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188 lines
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<title>29 March, 2023</title>
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<title>Covid-19 Sentry</title><meta content="width=device-width, initial-scale=1.0" name="viewport"/><link href="styles/simple.css" rel="stylesheet"/><link href="../styles/simple.css" rel="stylesheet"/><link href="https://unpkg.com/aos@2.3.1/dist/aos.css" rel="stylesheet"/><script src="https://unpkg.com/aos@2.3.1/dist/aos.js"></script></head>
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<h1 data-aos="fade-down" id="covid-19-sentry">Covid-19 Sentry</h1>
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<h1 data-aos="fade-right" data-aos-anchor-placement="top-bottom" id="contents">Contents</h1>
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<li><a href="#from-preprints">From Preprints</a></li>
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<li><a href="#from-clinical-trials">From Clinical Trials</a></li>
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<li><a href="#from-pubmed">From PubMed</a></li>
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<li><a href="#from-patent-search">From Patent Search</a></li>
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</ul>
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<h1 data-aos="fade-right" id="from-preprints">From Preprints</h1>
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<li><strong>Massively Parallel Profiling of RNA-targeting CRISPR-Cas13d</strong> -
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<div>
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Type VI CRISPR enzymes cleave target RNAs and are widely used for gene regulation, RNA tracking, and diagnostics. However, a systematic understanding of their RNA binding specificity and cleavage activation is lacking. Here, we describe RNA chip-hybridized association-mapping platform (RNA-CHAMP), a massively parallel platform that repurposes next-generation DNA sequencing chips to measure the binding affinity for over 10,000 RNA targets containing structural perturbations, mismatches, insertions, and deletions relative to the CRISPR RNA (crRNA). Deep profiling of Cas13d, a compact and widely used RNA nuclease, reveals that it does not require a protospacer flanking sequence (PFS) but is exquisitely sensitive to secondary structure within the target RNA. Cas13d binding is strongly penalized by mismatches, insertions, and deletions in the distal crRNA-target RNA regions, while alterations in the proximal region inhibit nuclease activity without affecting binding. A biophysical model built from these data reveals that target recognition begins at the distal end of unstructured target RNAs and proceeds to the proximal end. Using this model, we designed a series of partially mismatched guide RNAs that modulate nuclease activity to detect single nucleotide polymorphisms (SNPs) in circulating SARS-CoV-2 variants. This work describes the key determinants of RNA targeting by a type VI CRISPR enzyme to improve CRISPR diagnostics and in vivo RNA editing. More broadly, RNA-CHAMP provides a quantitative platform for systematically measuring protein-RNA interactions.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.03.27.534188v1" target="_blank">Massively Parallel Profiling of RNA-targeting CRISPR-Cas13d</a>
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<li><strong>Real time analysis of SARS-CoV-2 induced cytolysis reveals distinct variant-specific replication profiles</strong> -
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The continuous evolution of new SARS-CoV-2 variants with enhanced immune evasion capacity suggests the entire population is and will continue to be potentially vulnerable to infection despite pre-existing immunity. The ability of each new variant to evade host humoral immunity is the focus of intense research across the globe. Each variant may also harbor unique replication capabilities relevant for disease and transmission. Here we demonstrate the utility of a new approach to assessing viral replication kinetics using Real Time Cell Analysis (RTCA). Virus induced cell death is measured in real time by the detection of electrical impedance through cell monolayers. Using this system, we quantified replication kinetics of five clinically important viral variants; USA WA1/2020 (an A1 ancestral lineage isolate), Delta, and Omicron subvariants BA.1, BA.4, and BA.5. We identified multiple kinetic measures that proved useful in variant replication comparisons including time (in hours) to the maximum rate of cell death at each log10 viral dilution and the slope at the maximum rate of cell death. We found that WA1/2020 and Delta were the most rapid but in distinct ways. While WA1/2020 induced cell death most rapidly after inoculation, Delta was slightly slower to reach cell death, it appeared to kill cells faster once cytotoxic effects began. Interestingly, BA.1, showed substantially reduced replication kinetics relative to all other variants. Together, these data show that real time analysis of cell death is a robust method to assess replicative capacity of any given SARS-CoV-2 variant rapidly and quantitatively, which may be useful in assessment of newly emerging variants.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.03.28.534588v1" target="_blank">Real time analysis of SARS-CoV-2 induced cytolysis reveals distinct variant-specific replication profiles</a>
