Introducción: Los eventos cerebro vasculares son una de las principales causas de mortalidad a nivel mundial y la actual pandemia por la COVID-19 ha producido un gran impacto en la atención de estos pacientes. El objetivo es describir las características de los pacientes con evento cerebro vascular en pacientes hospitalizados con COVID-19 en un hospital peruano de referencia. El Estudio. Estudio retrospectivo, se incluyó a pacientes mayores de 18 años hospitalizados con el diagnostico de COVID-19 y evento cerebro vascular. Hallazgos. Se incluyeron 26 pacientes con ECV y COVID-19, la edad promedio fue 69.8 años y la mediana del tiempo de admisión fue 24 horas. La mortalidad fue elevada (42.3%) y estuvo asociada a la edad y al compromiso respiratorio por COVID-19. La mayoría de sobrevivientes obtuvieron un pobre resultado funcional. Conclusión. Es necesaria la mejora en los procesos de atención para así realizar un diagnóstico precoz y un tratamiento oportuno.

Background: We describe an 8-month-old boy with leukemia and SARS-CoV-2 infection who developed Kasabach-Merritt phenomenon. He had a positive SARSCOV-2 RT-PCR sample. Hematologic tests showed coagulopathy and intestinal involvement. She was managed in emergency receiving transfusion support and in hospitalization with social isolation measures, she started propanolol and corticotherapy as initial treatment of infantile angiomas. She presented with symptoms of intestinal obstruction and underwent surgery and evidence of hemorrhagic infarction with foci of intestinal ischemic necrosis, ending in ileostomy. We tried to understand a pathophysiological explanation of the dermatologic and gastrointestinal tract involvement by the virus and the atypical form of COVID-19. Given the emerging evidence of endotelial a n d v a s c u l a r i n v o l v e m e n t i n C O V I D - 1 9 , t h e development of tests to detect vascular lesions may be critical to guide the use of new therapeutic strategies.

Introducción: El Perú fue considerado la mayor tasa de letalidad por COVID-19 (9.39%); siendo Lambayeque en julio del 2020 presentó seroprevalencias más altas reportadas en el mundo para SARS-CoV-2 con 29,5%. Objetivo. Describir la experiencia de la estrategia implementada por Equipos de Respuesta Rápida y Seguimiento Clínico de Casos de COVID-19 (ERSC) para reducir la letalidad por COVID-19 durante la primera ola en el 2020. Descripción de la estrategia. Se realizó una investigación operativa en una cohorte retrospectiva. La población estudiada estuvo conformada por los casos COVID-19 sospechosos y confirmados durante el periodo abril-diciembre 2020, atendidos en la Red Asistencial de Lambayeque. La metodología se llevó a cabo bajo la Implementación y funcionamiento de los ERSC que realizaban la Vigilancia Epidemiológica, rastreo y seguimiento clínico domiciliario de los casos sospechosos y confirmados de COVID-19. El proceso de captación y tamizaje inicial de los pacientes se realizó mediante tres procesos: tamizaje diferenciado, “call center” y vigilancia de rumores. Tras el tamizaje, se categorizaba al paciente en base a la atención que requería. Los casos eran asignados a los equipos de respuesta rápida quiénes acudían al domicilio del paciente para realizar las actividades indicadas de acuerdo al tipo de brigada. Las brigadas eran cuatro: brigadas de evaluación clínica domiciliaría, de diagnóstico o laboratorio a domicilio, de seguimiento clínico y brigada topo. c. La letalidad en pacientes moderados/severos disminuyó de 60% (Semana Epidemiológica 19) a 10% (Semana Epidemiológica 50) (p<0,001). La estrategia implementada y ejecutada redujo la letalidad por COVID-19 en población atendida.

