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Långvariga effekter av COVID-19 på diffusionskapaciteten i lungorna - en litteraturstudie / Long-term effects of COVID-19 on lung diffusion capacity – a literature studyTan, Evelina January 2021 (has links)
I december 2019 i Wuhan, Kina, blev en grupp personer infekterade av det nya viruset SARS-CoV-2 som inducerade sjukdomen COVID-19. Sjukdomen påverkar lungfunktionen och studier har visat att långvarig påverkan på lungfunktionen kan förekomma. Syftet med den aktuella studien var att undersöka långvariga effekter av COVID-19 på diffusionskapaciteten i lungorna. Studier som undersökte diffusionskapaciteten, mätt med kolmonoxid (DLCO), hos patienter minst 30 dagar efter insjuknande i COVID-19 samlades in och analyserades. Resultatet visade att en stor del av deltagarna hade DLCO <80% av det förväntade värdet. Det visade även att diffusionskapaciteten kan vara nedsatt upp till sex månader efter utskrivning från sjukhus. Då COVID-19 är en ny sjukdom var den aktuella studien begränsad av antalet studier inom området. Framtida studier bör undersöka effekterna av COVID-19 på lungfunktionen under ett längre tidsspann. Slutsatsen i den här litteraturstudien var att COVID-19 påverkar diffusionskapaciteten i lungorna. Långvariga nedsättningar i diffusionskapaciteten har, än så länge, kunnat påvisas upp till sex månader efter sjukdom. Allvarligt insjuknande i COVID-19 ökar risken för långvariga DLCO -nedsättningar.
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Examining Virus Interactions with Host Serine Hydrolases in ImmunometabolismStern, Tiffany 12 January 2024 (has links)
As obligatory intracellular parasites, viruses are in a constant battle with their host to establish infection. They can facilitate their propagation by modulating host immune or metabolic pathways. This modulation involves targeting various molecular factors such as microRNAs (miRNA), enzymes, or small molecules. Understanding how viruses alter the chemical makeup of a cell is crucial to identifying what pathways are being targeted, furthering our understanding of the virus life cycle, and may aid in identifying biomarkers of disease. Here, we examine host-virus interactions in the context of two viruses, hepatitis c virus (HCV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). First, the modulation of serine hydrolases by a pro-viral microRNA, miRNA-122, is investigated using activity-based protein profiling (ABPP). This study identifies a downstream target of miRNA-122 that is differentially activated during HCV infection which can be targeted pharmacologically to reduce HCV infectivity. Second, we apply similar techniques to identify serine hydrolase changes associated with SARS-CoV-2 infection. Results point towards enrichment of endocannabinoid metabolism which may offer an alternative therapeutic avenue for combating SARS-CoV-2 infection. Together, the work presented in this thesis provides avenues for further investigation into miRNA-122 interactions during HCV infection and endocannabinoid metabolism in SARS-CoV-2 infection.
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Sars-Cov-2 Intra-Host Evolution in Immunocompromised Patients for the Emergence of Variants of Concerns, Including Omicron.Bantan, Azari I. 21 July 2022 (has links)
Unexpected high mutations detected in new emerging variants of concern (VOCs) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), especially in the case of omicron, raises concerns and efforts to understand their evolutionary trajectory. Several hypotheses have been discussed in literature to conceptualize the source of their emergence, including intra-host viral evolution in immunocompromised patients. These patients grant opportunities for the emergence of new variants through a persisting virus winning against host immunity, and selection for viral mutations driven by treatment interventions. VOCs have in common high mutation rate exceeding the average rate of 1-2 mutations per month. Not many studies have investigated the evolutionary rate of SARS-CoV-2 in immunocompromised candidates. Therefore, the purpose of this study is to reveal potential mechanisms underlying the emergence of VOCs by exploring substitution rate of SARS-CoV-2 genomes from surveyed COVID-19 immunocompromised patient’s studies. First, SARS-CoV-2 genome sequences were collected at sequential time series throughout host infection, which were reported in the previous studies. Filtration criteria was applied to reanalyze patients with prolonged infection documented for ≥ 2 months, and comprehensive sequenced samples for ≥ 6 time points. Then, phylogenetic analysis was conducted using Nextclade (https://clades.nextstrain.org/), followed by mutation rate analysis using two substantial similar approaches to calculate the rate in i) substitutions per month and ii) substitutions per site (per year). The mutation tendency of SARS-CoV-2 in immunocompromised hosts was compared to reported VOCs, particularly to omicron. The highest observed mutation rate accounted for approximately 2.2 mutations per month, which is higher than the average rate. High mutation rate was due to prolonged infection and selection pressure by treatment interventions (i.e., convalescent plasma and antibodies). Here, higher rate of intra-host viral evolution in immunocompromised patients is detected, potentially leading to the emergence of VOC. Hence, this research highlights the need for sequencing efforts in high-risk individuals, updating treatment strategies along with further analysis on adaptive mutants pronounced due to intra-host evolution. Together, such findings provide an ultimate synergy for future public health guidelines and infection control measures.
