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1.
Preprint | bioRxiv | ID: ppbiorxiv-518411

RESUMO

SARS-CoV-2 infection remains a major public health concern, particularly for the aged and those individuals with co-morbidities at risk for developing severe COVID-19. Understanding the pathogenesis and biomarkers associated with responses to SARS-CoV-2 infection remain critical components in developing effective therapeutic approaches, especially in cases of severe and long-COVID-19. In this study blood plasma protein expression was compared in subjects with mild, moderate, and severe COVID-19 disease. Evaluation of an inflammatory protein panel confirms upregulation of proteins including TNF{beta}, IL-6, IL-8, IL-12, already associated with severe cytokine storm and progression to severe COVID-19. Importantly, we identify several proteins not yet associated with COVID-19 disease, including mesothelin (MSLN), that are expressed at significantly higher levels in severe COVID-19 subjects. In addition, we find a subset of markers associated with T-cell and dendritic cell responses to viral infection that are significantly higher in mild cases and decrease in expression as severity of COVID-19 increases, suggesting that an immediate and effective activation of T-cells is critical in modulating disease progression. Together, our findings identify new targets for further investigation as therapeutic approaches for the treatment of SARS-CoV-2 infection and prevention of complications of severe COVID-19.

2.
Preprint em Inglês | bioRxiv | ID: ppbiorxiv-518473

RESUMO

Typical drug discovery and development processes are costly, time consuming and often biased by expert opinion. Aptamers are short, single-stranded oligonucleotides (RNA/DNA) that bind to target proteins and other types of biomolecules. Compared with small-molecule drugs, aptamers can bind to their targets with high affinity (binding strength) and specificity (uniquely interacting with the target only). The conventional development process for aptamers utilizes a manual process known as Systematic Evolution of Ligands by Exponential Enrichment (SELEX), which is costly, slow, dependent on library choice and often produces aptamers that are not optimized. To address these challenges, in this research, we create an intelligent approach, named DAPTEV, for generating and evolving aptamer sequences to support aptamer-based drug discovery and development. Using the COVID-19 spike protein as a target, our computational results suggest that DAPTEV is able to produce structurally complex aptamers with strong binding affinities.

3.
Preprint em Inglês | bioRxiv | ID: ppbiorxiv-518005

RESUMO

Reverse genetics systems have been crucial for studying specific viral genes and their relevance in the virus lifecycle, and become important tools for the rational attenuation of viruses and thereby for vaccine design. Recent rapid progress has been made in the establishment of reverse genetics systems for functional analysis of SARS-CoV-2, a coronavirus that causes the ongoing COVID-19 pandemic that has resulted in detrimental public health and economic burden. Among the different reverse genetics approaches, CPER (circular polymerase extension reaction) has become one of the leading methodologies to generate recombinant SARS-CoV-2 infectious clones due to its accuracy, efficiency, and flexibility. Here, we report an optimized CPER methodology which, through the use of a modified linker plasmid and by performing DNA nick ligation and direct transfection of permissive cells, overcomes certain intrinsic limitations of the "traditional" CPER approaches for SARS-CoV-2, allowing for efficient virus rescue. This optimized CPER system may facilitate research studies to assess the contribution of SARS-CoV-2 genes and individual motifs or residues to virus replication, pathogenesis and immune escape, and may also be adapted to other viruses.

