECTIVE: There are few descriptions of the clinical presentation and evolution of consecutive SARS-CoV-2 infections with a long-enough follow up. METHODS: Description of the first consecutive 100 patients with microbiologically-proven COVID-19 in a large hospital in Madrid, Spain including a minimum of two-month follow up. RESULTS: The median age of the patients (52% males) was 61.5 years (IQR=39.5-82.0) and the median BMI was 28.8 kg/m2 (IQR=24.7-33.7). Overall 72% of the patients had one or more co-morbid conditions with a median age-adjusted Charlson index of 2 (IQR=0-5.7). Five patients (5%) were immunosuppressed. The most common symptoms at the time of diagnosis were fever (80.0%), cough (53.0%) and dyspnea (23.0%). The median O2 saturation at the time of first examination was 94% (IQR=90-97). Chest X-ray on admission was compatible with pneumonia in 63% of the cases (bilateral in 42% and unilateral in 21%). Overall, 30% were managed at home and 70% were admitted to the hospital. Thirteen patients were admitted to the ICU with a median of 11 days of stay in the Unit (IQR=6.0-28.0). CALL score of our population ranged from 4 to 13. Overall, 60.0% of patients received antibiotic treatment and 66.0%, empirical antiviral treatment, mainly with lopinavir/ritonavir (65%) or hydroxychloroquine (42%). Mortality, with a minimum of 60 days of follow up, was 23%. The median age of the deceased patients was 85 years (IQR=79-93). CONCLUSIONS: We found a high mortality in the first 100 patients diagnosed with COVID-19 at our institution, associated with advanced age and the presence of serious underlying diseases.