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DIASTEREOSELECTIVE OXIDOPYRYLIUM-OLEFIN [5+2]- CYCLOADDITION, DESIGN AND SYNTHESIS OF A NOVEL CLASS OF SARS-COV-2 3CL PROTEASE INHIBITORS, AND SYNTHETIC APPROACH TO (-)-RASFONIN, AN ANTITUMOR AGENTMonika Yadav (13123668) 20 July 2022 (has links)
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<p>Seven-membered ring structures are one of the most important structural motifs found widely in natural products and bioactive molecules. Although several [5+2]-cycloaddition reactions have been developed to construct these seven membered cores, asymmetric cycloaddition reactions are less explored. Described in Chapter-1 is a base mediated intramolecular diastereoselective [5+2]-cycloaddition reaction that afforded highly functionalized seven membered rings in good yields and excellent diastereoselectivities. The high diastereoselectivity is controlled by the alkyl stereocenter and the chain length of the alkene tether. The existing chirality of the substrate can direct the stereochemical outcome of the [5+2]-cycloaddition reaction. Furthermore, this methodology has been applied to synthesize various potent HIV-1 protease inhibitors. </p>
<p>COVID-19 pandemic has profoundly affected life around the globe and costed us 6 million lives. Therefore, there is an urgent need for rational design of new drug candidates to specifically target different SARS-CoV-2 proteins. Recently, Pfizer developed an FDA-approved antiviral therapeutic agent, Paxlovid, targeting SARS-CoV-2 3CLpro. Chapter-2 discusses a concise synthetic route to synthesize active component of Paxlovid, Nirmatrelvir, in 6-steps without any epimerization. We have also developed a series of potent covalent inhibitors targeting SARS-CoV-2 3CLprotease and compared the antiviral activities of these inhibitors with that of Nirmatrelvir. </p>
<p>In the final chapter, a concise partial synthesis of the segment A of (-)-Rafonin is discussed. (-)-Rasfonin is an antitumor agent that induces apoptosis in <em>ras</em>-dependent cells. We have proposed an asymmetric chiron approach to install the α-pyranone ring of rasfonin. Our goal is to perform SAR studies on this natural product by designing various analogues. </p>
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Role of the Cytosolic Chaperonin CCT in the Folding of Novel SubstratesSmith, Theresa M. 10 March 2023 (has links) (PDF)
All cells depend on properly folded proteins for survival and function. Misfolding of proteins results in loss of critical functions and may trigger the misfolding of other nearby proteins leading to toxic aggregation. While many proteins can fold on their own, others with complicated domain structures require assistance from protein folding machines called chaperones. The most complex and highly specialized of all chaperones is the eukaryotic chaperonin complex CCT which is necessary for the folding of a wide variety of essential proteins. These include the cytoskeletal proteins actin and tubulin as well as the Gβ subunit of the G protein heterotrimer. However, CCT activity can also drive diseases such as cancer and viral infections and could represent a high value therapeutic target if the mechanisms by which it folds its different client proteins were better understood. To this end, we identified and characterized an interaction between CCT and the RNA-dependent RNA polymerase of SARS-CoV-2, the virus responsible for the deadly global pandemic that began in 2019. We showed that SARS-CoV-2 replication is impaired by loss of CCT and that the polymerase, designated Nsp12, interacts with CCT upon synthesis and quickly releases - the hallmark pattern of a CCT substrate. Furthermore, we solved a 3.3 Å cryo-EM structure of Nsp12 bound to open CCT showing Nsp12 binding between the two rings of CCT and extending up through of the folding chambers and out of CCT. At 107 kD, Nsp12 is the largest substrate ever visualized inside of CCT and answers a long-standing question in the field of how CCT could accommodate substrates larger than its 70 kD folding chamber. Given that CCT is known to fold proteins with WD40-repeat domains, we also investigated a potential relationship between CCT and RPE65. RPE65, which contains a WD40 domain, is the retinyl ester isomerase that converts all-trans retinyl esters into 11-cis retinol, a key step in the visual cycle, and its mutation is a common cause of hereditary retinal dystrophies. We showed that CCT interacts with RPE65 and that nascent RPE65 binds and releases from CCT albeit with relatively slow kinetics. However, RPE65 is not dependent on CCT for expression or activity. This suggests that the relationship between RPE65 and CCT may represent a novel CCT function distinct from the canonical obligate substrate dynamic.