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</div></li>
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<li><strong>Recognition and Cleavage of Human tRNA Methyltransferase TRMT1 by the SARS-CoV-2 Main Protease</strong> -
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The SARS-CoV-2 main protease (Mpro) plays a crucial role in the production of functional viral proteins during infection and, like many viral proteases, can also target and cleave host proteins to subvert their cellular functions. Here, we show that the human tRNA methyltransferase TRMT1 can be recognized and cleaved by SARS-CoV-2 Mpro. TRMT1 installs the N2,N2-dimethylguanosine (m2,2G) modification at the G26 position of mammalian tRNA, which promotes global protein synthesis, cellular redox homeostasis, and has links to neurological disability. We find that Mpro can cleave endogenous TRMT1 in human cell lysate, resulting in removal of the TRMT1 zinc finger domain that is required for tRNA modification activity in cells. Evolutionary analysis shows that the TRMT1 cleavage site is highly conserved in mammals, except in Muroidea, where TRMT1 may be resistant to cleavage. In primates, regions outside of the cleavage site with rapid evolution could indicate possible adaptation to ancient viral pathogens. To visualize how Mpro recognizes the TRMT1 cleavage sequence, we determined the structure of a TRMT1 peptide in complex with Mpro, which reveals a substrate binding conformation distinct from the majority of available SARS-CoV-2 Mpro-peptide complexes. Kinetic parameters for peptide cleavage showed that while TRMT1(526-536) is cleaved much slower than the Mpro nsp4/5 autoprocessing sequence, it is proteolyzed with comparable efficiency to the Mpro-targeted nsp8/9 viral cleavage site. Mutagenesis studies and molecular dynamics simulations together indicate that kinetic discrimination occurs during a later step of Mpro-mediated proteolysis that follows substrate binding. Our results provide new information about the structural basis for Mpro substrate recognition and cleavage that could help inform future therapeutic design and raise the possibility that proteolysis of human TRMT1 during SARS-CoV-2 infection may impact protein translation or oxidative stress response and contribute to viral pathogenesis.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.02.20.529306v2" target="_blank">Recognition and Cleavage of Human tRNA Methyltransferase TRMT1 by the SARS-CoV-2 Main Protease</a>
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<li><strong>Clinical outcomes after extended 12-month antiretroviral therapy prescriptions in a community-based differentiated HIV service delivery programme in South Africa: a retrospective cohort study</strong> -
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Introduction There is an urgent need for more efficient models of differentiated antiretroviral therapy (ART) delivery for people living with HIV (PLHIV), with the World Health Organization calling for evidence to guide whether annual ART prescriptions and consultations (12M scripts) should be recommended in global guidelines. We assessed the association between 12M scripts (allowed temporarily during the COVID-19 pandemic) versus standard 6-month prescriptions and clinical review (6M scripts) and clinical outcomes. Methods We performed a retrospective cohort study using routine, de-identified data from 59 public clinics in KwaZulu-Natal, South Africa. We included PLHIV aged >18 years with a recent suppressed viral load (VL) who had been referred for community ART delivery with 6M or 12M scripts. We used modified Poisson regression to compare 12-month retention-in-care (not >90 days late for any visit) and viral suppression (<50 copies/mL) between prescription groups. Results Among 27,148 PLHIV referred for community ART between Jun-Dec 2020, 42.6% received 6M scripts and 57.4% 12M scripts. The median age was 39 years (interquartile range [IQR] 33-46) and 69.4% were women. Age, gender, prior community ART use and time on ART were similar in the two groups. However, more of the 12M script group had a dolutegravir-based regimen (60.0% versus 46.3%). The median (IQR) number of clinic visits in the 12 months of follow-up was 1(1-1) in the 12M group and 2(2-3) in the 6M group. Retention at 12 months was 94.6% (95% confidence interval [CI] 94.2%-94.9%) among those receiving 12M scripts and 91.8% (95% CI 91.3%-92.3%) among those with 6M scripts. 17.1% and 16.9% of clients in the 12M and 6M groups were missing follow-up VL data, respectively. Among those with VLs, 91.0% (95% CI 90.5%-91.5%) in the 12M group and 89.7% (95% CI 89.0%-90.3%) in the 6M group were suppressed. After adjusting for age, gender, ART regimen, time on ART, prior community ART use and calendar month, retention (adjusted risk ratio [aRR]: 1.03, 95% CI 1.01-1.05) and suppression (aRR: 1.01, 95% CI 1.00-1.02) were similar in the prescription groups. Conclusions Wider use of 12M scripts could reduce clinic visits without impacting short-term clinical outcomes.