4.
Preprint em Inglês | bioRxiv | ID: ppbiorxiv-518257

RESUMO

Endoplasmic reticulum (ER) aminopeptidase associated with antigen processing (ERAAP) trims peptide precursors in the ER for presentation by major histocompatibility (MHC)-I molecules to surveying CD8+T-cells. This function allows ERAAP to regulate the nature and quality of the peptide repertoire and, accordingly, the resulting immune responses. We recently showed that infection with murine cytomegalovirus leads to a dramatic loss of ERAAP levels in infected cells. In mice, this loss is associated with the activation of QFL T-cells, a subset of T-cells that monitor ERAAP integrity and eliminate cells experiencing ERAAP dysfunction. In this study, we aimed to identify host factors that regulate ERAAP expression level and determine whether these could be manipulated during viral infections. We performed a CRISPR knockout screen and identified ERp44 as a factor promoting ERAAP retention in the ER. ERp44's interaction with ERAAP is dependent on the pH gradient between the ER and Golgi. We hypothesized that viruses that disrupt the pH of the secretory pathway interfere with ERAAP retention. Here, we demonstrate that expression of the Envelope (E) protein from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) leads to Golgi pH neutralization and consequently decrease of ERAAP intracellular levels. Furthermore, SARS-CoV-2-induced ERAAP loss correlates with its release into the extracellular environment. ERAAP's reliance on ERp44 and a functioning ER/Golgi pH gradient for proper localization and function led us to propose that ERAAP serves as a sensor of disturbances in the secretory pathway during infection and disease.

5.
Preprint em Inglês | bioRxiv | ID: ppbiorxiv-518438

RESUMO

The SARS-CoV-2 virus has been on a rampage for more than two years. Vaccines in combination with neutralizing antibodies (NAbs) against SARS-CoV-2 carry great hope in the treatment and final elimination of COVID-19. However, the relentless emergence of variants of concern (VOC), including the most recent Omicron variants, presses for novel measures to counter these variants that often show immune evasion. Hereby we developed a targeted photodynamic approach to neutralize SARS-CoV-2 by engineering a genetically encoded photosensitizer (SOPP3) to a diverse list of antibodies targeting the WT spike protein, including human antibodies isolated from a 2003 SARS patient, potent monomeric and multimeric nanobodies targeting RBD, and non-neutralizing antibodies (non-NAbs) targeting the more conserved NTD region. As confirmed by pseudovirus neutralization assay, this targeted photodynamic approach significantly increased the efficacy of these antibodies, especially that of non-NAbs, against not only the WT but also the Delta strain and the heavily immune escape Omicron strain (BA.1). Subsequent measurement of infrared phosphorescence at 1270 nm confirmed the generation of singlet oxygen (1O2) in the photodynamic process. Mass spectroscopy assay uncovered amino acids in the spike protein targeted by 1O2. Impressively, Y145 and H146 form an oxidization hotspot, which overlaps with the antigenic supersite in NTD. Taken together, our study established a targeted photodynamic approach against the SARS-CoV-2 virus and provided mechanistic insights into the photodynamic modification of protein molecules mediated by 1O2.

6.
Preprint | medRxiv | ID: ppmedrxiv-22282857

RESUMO

Introduction COVID-19 causes global health and psychosocial devastation, particularly to high-risk patients such as those with neuromuscular diseases (NMDs). The mRNA-based BNT162b2 and inactivated whole-virus CoronaVac are two novel COVID-19 vaccines widely used across the world that confer immune protection to healthy individuals. However, hesitancy towards COVID-19 vaccination was common for patients with NMDs early in the pandemic due to the paucity of data on the safety and efficacy in this specific patient population. Therefore, we examined the underlying factors associated with vaccine hesitancy across time for these patients and included the assessment of the reactogenicity and immunogenicity of these two vaccines. Methods Pediatric patients were screened from our NMD registry. For the vaccine hesitancy arm, those aged 8-18 years with no cognitive delay were invited to complete surveys in January and April 2022. For the reactogenicity and immunogenicity arm, patients aged 2-21 years were enrolled for COVID-19 vaccination between June 2021 to April 2022. Participants recorded adverse reactions (ARs) for 7 days after vaccination. Peripheral blood was obtained before BNT162b2 or CoronaVac and within 49 days after vaccination to measure their serological antibody responses as compared to healthy children and adolescents. Results Forty-one patients completed vaccine hesitancy surveys for both timepoints, and 22 joined our reactogenicity and immunogenicity arm of the study. Two or more family members vaccinated against COVID-19 was positively associated with intention of vaccination (odds ratio 11.7, 95% CI 1.81-75.1, p=0.010). Pain at the injection site, fatigue and myalgia were the commonest ARs. Most ARs were mild (75.5%, n=71/94). All 19 patients seroconverted against the wildtype SARS-CoV-2 after two doses of BNT162b2 or CoronaVac, although there was lower neutralization against the Omicron BA.1 variant. Discussion This study demonstrated vaccine hesitancy amongst patients with NMDs was influenced by family members and changed across time. BNT162b2 and CoronaVac were safe and immunogenic even for patients on low-dose corticosteroids. Future research is required to assess the durability of the COVID-19 vaccines, the effectiveness of booster doses and other routes of administration against emerging SARS-CoV-2 variants for these patients.