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Shotgun metagenomic analysis of antimicrobial resistance in wastewaterMaile-Moskowitz, Ayella Zorka 13 March 2023 (has links)
Antimicrobial resistance (AMR) threatens our modern standard of living with the potential return to a pre-antibiotic condition where deadly infections are no longer treatable. Wastewater treatment plants (WWTPs) are vital components in water sanitation infrastructure and are now also being recognized as valuable monitoring points for antibiotics, antibiotic resistant bacteria (ARB), and antibiotic resistance genes (ARGs) disposed of or excreted by human populations. Hospital waste water is of special interest as a potential focused monitoring point and in general research is needed to establish the benefits of both on-site and community-scale wastewater treatment as important barriers to the disseminators of ARGs into the environment. The research aims described herein examine these components of wastewater treatment and how they relate to AMR indicators identified through metagenomic sequencing. Through monitoring of local WWTPs, it was found that AMR indicators shifted over time and in relation to human behavior that changed due to the COVID-19 pandemic. Hospital wastewater did not measurably impact the microbiome during simulated activated sludge wastewater treatment according to broad-scale metagenomic ARG profiling; however, some clinically-relevant ARGs escaped treatment. Lastly, a study of a transect of WWTPs indicated impacts on the abundance of certain ARGs in downstream riverine receiving environments. Nonetheless, there appeared to be a number of other factors at play, and upstream and downstream resistomes tended to remain similar, calling for further research to delineate impacts of various wastewaters and treatments on ARGs in affected aquatic environments. / Doctor of Philosophy / Antimicrobial resistance (AMR) occurs when bacteria, viruses, and fungi are able to survive in the presence of antibiotics because they carry antibiotic resistance genes (ARGs) encoded in their DNA. AMR is a major public health concern as it makes it so that antibiotics are no longer effective against potentially deadly infections. Wastewater treatment plants (WWTPs) are being discovered as a hub of opportunity for monitoring potential AMR problems in a community. WWTPs receive sewage from homes and various industries. This sewage contains rich information for researchers to examine in terms of which antibiotics, bacteria, and ARGs are circulating in the community. This makes it possible to find out which antibiotics are being consumed in the community and which ARGs might be prevalent. The purpose of this research was to better understand both how WWTPs can be used as monitoring points for AMR and how they can be improved to help reduce ARGs emitted to rivers and streams where treated water is discharged. It was found that the types of ARGs prevalent in wastewater changed over time, especially during the COVID-19 pandemic as people worked from home and changed habits regarding doctors' visits, which impacted antibiotic use. Hospital sewage was studied as a useful indicator of pathogens and ARGs that are challenging a community and also the antibiotics being used. This research explored what happened to ARGs during the treatment of domestic (i.e., from people's homes) wastewater along with hospital wastewater and found that hospital wastewater introduced some ARGs that are typically found in clinical settings, but did not negatively impact the overall wastewater treatment process. Finally, the impact that WWTPs have on rivers to which treated water is discharged was explored. The results indicated that certain ARGs were elevated downstream of the WWTPs. However, when examining all ARGs together, no major shifts due to the treated wastewater were apparent.