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</p>
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.03.24.23287654v1" target="_blank">Clinical outcomes after extended 12-month antiretroviral therapy prescriptions in a community-based differentiated HIV service delivery programme in South Africa: a retrospective cohort study</a>
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<li><strong>Complementary, Alternative, and Integrative Medicine-Specific COVID-19 Misinformation on Social Media: A Scoping Review</strong> -
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Background: The sharing of health-related information has become increasingly popular on social media. Unregulated information sharing has led to the spread of misinformation, especially regarding complementary, alternative, and integrative medicine (CAIM). This scoping review synthesized evidence surrounding the spread of CAIM-related misinformation on social media during the COVID-19 pandemic. Methods: This review was informed by a modified version of the Arksey and O’Malley scoping review framework. AMED, EMBASE, PsycINFO and MEDLINE databases were searched systematically from inception to January 2022. Eligible articles explored COVID-19 misinformation on social media and contained sufficient information on CAIM therapies. Common themes were identified using an inductive thematic analysis approach. Results: Twenty-eight articles were included. The following themes were synthesized: 1) misinformation prompts unsafe and harmful behaviours, 2) misinformation can be separated into different categories, 3) individuals are capable of identifying and refuting CAIM misinformation, 4) non-representative study samples have resulted in considerable generalizability issues, and 5) studies argue governments and social media companies have a responsibility to resolve the spread of COVID-19 misinformation. Conclusions: Misinformation can spread more easily when shared on social media. Our review suggests that misinformation about COVID-19 related to CAIM that is disseminated online contributes to unsafe health behaviours, however, this may be remedied via public education initiatives and stricter media guidelines. The results of this scoping review are crucial to understanding the behavioural impacts of the spread of COVID-19 misinformation about CAIM therapies, and can inform the development of public health policies to mitigate these issues.
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🖺 Full Text HTML: <a href="https://osf.io/d2mkr/" target="_blank">Complementary, Alternative, and Integrative Medicine-Specific COVID-19 Misinformation on Social Media: A Scoping Review</a>
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<li><strong>An App-Based Ecological Momentary Assessment of Undergraduate Mental Health During the COVID-19 pandemic in Canada (Smart Healthy Campus Version 2.0): Longitudinal Study</strong> -
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This paper presents results from the Smart Healthy Campus 2.0 study/smartphone app, developed and used to collect mental health-related lifestyle data from 86 Canadian undergraduates January – August 2021. This was a longitudinal repeat measures study conducted over 40 weeks. A 9-item mental health questionnaire was accessible once daily in the app. Two variants of this mental health questionnaire existed; the first was a weekly variant, available each Monday or until a participant responded during the week. The second was a daily variant available after the weekly variant. Mixed models were fit for responses to the two variants and 12 phone digital measures (e.g. GPS, step counts). A second round of models was fit based on backward elimination to determine associations between the 12 digital measures and the variants. 6518 digital measure samples and 1722 questionnaire responses were collected. The daily questionnaire had positive associations with floors walked, installed apps, and campus proximity, while having negative associations with uptime, and daily calendar events. Daily depression had a positive association with uptime. Daily resilience appeared to have a slight positive association with campus proximity. The weekly questionnaire variant had positive associations with device idling and installed apps, and negative associations with floors walked, calendar events, and campus proximity. Physical activity, weekly, had a negative association with uptime, and a positive association with calendar events and device idling. SHC 2.0, via phone digital measures, identified indicators of lifestyle that appeared to be associated with measures of mental health in undergraduates during COVID-19.