7.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-22282922

RESUMO

Background In England, free testing for COVID-19 was widely available from early in the pandemic until 1 April 2022. Based on apparent differences in the rate of positive PCR tests at a single laboratory compared to the rest of the laboratory network, we hypothesised that a substantial number of UK PCR tests processed during September and October 2021 may have been incorrectly reported as negative, compared with the rest of the laboratory network. We investigate the epidemiological impact of this incident. Methods We estimate the additional number of COVID-19 cases that would have been reported had the sensitivity of the laboratory test procedure not dropped for the period 2 September to 12 October. In addition, by making comparisons between the most affected local areas and comparator populations, we estimate the number of additional infections, cases, hospitalisations and deaths that could have occurred as a result of increased transmission due to the misclassification of tests. Results We estimate that around 39,000 tests may have been incorrectly classified during this period and, as a direct result of this incident, the most affected areas in the South West could have experienced between 6,000 and 34,000 additional reportable cases, with a central estimate of around 24,000 additional reportable cases. Using modelled relationships between key variables, we estimate that this central estimate could have translated to approximately 55,000 additional infections, which means that each incorrect negative test likely led to just over two additional infections. In those same geographical areas, our results also suggest an increased number of admissions and deaths. Conclusion The incident is likely to have had a measurable impact on cases and infections in the affected areas in the South West of England.

8.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-22282916

RESUMO

Following primary SARS-CoV-2 vaccination, understanding the relative extent of protection against SARS-CoV-2 infection from boosters or from breakthrough infections (i.e. infection in the context of previous vaccination) has important implications for vaccine policy. In this study, we investigated correlates of protection against Omicron BA.4/5 infections and anti-spike IgG antibody trajectories after a third/booster vaccination or breakthrough infection following second vaccination in 154,149 adults [≥]18y from the United Kingdom general population. We found that higher anti-spike IgG antibody levels were associated with increased protection against Omicron BA.4/5 infection and that breakthrough infections were associated with higher levels of protection at any given antibody level than booster vaccinations. Breakthrough infections generated similar antibody levels to third/booster vaccinations, and the subsequent declines in antibody levels were similar to or slightly slower than those after third/booster vaccinations. Taken together our findings show that breakthrough infection provides longer lasting protection against further infections than booster vaccinations. For example, considering antibody levels associated with 67% protection against infection, a third/booster vaccination did not provide long-lasting protection, while a Delta/Omicron BA.1 breakthrough infection could provide 5-10 months of protection against Omicron BA.4/5 reinfection. 50-60% of the vaccinated UK population with a breakthrough infection would still be protected by the end of 2022, compared to <15% of the triple-vaccinated UK population without previous infection. Although there are societal impacts and risks to some individuals associated with ongoing transmission, breakthrough infection could be an efficient immune-boosting mechanism for subgroups of the population, including younger healthy adults, who have low risks of adverse consequences from infection.

9.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-22282903

RESUMO

Abstract: Background: Pregnant females affected with COVID-19 are reported to have poorer disease outcomes as compared to non-pregnant females of a similar age group. COVID-19 may lead to adverse changes in the placenta, which needs to be studied. Methods: This is a case series of 63 pregnant women hospitalized with COVID-19 from May 2020 to February 2021.The primary outcomes were maternal death or complications. Results: 63 women were studied. 83.3% of women were in the age group of 26 to 35 years. 33% women had associated comorbidities. 68.3% of women tested positive in their third trimester, 15.9% and 11% tested positive in their second and first trimesters respectively. 73% women had mild disease and 27% women required oxygen support. 3/63 women died. One woman in the second and two women in the third trimester died respectively. Histopathological examination in 13 placentae (of 19 placentae examined) were suggestive of maternal and fetal malperfusion. Conclusion: Pregnant COVID-19 women may develop disease-related as well as obstetric complications.