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Commentary on Viewpoint: The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathiesTan, A.L., Farrow, Matthew, Biglands, J. 27 April 2021 (has links)
Yes
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Epidemiological Insights of Covid-19: Understanding Variant Dynamics, Environmental Surveillance and Disparities in FloridaAli, Md Sobur 01 January 2024 (has links) (PDF)
The COVID-19 pandemic, caused by SARS-CoV-2, has emerged as one of most significant health emergencies in recent history. SARS-CoV-2 has been characterized by the emergence of highly mutated variants that exhibit high transmissibility, virulence, and the capability of immune escape. The constantly evolving nature of the COVID-19 pandemic has underscored the necessity for a thorough comprehension of viral transmission dynamics, the effectiveness of novel monitoring techniques, and the determinants of health inequalities. This study explored several aspects of the pandemic, specifically emphasizing the emergence and dissemination of the Delta variant in Florida, the significance of environmental surveillance, and the factors associated with COVID-19 outcomes. Phylogenetic analysis using SARS-CoV-2 genome revealed that multiple independent introductions of the Delta variant fueled its spread within Florida. Further, we hypothesized that high-touch surface monitoring can be an alternative noninvasive approach to determine infection trend and detect variants. The study found high contamination rate on high-touch surfaces and the viral gene copy was positively correlated to the clinical cases in the university. Moreover, genome sequencing of environmental surface samples detected circulating and emerging variants. Additionally, spatial autocorrelation and regression analysis was conducted to investigate the relationship between county-level demographic, socioeconomic, and health-related factors and variation in COVID-19 cases, mortality, and case fatality rates. This study identified significant variations in COVID-19 outcomes across Florida counties, with factors such as age, obesity, rurality and importantly, vaccination rates playing key roles in explaining these disparities. Overall, this study emphasizes the importance of robust genomic surveillance for monitoring the emergence and spread of viral variants, the potential of environmental surface monitoring as a complementary public health tool, and the urgent need to address the underlying drivers of health disparities. These findings contribute to a more nuanced understanding of pandemic dynamics and inform data-driven strategies to mitigate the impact of future public health emergencies.
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Covid-19 - kortikosteroidbehandling vid svår sjukdom : En jämförande analys / Covid-19 - corticosteroid therapy in severe illness : A comparative analysisWoin, Nicolas January 2021 (has links)
Sammanfattning Sedan sjukdomen Covid-19s uppdykande i början av 2020 har forskning pågått för att karaktärisera sjukdomen ur alla tänkbara vinklar för att på kortast möjliga tid bereda väg för ett fungerande botemedel. Effektiva läkemedel som kan minska risken för allvarligt sjuka patienter att avlida i sjukdomen behövs; många preparat har föreslagits och testats och i Sverige har hittills två läkemedel godkänts för Covid-19. Ett av dessa är kortikosteroiden dexametason som godkänts för Covid-19-patienter i behov av syrgas eller respirator. Syftet med detta arbete var att undersöka hur effektiv kortikosteroidbehandling av svårt sjuka Covid-19-patienter var i jämförelse med standardbehandling utan kortikosteroider. En litteratursökning gjordes i PubMed och i covid-nma efter randomiserade kliniska studier av kortikosteroider jämfört med standardbehandling till patienter med Covid-19. Ur resultatet som inkluderade 7 kontrollerade studier med 7784 svårt sjuka patienter från 11 länder och fem kontinenter, gjordes en sammanvägning av den primära utfallsvariabeln mortalitet 28 dagar efter randomisering varpå relativ risk (RR) räknades ut individuellt per studie och sammanvägt för alla studier. Analysen gjordes också med den mest dominanta studien borträknad. Vidare utforskades möjliga samband mellan sjukdomsgrad och effektstorlek, dels genom ett försök till metaregression av studiemortalitet och andningshjälpsnivå mot RR som var inkonklusivt, men också genom att leta efter speciellt sjuka undergrupper i studierna. 