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<div class="article-link article-html-link">
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.03.22.23287598v1" target="_blank">An App-Based Ecological Momentary Assessment of Undergraduate Mental Health During the COVID-19 pandemic in Canada (Smart Healthy Campus Version 2.0): Longitudinal Study</a>
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</div></li>
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<li><strong>Protection against symptomatic SARS-CoV-2 BA.5 infection conferred by the Pfizer-BioNTech Original/BA.4-5 bivalent vaccine compared to the mRNA Original (ancestral) monovalent vaccines - a matched cohort study in France</strong> -
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This cohort study aimed to evaluate the protection against symptomatic SARS-CoV-2 infection conferred by the Pfizer-BioNTech Original/BA.4-5 bivalent vaccine compared to mRNA Original (ancestral) monovalent vaccines. Individuals of ≥60 years old who received a booster dose between 03/10/2022 and 06/11/2022, when both the bivalent and monovalent vaccines were used in France, were included. Individuals who received a booster dose with (1) a monovalent Original mRNA vaccine (Pfizer- BioNTech or Moderna) or (2) the bivalent Pfizer-BioNTech Original/BA.4-5 vaccine were matched. The outcome of interest was a positive SARS-CoV-2 RT-PCR or antigenic test associated to self-reported symptoms, at least seven days after receiving the booster dose. Data were analysed with a Cox Proportional-Hazards model adjusted for the presence of previous infection, age, sex, and the presence of medium risk comorbidities. A total of 136,852 individuals were included and followed for a median period of 77 days. The bivalent vaccine conferred an additional protection of 8% [95% CI: 0% - 16%, p=0.045] against symptomatic SARS-CoV-2 infection compared to the monovalent vaccines.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.03.17.23287411v2" target="_blank">Protection against symptomatic SARS-CoV-2 BA.5 infection conferred by the Pfizer-BioNTech Original/BA.4-5 bivalent vaccine compared to the mRNA Original (ancestral) monovalent vaccines - a matched cohort study in France</a>
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<li><strong>Novel Findings in Travel-related Thrombosis and COVID-19 Related Cardiovascular Data: Data Mining Method for Previously Published Data</strong> -
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Image analysis software is used in the review process to detect research misconduct (<i>1</i>), but not for positive motives (e.g., for missing findings). Also, scientists analyze ″raw images″ (e.g., MRI), but there are no methods for published ″charts.″ So, we conceived an analysis method. We applied our idea to two cardiovascular data related to thrombosis (traveler′s or travel-related thrombosis and COVID-19) because there are still controversial discussions that might be due to some overlooked information. We found overlooked an approximately 28 days cycle of thrombosis onset over several weeks after travel in a figure (Cannegieter et al., <i>PLoS Med.</i> 2006, in the top 25% of all research scored by Altmetric) (<i>2</i>). Also, we found an eighteen-day cycle of thrombosis onset in another chart (Kelman et al., <i>BMJ.</i> 2003, in the top 5% of research) (<i>3</i>). In COVID-19, we found overlooked subgroup patterns in a scatterplot of Troponin T and NT-proBNP (Guo et al. <i>JAMA Cardiol.</i> 2020, top 5% research) (<i>4</i>), which has already appeared in the cardiomyopathy study in 2016 (Budnik et al., <i>Int J Cardiol.</i> 2016) (<i>5</i>). The above cyclic patterns suggested that travel-related oral contraceptive initiation (e.g., honeymoon and OC initiation) or hormone replacement therapy caused thrombosis. Also, the in-flight environment can likely not explain the cyclic patterns. In conclusion, women′s life-stage-related events, which are also related to travel, may be the underlying cause. In COVID-19, biomarker data should require a re-analysis. Our findings in the well-known figures suggest that our tips can be an essential review technique.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2022.06.06.22275944v2" target="_blank">Novel Findings in Travel-related Thrombosis and COVID-19 Related Cardiovascular Data: Data Mining Method for Previously Published Data</a>
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<li><strong>Prevalence and risk factors of adverse effects after the first COVID-19 booster dose: evidence from Greece</strong> -