Purpose: To report a case of COVID-19 presenting with acute psychosis, without the hallmark respiratory symptoms of fever, cough, and shortness of breath associated with the novel virus. Case Summary: A 58 year-old male presented with acute psychosis and no symptoms associated with COVID-19. He denied fever, chills, chest pain, shortness of breath, or gastrointestinal symptoms. The patient had a medical history of coronary artery disease, chronic hepatitis C, polysubstance abuse (including cocaine and alcohol), liver disease, anxiety, and panic disorder. Patient was confused, disruptive, unable to communicate, and admitted to hallucinations. Prior to transfer to a psychiatric facility, the patient developed a cough, triggering COVID-19 testing and a positive result. He was initially treated with hydroxychloroquine before this was discontinued. The patient was treated with haloperidol and lorazepam before returning to baseline. He was discharged home with continued isolation. Conclusion: Acute psychosis, with or without other symptoms, appears to be a potential presentation of COVID-19 and should be considered by clinicians as a possible presenting manifestation. Other coronaviruses appear to have also been linked to neurological manifestations, including psychosis. Neurological manifestations of the virus vary widely, but have been reported multiple times. Treatment, as shown in this case report, appears to be supportive and symptom based for the associated psychotic symptoms. Optimal antiviral treatment is still yet to be clearly defined, as research continues on how to best treat the virus itself.

Die COVID-19-Pandemie stellte die Gesundheitssysteme weltweit vor große Herausforderungen. Um die weitere Verbreitung von SARS-CoV-2 zu verhindern, verhängten zahlreiche Staatsregierungen einen Lockdown mit Kontakt- und Ausgangsbeschränkungen. Auch in Bayern wurde das öffentliche Leben zwischen 16. März und 26. April 2020 reguliert. Krankenhäuser und Kliniken sollten sich auf eine Notfallversorgung beschränken, um ihre Kapazitäten für SARS-CoV-2-Infizierten freizuhalten. Das ZMK reduzierte im Zuge dessen ebenfalls seinen Klinikbetrieb und setzte für sechs Wochen alle planbaren Behandlungen aus. Ziel dieser retrospektiven Studie war es, den Einfluss der COVID-19-Pandemie auf die Inanspruchnahme des Notdienstes des ZMK zu untersuchen. Hierzu wurden die Behandlungsdokumente der 1299 NotfallpatientInnen, die sich zwischen 3. Februar und 7. Juni 2020 vorstellten, analysiert. Besonderes Augenmerk lag auf PatientInnen höheren Alters und/oder mit Grunderkrankung, die anfällig für einen schweren COVID-19-Verlauf sind. Während des Lockdowns halbierte sich die Anzahl der NotfallpatientInnen des ZMK. Der Anteil der COVID-19-RisikopatientInnen änderte sich jedoch nicht signifikant. Auch hinsichtlich des Geschlechtes und der Vorerkrankungen konnten keine signifikanten Änderungen festgestellt werden. Die häufigste Diagnose im Notdienst waren unkontrollierbare Schmerzen, meist endodontischen oder parodontologischen Ursprungs, gefolgt vom Abszess und vom dentalen Trauma. Zudem stieg während des Lockdowns der Anteil der NotfallpatientInnen, die stationär aufgenommen werden mussten, um 4% an. Das pandemiebedingt ohnehin stark ausgelastete Gesundheitssystem sollte nicht zusätzlich belastet werden, insbesondere wenn im Pandemieverlauf mit einem Anstieg des zahnmedizinischen Behandlungsbedarfes zu rechnen ist. Notfälle sind frühzeitig zu behandeln, Routineuntersuchungen aufrecht zu erhalten und PatientInnen über die etablierten Hygiene- und Infektionsschutzmaßnahmen und das geringe Infektionsrisiko in zahnmedizinischen Einrichtungen aufzuklären. Ziel ist, die Mundgesundheit der PatientInnen während der Pandemie aufrecht zu erhalten und einer Verschlimmerung bestehender Erkrankungen vorzubeugen. Die frühe Phase der Pandemie und der ersten Lockdown bedeuteten keine übermäßige Mehrbelastung für das ZMK. Nach meiner Einschätzung kann eine Notfallversorgung aller PatientInnen im Pandemieverlauf oder während einer zukünftigen