3 studier rapporterade mortalitet efter 28 dagar, 1 studie rapporterade mortalitet efter 21 dagar, 2 studier rapporterade död på sjukhus och en studie rapporterade död efter 15 dagar. Testade preparat var dexametason, hydrokortison och metylprednisolon. Av 2885 patienter som randomiserats till någon kortikosteroid, dog 739, medan det av de 4899 som randomiserats till standardbehandling dog 1347 patienter vilket gav en icke signifikant RR på 0,93 (95% CI 0,86–1,01). Vid borträkning av den största studien som bestod av relativt friskare patienter erhölls en starkare och signifikant effekt med RR 0,80 (95% CI 0,70–0,92) baserat på 257 av 781 döda i steroidgrupperna jämfört med 237av 578 döda i någon kontrollgrupp med standardbehandling. Resultatet var även i linje med analysen av olika sjuka undergrupper från största studien som visade bäst effekt hos de med invasiv mekanisk andningshjälp (absolut riskreduktion 12,1%) samt en icke signifikant försämring hos de friskaste patienterna utan syrgasbehov. Sammantaget tyder dessa resultat på att behandling av svårt sjuka Covid-19-patienter med kortikosteroider minskar mortaliteten efter 28 dagar. Dessutom ger studien en stark indikation på att bästa effekten fås om kortikosteroiderna ges till patienter där den systemiska inflammationen i lungorna nått en gasutbyteshämmande nivå / ABSTRACT Since the emergence of the new corona virus disease, Covid-19, much research effort has gone into characterising every possible angle of the disease to pave the way for a possible cure in the shortest possible time. Effective therapies are needed that will reduce the risk of dying for severely to critically ill Covid-19 patients. Many existing therapies have been suggested, tested and repurposed for the treatment of Covid-19 but so far only two drugs have been approved in Sweden for this indication, namely the antiviral drug remdesivir and the corticosteroid dexamethasone. Corticosteroids are both immunosuppressive and anti-inflammatory and when they were administered previously for severe acute respiratory syndrome (SARS), middle east respiratory syndrome (MERS) and influenza they were found to increase the time to rid the body of virus. The purpose of this study was to investigate evidence found in the research literature of how effective corticosteroids are in reducing the risk of dying as compared to standard treatment with no corticosteroids when administered to hospitalised patients with severe Covid-19. A literature search was made in the PubMed and covid-nma databases for randomized clinical studies of corticosteroids versus standard treatment to patients with Covid-19. The result included 7 studies with 7784 patients from 11 countries and 5 continents which all reported death as an outcome in groups that were receiving corticosteroids compared to groups that were receiving standard care. The studies used one of the following corticosteroids as intervention: dexamethasone, methylprednisolone and hydrocortisone in different doses. In the groups receiving standard care, 1347 patients out of 4899 died while in the corticosteroid groups 739 of 2885 patients died. When doing a statistical calculation these figures indicated that the risk of dying when getting corticosteroids was 93% of the risk when not getting corticosteroids, however the difference was not statistically significant. After omitting the largest study from the material, that contributed the absolute majority of total participants, who were deemed relatively healthy or well taken care of, the results were instead that 257 out of 781 died in the steroid groups and 237 of 578 died in the control groups. This later comparison among supposedly sicker patients, gave a statistically significant 8,1% lower absolute risk of dying in the corticosteroid groups; an effect that could also be expressed as for every 25 patients treated, 2 more lives would be saved. A further control of a more severely sick subgroup of patients from the largest study, in need of invasive mechanical ventilation, revealed an absolute reduction of the risk of dying when given corticosteroids of 12,1%. This group showed the most effectful response to the administered corticosteroids in this study which could also be expressed as 1 more life saved for every 8 patients treated. Another sub group analysis of the patients from the largest study that were not in need of any type of oxygen support, indicated on the other hand a possible harm of corticosteroids. This potentially harmful effect was however not statistically significant. In summary, the results of this study imply that administration of corticosteroids to patients with severe Covid-19 will reduce the risk of dying. The greatest effect is seen in those patients that has reached a level of illness were the gas exchange in the lungs is impaired by the inflammation. Furthermore, caution must be taken not to introduce harm by giving corticosteroids to patients with milder disease in which the immunosuppressive properties of the drug could lead to unintended worsening of the illness.