10.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-22282907

RESUMO

COVID-19 impacted multiple facets of life, with implications on physical, mental, and societal health. Specifically, long COVID and related losses have exacerbated complex and prolonged grief responses and mental disorders including depression and anxiety. These mental health concerns are in turn associated with increased detrimental coping strategies including substance use disorders (SUD). The social and interpersonal implications of SUD are varied. Secondary data analyses from the National Survey on Drug Use and Health (NSDUH) collected during the COVID-19 pandemic revealed an increase in substance use behaviors and mental health problems. Self-reported religious activities had a positive meditating effect on reducing substance use behaviors. Accordingly, we explored the importance of one's religion and faith in coping with stress, grief, and mental health challenges during the COVID-19 pandemic, highlighting the impact of religion and faith in bringing hope and purpose during periods of loss, grief, mental health challenges, and SUD.

11.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-22282819

RESUMO

Introduction: Acute Respiratory Distress Syndrome (ARDS) is a feared consequence of Covid 19 Pneumonia. Traditional guidance was for ARDS to be treated with Intubation and Mechanical Ventilation (IMV), when failing simple oxygen. However globally numbers of patients with Covid 19 ARDS (CARDS) quickly overwhelmed IMV capacity, with Continuous Positive Airway Pressure (CPAP) has been used as a bridge or alternative to IMV. However, the evidence base remains limited in quality despite widespread adoption in guidelines. Methods: Pubmed (15.6.2022), Embase (30.7.2022) and Google Scholar (4.8.2022) were searched to identify studies with the primary outcome of IMV free survival in patients with CARDS receiving CPAP, ideally with simple oxygen as a comparator. Secondary outcomes were overall survival with CPAP, length of stay and adverse events. All studies were assessed by the relevant Critical Appraisal Skills Programme Tool (CASP). Results: 13 studies were identified, out of which only 1 was a Randomised Control Trial (RCT) with simple oxygen as a comparator. There were 11 Cohort studies and one Systematic review. Discussion: There is much heterogeneity in CPAP success rates (50 to 70%), which may be linked to variation in candidate selection, resource setting, application protocols and combined use with other respiratory support modalities (Non Invasive Ventilation: NIV, and High Flow Nasal Oxygen: HFNO). Adverse events and economic data such as length of stay are under reported. Conclusion: CPAP is an effective respiratory support in CARDS particularly in resource poor settings. However further research is needed to refine optimum candidate selection, application protocols and any added benefit from combination with NIV or HFNO. No funding was received for this study. This review was not registered.

12.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-22282632

RESUMO

In situations like the COVID-19 pandemic, healthcare systems are under enormous pressure as they can rapidly collapse under the burden of the crisis. Machine learning (ML) based risk models could lift the burden by identifying patients with high risk of severe disease progression. Electronic Health Records (EHRs) provide crucial sources of information to develop these models because they rely on routinely collected healthcare data. However, EHR data is challenging for training ML models because it contains irregularly timestamped diagnosis, prescription, and procedure codes. For such data, transformer-based models are promising. We extended the previously published Med-BERT model by including age, sex, medications, quantitative clinical measures, and state information. After pre-training on approximately 988 million EHRs from 3.5 million patients, we developed models to predict Acute Respiratory Manifestations (ARM) risk using the medical history of 80,211 COVID-19 patients. Compared to XGBoost and Random Forests, our transformer-based models more accurately forecast the risk of developing ARM after COVID-19 infection. We used Integrated Gradients and Bayesian networks to understand the link between the essential features of our model. Finally, we evaluated adapting our model to Austrian in-patient data. Our study highlights the promise of predictive transformer-based models for precision medicine.