Pandemie mit konsequentem Hygienekonzept neben dem regulären Klinikbetrieb ermöglicht werden. / The COVID-19 pandemic poses a major challenge to health care worldwide. In order to decelerate the further spread of SARS-CoV-2, numerous state governments imposed a lockdown with contact restrictions. In Bavaria, public life was restricted between 16 March and 26 April 2020. Hospitals were required to suspend all scheduled treatments and focus on an emergency care in order to increase their capacity for treatment of SARS-CoV-2 infected people. The Dental school of the University Hospital Wuerzburg (ZMK) suspended elective dental health care for the six weeks of the lockdown in Bavaria and limited their service to only urgent emergency care. The aim of this study was to evaluate the influence of the COVID-19 pandemic on patients’ utilization of the dental emergency service. Therefore, files of 1299 patients of the ZMK between 3 February and 7 June 2020 were retrospectively analysed focusing on patients of older age and/or with underlying diseases vulnerable to a severe course of COVID-19. During lockdown, the number of dental emergency patients decreased by approximately 50%. However, the proportion of COVID-19 risk patients did not change significantly. Regarding sex and underlying diseases, no significant changes were found as well. The most frequent diagnosis was uncontrollable pain, usually of endodontic or periodontal origin, followed by abscess and dental trauma. Stationary admissions increased during lockdown by approximately 4%. The due to the pandemic already heavily utilized health care should not be stressed additionally, especially if expecting an increase in the demand of dental treatment in the course of the pandemic. Dental emergencies should be treated early to avoid stationary admissions to preserve hospital bed capacities. Routine check-ups should be maintained and patients should be informed about the established anti-infective hygienic measures and the low risk of infection in dental facilities in order to preserve patients’ oral health during the pandemic and prevent the exacerbation of existing, chronic diseases. The early phase of the COVID-19 pandemic and the first lockdown in Bavaria did not pose an additional burden on the ZMK. In my opinion, it is possible to preserve emergency dental care with strict anti-infective hygienic measures during this and possible further pandemics.

Yes / Since December 2019, a new type of coronavirus called novel coronavirus (2019-nCoV, or COVID-19) was identified in Wuhan, China and on March 11, 2020, the World Health Organization (WHO) has declared the novel coronavirus (COVID-19) outbreak a global pandemic. With more than 101,797,158 confirmed cases, resulting in 3,451,354 deaths as of May 21, 2021, the world faces an unprecedented economic, social, and health impact. The clinical spectrum of COVID-19 has a wide range of manifestations, ranging from an asymptomatic state or mild respiratory symptoms to severe viral pneumonia and acute respiratory distress syndrome. Several diagnostic methods are currently available for detecting the coronavirus in clinical, research, and public health laboratories. Some tests detect the infection directly by detecting the viral RNA using real time reverse transcriptase polymerase chain reaction (RT-PCR) and other tests detect the infection indirectly by detecting the host antibodies. Additional techniques are using medical imaging diagnostic tools such as X-ray and computed tomography (CT). Various approaches have been employed in the development of COVID-19 therapies. Some of these approaches use drug repurposing (eg Remdesivir and Dexamethasone) and combinational therapy (eg Lopinavir/Ritonavir), whilst others aim to develop anti-viral vaccines (eg mRNA and antibody). Additionally, health experts integrate data sharing, provide with guidelines and advice to minimize the effects of the pandemic. These guidelines include wearing masks, avoiding direct contact with infectious people, respiratory and personal hygiene.