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Mental distress in healthcare workers affected by the SARS-CoV-2 pandemic and previous interventions that may be useful in promoting mental health in healthcare workers : A systematic literature review / Psykisk ohälsa hos sjukvårdspersonal som påverkats av SARS-CoV-2 pandemin och tidigare interventioner som kan vara användbara för att främja psykisk hälsa hos sjukvårdspersonal : En systematisk litteraturstudieLindblom Ekman, Josefin, Karlsson, Michaela January 2021 (has links)
Introduktion: Sjukvårdspersonal runt om i världen har stått på frontlinjen i stressiga arbetsmiljöer och tagit hand om COVID-19-patienter sedan SARS-CoV-2 förklarades som en global pandemi. Under pandemiska förhållanden står sjukvårdspersonal inför specifika utmaningar, där vissa leder till symptom på psykisk ohälsa. Statliga resurser till sjukvårdspersonal har ofta avsatts för kortsiktiga insatser. Långsiktiga investeringar med fokus på främjande av sjukvårdpersonalens psykiska hälsa behövs för att förhindra förvärrade folkhälsoproblem på grund av SARS-CoV-2. Syfte: Studiens syfte var att belysa hur sjukvårdspersonal rapporterar att deras psykiska hälsa påverkats av SARS-CoV-2-pandemin och vilka erfarenheter från tidigare interventioner för psykisk hälsa som skulle kunna vara användbara för att förbättra sjukvårdspersonals psykiska hälsa genom att belysa några exempel. Metod: En systematisk litteraturöversikt genomfördes, där 20 vetenskapliga artiklar inkluderades och analyserades med tematisk analys. Resultat: Totalt nio teman identifierades: psykisk ohälsa hos sjukvårdspersonal, SARS-CoV-2-pandemin, interventioner för psykisk hälsa, vårdkvalitet, säkerhetskultur, arbetsplatsbaserade tillvägagångssätt, mindfulness och konstaktivitetsmetoder, biomarkörbaserade tillvägagångssätt samt tekniska tillvägagångssätt. Viktiga fynd i denna litteraturöversikt är att teman säkerhetskultur och vårdkvalitet är associerade med de andra teman. Slutsats: När tillvägagångssätt implementeras i insatser för sjukvårdspersonals psykiska hälsa som främjar säkerhetskultur och vårdkvalitet främjar det också, enligt resultaten i denna översikt, långsiktiga effekter på individuell psykisk hälsa hos sjukvårdspersonal. Detta bör omedelbart beaktas av dem som utvecklar nya program för att främja psykisk hälsa för att stödja sjukvårdspersonal i effekterna av pandemin. / Introduction: Healthcare workers around the world have stood on the front lines in stressful work-environments, caring for COVID-19 patients since SARS-CoV-2 was declared a global pandemic. Under pandemic conditions healthcare workers face specific challenges, where some lead to symptoms of mental illness. Governmental resources to the healthcare workforce have often been allocated to short-term efforts. Long-term investments focusing on mental health promotion for HCW are needed to prevent worsening public health issues due to SARS-CoV-2. Aim: The aim of the study was to illuminate how HCW report that their mental health has been affected by the SARS-CoV-2 pandemic and what experiences from previous mental health interventions that may be useful in promoting HCW mental health by highlighting some examples. Methods: A systematic literature review was conducted, including 20 scientific articles analyzed with thematic analysis. Results: A total of nine themes were identified: mental distress in HCW, SARS-CoV-2 pandemic, mental health interventions, quality of care, safety culture, workplace-based approaches, mindfulness and art activity approaches, biomarker-based approaches as well as technology approaches. Important findings in this literature review are the themes safety culture and quality of care being associated with the other themes. Conclusion: When implementing approaches in mental health interventions for HCW that promote safety culture and quality of care, it also promotes, according to the findings in this review, long-term effects in individual mental health in HCW. This should be urgently taken into consideration by those developing new mental health promotion programs to support HCW in the effects of the pandemic.
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