13.
Preprint em Inglês | medRxiv | ID: ppmedrxiv-22282923

RESUMO

Findings of recent observational studies have been interpreted as supporting immune imprinting of COVID-19 vaccines. In this work, we clarify that the current discussion can be mapped to an attempt to estimate the direct effect of vaccine boosters on SARS-CoV-2 reinfections, and that such direct effect cannot be correctly estimated with observational data. We conclude that recent observational estimates regarding immune imprinting are fundamentally biased, and that the increased risk of reinfection in individuals vaccinated with a vaccine booster compared to no booster is expected even if the immune imprinting hypothesis is false. We use graphical methods (directed acyclic graphs), data simulations and analysis of real-life data to illustrate the mechanism and magnitude of this bias.

14.
Health Promot Int ; 36(5): 1324-1333, 2021 Oct 13.
Artigo | MEDLINE | ID: covidwho-2107483

RESUMO

Global shifts toward a disease-oriented, vertical approach to health has involved limiting the right for communities to participate in decision-making. Ecuador's authoritarian legacy has forced civil society and social organizations to adopt 'coping strategies', while large protests recently derived into violent struggles. The country has been severely hit by the COVID-19 pandemic amid corruption scandals involving hospital and food purchases by government during the response. This study critically examines how Ecuador's government took into consideration 'community participation' as a value and tenet of health promotion. Our systematic textual analysis focuses on 53 consecutive resolutions by the National Emergency Operations Committee (EOC) leading the decision-making processes, which, explicitly requires community participation. Results show that the 'lifecycle' of the central government's evolving policy framing centered on law enforcement and the private sector, followed by the social sector. Further, there is no evidence of stakeholders from civil society or organizations taking part in decision-making. Having legitimized the exclusion of community participation in Ecuador's response to the COVID-19 pandemic, it is possible that the government will fail to consider the wider social implications of its impact. In particular, the limits to local governments becoming informed and making decisions without mediation by the National EOC will further impede community participation in health decision-making in the future. This implies that local knowledge and experiences will also not inform health policy.


Assuntos
COVID-19 , Participação da Comunidade , Equador , Política de Saúde , Humanos , Pandemias , SARS-CoV-2
15.
Cyberpsychol Behav Soc Netw ; 25(2): 124-129, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: covidwho-2107297

RESUMO

Viewing self-video during videoconferences potentially causes negative self-focused attention that contributes to virtual meeting (VM) or "Zoom" fatigue. The present research examines this proposition, focusing on facial dissatisfaction-feeling unhappy about one's own facial appearance-as a potential psychological mechanism of VM fatigue. A study of survey responses from a panel of 613 adults found that VM fatigue was 14.9 percent higher for women than for men, and 11.1 percent higher for Asian than for White participants. These gender and race/ethnicity differences were found to be mediated by facial dissatisfaction. This study replicates earlier VM fatigue research, extends the theoretical understanding of facial dissatisfaction as a psychological mechanism of VM fatigue, and suggests that practical approaches to mitigating VM fatigue could include implementing technological features that reduce self-focused attention during VMs (e.g., employing avatars).


Assuntos
Emoções , Fadiga , Adulto , Imagem Corporal , Face , Feminino , Humanos , Masculino , Inquéritos e Questionários
16.
Int J Environ Health Res ; : 1-10, 2021 Oct 24.
Artigo em Inglês | MEDLINE | ID: covidwho-2106932

RESUMO

Brazil has become the epicenter of coronavirus disease, and the São Paulo State has the worst scenario. This study evaluated the effect of the COVID-19 in dentists of São Paulo State, Brazil. A self-administered web-based survey with 33 multiple-choice questions was sent to dentists. Descriptive statistics were used to assess the 302 valid responses. Data were analyzed by Chi-square, McNemar and Wilcoxon tests (α = 0.05). Most of the participants aged until 34 years (61.6%) and were female (74.5%). They reduced work to less than 20 h per week. Monthly remuneration was reduced (86.8%). Personal protective equipment at the office was changed (p < 0.05). A few dentists (7.6%) had COVID-19, and more than 99% were aware of the disease. Most of the participants (90.2%) were insecure about being contaminated. The dentists of São Paulo State had coronavirus knowledge and have adopted strict biosafety protocols, but the pandemic affected their financial and psychological features.