Mit dem Auftreten des SARS-CoV-2 Virus im Jahr 2020 war der Informationsgewinn für vulnerable Patientengruppen essentiell. Ziel dieser Arbeit war es maternale Charakteristika und das klinische Bild SARS-CoV-2 positiver Frauen mit Notwendigkeit einer intensivmedizinischen Behandlung während der Schwangerschaft und postpartal darzustellen, und diese Kohorte mit den SARS-CoV-2 positiven Schwangeren ohne intensivmedizinischen Handlungsbedarf zu vergleichen. Die Daten stammten aus dem deutschen CRONOS-Register, einem prospektiven, multizentrischen Register für SARS-CoV-2 positive schwangere Frauen. Eingeschlossen wurden alle schwangeren und postpartalen Frauen, die während ihrer SARS-CoV-2 Infektion auf eine ITS aufgenommen wurden. Diese wurden hinsichtlich maternaler Charakteristika, Krankheitsverlauf, sowie Outcomes verglichen. In 101 von 2650 Fällen (4%) der Patientinnen des CRONOS-Registers, kam es zu einer Aufnahme auf die ITS. Als invasivste Form der COVID-19 Behandlung war bei 6 Patientinnen nur eine Überwachung notwendig, 30 Patientinnen benötigten eine Sauerstoffinsufflation, 22 wurden nicht-invasiv beatmet, 28 erhielten eine invasive Beatmung und bei 15 Frauen wurde die Behandlung zur ECMO-Therapie eskaliert. Es wurden keine klinisch signifikanten Unterschiede zwischen Patientinnen gefunden, die unterschiedliche Behandlungsformen benötigten. Die Gruppe der ITS und Non-ITS Patientinnen unterschied sich statistisch signifikant beim Einfluss von Alter, BMI bei Einschluss und der Herkunft. Die Prävalenz der Frühgeburtlichkeit war unter den invasiv behandelten Patientinnen signifikant höher und auch im Vergleich der ITS mit den Non-ITS Patientinnen zeigte sich ein signifikanter Unterschied. Vier Frauen verstarben an COVID-19 und sechs Feten der ITS-Gruppe waren Totgeburten. Diese Kohorte zeigt, dass schwere COVID-19 Erkrankung bei schwangeren Frauen und Wöchnerinnen selten sind. Die Frühgeburtenrate ist hoch und COVID-19 mit Notwendigkeit einer Atemunterstützung erhöht das Risiko für ein schlechtes maternales und neonatales Outcome. Unter anderem ein höheres Alter und BMI sind mit einem höheren Risiko für eine ITS-Aufnahme verbunden. / With the spreading of the SARS-CoV-2 virus in the year 2020, gain of information regarding vulnerable groups of patients was essential. We aimed to describe maternal characteristics and clinical presentation of SARS-CoV-2 positive women requiring intensive care treatment for COVID-19 during pregnancy and postpartum period, based on data of a comprehensive German surveillance system in obstetric patients. Data from COVID-19 Related Obstetric and Neonatal Outcome Study (CRONOS), a prospective multicenter registry for SARS-CoV-2 positive pregnant women, was analyzed with respect to ICU treatment. All women requiring intensive care treatment for COVID-19 were included and compared regarding maternal characteristics, course of disease, as well as maternal and neonatal outcomes. Also the ICU-cohort was compared to the cohort of pregnant and postpartum women not requiring intensive care treatment searching for characteristics and risk factors. Of 2650 cases in CRONOS, 101 women (4%) had a documented ICU stay. As the most invasive form of COVID-19 treatment interventions, patients received either continuous monitoring of vital signs without further treatment requirement (n = 6), insufflation of oxygen (n = 30), non-invasive ventilation (n = 22), invasive ventilation (n = 28), or escalation to extracorporeal membrane oxygenation (n = 15). No significant clinical differences were identified between patients receiving different forms of ventilatory support for COVID-19. Prevalence of preterm delivery was significantly higher in women receiving invasive respiratory treatments as well as in women receiving intensive care treatment in general. Four women died of COVID-19 and six fetuses were stillborn. Our cohort shows that progression of COVID-19 in pregnant and postpartum women with admission to ICU is rare. Preterm birth rate is high and COVID-19 requiring respiratory support increases the risk of poor maternal and neonatal outcome. Admission to ICU in this cohort was associated with a higher maternal age and maternal BMI before pregnancy.