17.
Med Teach ; : 1, 2021 Oct 22.
Artigo em Inglês | MEDLINE | ID: covidwho-2106755
19.
Lancet ; 398(10303): 843-855, 2021 09 04.
Artigo em Inglês | MEDLINE | ID: covidwho-2106189

RESUMO

BACKGROUND: A previous efficacy trial found benefit from inhaled budesonide for COVID-19 in patients not admitted to hospital, but effectiveness in high-risk individuals is unknown. We aimed to establish whether inhaled budesonide reduces time to recovery and COVID-19-related hospital admissions or deaths among people at high risk of complications in the community. METHODS: PRINCIPLE is a multicentre, open-label, multi-arm, randomised, controlled, adaptive platform trial done remotely from a central trial site and at primary care centres in the UK. Eligible participants were aged 65 years or older or 50 years or older with comorbidities, and unwell for up to 14 days with suspected COVID-19 but not admitted to hospital. Participants were randomly assigned to usual care, usual care plus inhaled budesonide (800 µg twice daily for 14 days), or usual care plus other interventions, and followed up for 28 days. Participants were aware of group assignment. The coprimary endpoints are time to first self-reported recovery and hospital admission or death related to COVID-19, within 28 days, analysed using Bayesian models. The primary analysis population included all eligible SARS-CoV-2-positive participants randomly assigned to budesonide, usual care, and other interventions, from the start of the platform trial until the budesonide group was closed. This trial is registered at the ISRCTN registry (ISRCTN86534580) and is ongoing. FINDINGS: The trial began enrolment on April 2, 2020, with randomisation to budesonide from Nov 27, 2020, until March 31, 2021, when the prespecified time to recovery superiority criterion was met. 4700 participants were randomly assigned to budesonide (n=1073), usual care alone (n=1988), or other treatments (n=1639). The primary analysis model includes 2530 SARS-CoV-2-positive participants, with 787 in the budesonide group, 1069 in the usual care group, and 974 receiving other treatments. There was a benefit in time to first self-reported recovery of an estimated 2·94 days (95% Bayesian credible interval [BCI] 1·19 to 5·12) in the budesonide group versus the usual care group (11·8 days [95% BCI 10·0 to 14·1] vs 14·7 days [12·3 to 18·0]; hazard ratio 1·21 [95% BCI 1·08 to 1·36]), with a probability of superiority greater than 0·999, meeting the prespecified superiority threshold of 0·99. For the hospital admission or death outcome, the estimated rate was 6·8% (95% BCI 4·1 to 10·2) in the budesonide group versus 8·8% (5·5 to 12·7) in the usual care group (estimated absolute difference 2·0% [95% BCI -0·2 to 4·5]; odds ratio 0·75 [95% BCI 0·55 to 1·03]), with a probability of superiority 0·963, below the prespecified superiority threshold of 0·975. Two participants in the budesonide group and four in the usual care group had serious adverse events (hospital admissions unrelated to COVID-19). INTERPRETATION: Inhaled budesonide improves time to recovery, with a chance of also reducing hospital admissions or deaths (although our results did not meet the superiority threshold), in people with COVID-19 in the community who are at higher risk of complications. FUNDING: National Institute of Health Research and United Kingdom Research Innovation.


Assuntos
Budesonida/administração & dosagem , COVID-19/tratamento farmacológico , Glucocorticoides/administração & dosagem , Administração por Inalação , Idoso , Teorema de Bayes , COVID-19/mortalidade , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , SARS-CoV-2 , Resultado do Tratamento
20.
Nefrologia (Engl Ed) ; 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: covidwho-2105644

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide over the last year causing more than one million deaths. Several treatments have tried to modify the natural history of the coronavirus disease 2019 (COVID-19) but only corticosteroids have demonstrated to be effective in moderate or severe affectation. In that situation, the development of vaccines for preventing the SARS-CoV-2 infection has focused the attention of the scientific community. At present, available messenger RNA-based technology vaccines have received the approval of local and international sanitary authorities. In this position statement, the Spanish Society of Nephrology wants to state that patients with chronic kidney disease and healthcare workers are at high-risk for contagion and complications of COVID-19 so they must have priority in the vaccine administration.

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