This thesis aims to describe the epidemiology of SARS-CoV-2 and other seasonal respiratory viruses (SRV) in the Ottawa region and determine if there are demographic or occupational risk factors associated with viral infection. This was accomplished in three articles: a rapid review of the literature evaluating SARS-CoV-2 seroprevalence in transit users, an account of SRV activity in Ottawa, Ontario from August, 2018 to January, 2022, and an analysis of coronavirus (CoV) incidence and prevalence in several at risk groups. Results indicated a reduction in SRV incidence during the COVID-19 pandemic correlated with the introduction of non-pharmaceutical public health measures. SARS-CoV-2 seroprevalence indicative of natural infection was not greater in population groups hypothesized to be at greater risk of infection, such as transit users and those exposed to children. Lower socioeconomic status and racial or ethnic minority were consistently associated with higher SARS-CoV-2 seroprevalence. SRVs are expected to resurge and co-circulate with SARS-CoV-2. Results from this thesis suggest those of ethnic minority, low income or immunocompromised individuals may at greater risk.

Beyond the four canonical nucleosides as primary building blocks of RNA, posttranscriptional modifications give rise to the epitranscriptome as a second layer of genetic information. In eukaryotic mRNA, the most abundant posttranscriptional modification is N6-methyladenosine (m6A), which is involved in the regulation of cellular processes. Throughout this thesis, the concept of atomic mutagenesis was employed to gain novel mechanistic insights into the substrate recognition by human m6A reader proteins as well as in the oxidative m6A demethylation by human demethylase enzymes. Non-natural m6A atomic mutants featuring distinct steric and electronic properties were synthesized and incorporated into RNA oligonucleotides. Fluorescence anisotropy measurements using these modified oligonucleotides revealed the impact of the atomic mutagenesis on the molecular recognition by the human m6A readers YTHDF2, YTHDC1 and YTHDC2 and allowed to draw conclusions about structural prerequisites for substrate recognition. Furthermore, substrate recognition and demethylation mechanism of the human m6A demethylase enzymes FTO and ALKBH5 were analyzed by HPLC-MS and PAGE-based assays using the modified oligonucleotides synthesized in this work. Modified nucleosides not only expand the genetic alphabet, but are also extensively researched as drug candidates. In this thesis, the antiviral mechanism of the anti-SARS-CoV-2 drug remdesivir was investigated, which causes delayed stalling of the viral RNA-dependent RNA polymerase (RdRp). Novel remdesivir phosphoramidite building blocks were synthesized and used to construct defined RNA-RdRp complexes for subsequent studies by cryogenic electron microscopy (cryo-EM). It was found that the 1'-cyano substituent causes Rem to act as a steric barrier of RdRp translocation. Since this translocation barrier can eventually be overcome by the polymerase, novel derivatives of Rem with potentially improved antiviral properties were designed. / Über die vier kanonischen Nukleoside als primäre RNA-Bausteine hinausgehend bauen posttranskriptionelle Modifikationen eine zweite Informationsebene, das Epitranskriptom, auf. Die häufigste posttranskriptionelle Modifikation in eukaryotischer mRNA ist N6-Methyladenosin (m6A), welches in die Regulierung zellulärer Prozesse involviert ist. In dieser Arbeit wurde das Konzept der atomaren Mutagenese genutzt, um neue Einblicke in die Erkennung von m6A durch menschliche m6A-bindende Proteine sowie in die oxidative Demethylierung von m6A durch menschliche Demethylase-Enzyme zu gewinnen. Es wurden nicht natürlich vorkommende m6A Atommutanten mit unterschiedlichen elektronischen und sterischen Eigenschaften synthetisiert und in RNA-Oligonukleotide eingebaut. Durch Fluoreszenzanisotropie-Messungen mit diesen Oligonukleotiden wurde der Einfluss der Atommutagenese auf die molekulare Erkennung durch die menschlichen m6A-bindenden Proteine YTHDF2, YTHDC1 und YTHDC2 untersucht. Die erhaltenen Ergebnisse ließen Rückschlüsse auf die strukturellen Voraussetzungen für die Erkennung eines Substrates zu. Weiterhin wurden die in dieser Arbeit synthetisierten modifizierten Oligonukleotide zur Untersuchung von Substraterkennung und Demethylierungs-Mechanismus der menschlichen m6A-Demethylasen FTO und ALKBH5 mittels HPLC-MS- und PAGE-basierter Analysen verwendet. Modifizierte Nukleoside dienen nicht nur zur Erweiterung des genetischen Alphabets, sondern werden auch als potentielle Wirkstoff-Kandidaten erforscht. In dieser Arbeit wurde der antivirale Wirkmechanismus des Anti-SARS-CoV-2-Wirkstoffes Remdesivir untersucht, der eine verzögerte Blockade der viralen RNA-abhängigen RNA-Polymerase (RdRp) bewirkt. Neuartige Remdesivir Phosphoramidit-Bausteine wurden synthetisiert und genutzt, um RNA-RdRp-Komplexe mit definierter Struktur zu konstruieren, welche anschließend mittels Cryoelektronenmikroskopie (Cryo-EM) untersucht wurden. Es wurde herausgefunden, dass der 1'-Cyano-Substituent dazu führt, dass Rem als sterische Blockade der RdRp-Translokation agiert. Da diese Tranlokationsbarriere von der Polymerase überwunden werden kann, wurden neuartige Rem-Derivate mit potentiell verbesserten antiviralen Eigenschaften entworfen.

The analysis of real-world data and the development of mathematical models played a fundamental role in understanding the epidemiology of COVID-19 and informing public policies throughout the recent pandemic. This thesis presents a collection of modeling approaches and results addressing key questions that arose during the COVID-19 crisis, with a specific focus on the emergence and epidemiological features of SARS-CoV-2 variants of concern (VOC) in Italy and related public health implications. In the first chapter, conducted analyses suggest that the Alpha variant was approximately 50% more transmissible than historical lineages of SARS-CoV-2, and that this transmissibility advantage was enough to outcompete a variant associated with immune escape phenomena and circulating in central Italy in February 2021 (i.e., the Gamma variant). In the second chapter, by investigating the potential impact of new hypothetical VOCs in Italy in late 2021, modeling results highlighted that the emergence of variants associated with significant immune escape (i.e., with a rate at which vaccinated or recovered individuals from infection with pre-circulating lineages become infected being at least one-fifth that of unvaccinated individuals who never experienced SARS-CoV-2 infection) would have been able to replace pre-circulating lineages in a couple of weeks. Strict restrictions would have been required to prevent a new large epidemic wave. In the third chapter, the analysis of genomic and epidemiological data associated with the expansion of the Omicron variant over the Italian territory revealed that this variant was able to become dominant at the national level in less than a month, increasing the net reproduction number from 1.15 to 1.83. Despite the marked growth advantage of Omicron compared to the previously circulating Delta variant, a moderate impact on the number of severe cases was observed, likely due to the high proportion of vaccinated individuals in the country by the end of 2021. In the fourth chapter, the estimation of the intrinsic generation time of the Omicron variant (mean: 6.84 days) was found to be similar to that of previous lineages. Such estimates have been key to define adequate isolation, quarantine, surveillance, and contact tracing protocols in 2022. The prevention of SARS-CoV-2 transmission in educational settings represented a key challenge during the pandemic, due to the large proportion of asymptomatic carriers in young individuals. The last chapter presented in this thesis shows that, when the Alpha variant was circulating in Italy, almost half of positive students and school personnel ascertained during in-person education were likely infected by school contacts. The mean number of secondary cases caused at schools was found to be 0.33, with high heterogeneity in the chance of onward transmission. Provided estimates suggest that the timely identification of cases combined with reactive quarantine policies had the potential of reducing SARS-CoV-2 transmission in schools by at least 30%.