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Background: In general, COVID-19 vaccines are safe and effective, but minor adverse effects are common. Objective: To estimate the prevalence of adverse effects after the first COVID-19 booster dose, and to identify possible risk factors. Material and methods: We conducted a cross-sectional study with a convenience sample in Greece during November 2022. We measured several adverse effects after the booster dose, such as pain at the injection site, swelling at the injection site, fatigue, muscle pain, headaches, fever, chills, nausea, etc. We considered gender, age, chronic disease, self-assessment of health status, COVID-19 diagnosis, and self-assessment of COVID-19 course as possible predictors of adverse effects. Results: In our sample, 96% developed at least one adverse effect. Half of the participants (50.2%) developed one to five adverse effects, 35.9% developed six to ten adverse effects, and 9.5% developed 11 to 16 adverse effects. Mean number of adverse effects was 5.5. The most frequent adverse effects were pain at the injection site (84.3%), fatigue (70.8%), muscle pain (61%), swelling at the injection site (55.2%), headache (49.8%), fever (42.9%), and chills (41%). Females developed more adverse effects than males (p<0.001). Also, we found a positive relationship between severity of COVID-19 symptoms and adverse effects of COVID-19 vaccines (p=0.005). Moreover, younger age was associated with increased adverse effects (p<0.001). Conclusions: Almost all participants in our study developed minor adverse effects after the booster dose. Female gender, worse clinical course of COVID-19, and decreased age were associated with increased adverse effects.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.03.27.23287816v1" target="_blank">Prevalence and risk factors of adverse effects after the first COVID-19 booster dose: evidence from Greece</a>
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<li><strong>The Long-term Effects of the COVID-19 Pandemic on U.S. Population Structure</strong> -
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The immediate, direct effects of the COVID-19 pandemic on the United States population are immense. Millions of people were affected by the pandemic: many died, others did not give birth, and still others could not migrate. Research that has examined these individual phenomena is important, but fragmented. The disruption of mortality, fertility, and migration jointly affected U.S. population counts and, consequently, future population structure. We use data from the United Nations World Population Prospects and the cohort component projection method to isolate the effect of the pandemic on U.S. population estimates until 2060. If the pandemic had not occurred, the population of the U.S. would have 2.1 million (0.63%) more people in 2025, and 1.7 million (0.44%) more people in 2060. Perhaps most striking is that pandemic-induced migration changes will likely have a larger long-term effect on future population size than mortality, despite comparable short-term effects.
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🖺 Full Text HTML: <a href="https://osf.io/preprints/socarxiv/rqn9j/" target="_blank">The Long-term Effects of the COVID-19 Pandemic on U.S. Population Structure</a>
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<li><strong>SARS-CoV-2 accessory proteins involvement in inflammatory and profibrotic processes through IL11 signaling</strong> -
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SARS-CoV-2, the cause of the COVID19 pandemic, possesses eleven accessory proteins encoded in its genome. Their roles during infection are still not completely understood. Transcriptomic analysis revealed that both WNT5A and IL11 were significantly up-regulated in A549 cells expressing individual accessory proteins ORF6, ORF8, ORF9b or ORF9c from SARS-CoV-2 (Wuhan-Hu-1 isolate). IL11 signaling-related genes were also differentially expressed. Bioinformatics analysis disclosed that both WNT5A and IL11 were involved in pulmonary fibrosis idiopathic disease. Functional assays confirmed their association with profibrotic cell responses. Subsequently, data comparison with lung cell lines infected with SARS-CoV-2 or lung biopsies from patients with COVID19 evidenced altered gene expression that matched those obtained in this study. Our results show ORF6, ORF8, ORF9b and ORF9c involvement in inflammatory and profibrotic responses. Thus, these accessory proteins could be targeted by new therapies against COVID19 disease.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.03.27.534381v1" target="_blank">SARS-CoV-2 accessory proteins involvement in inflammatory and profibrotic processes through IL11 signaling</a>
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<li><strong>Shedding light on human olfaction: electrophysiological recordings from sensory neurons in acute slices of olfactory epithelium</strong> -
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The COVID-19 pandemic brought attention to our limited understanding of human olfactory physiology. While the cellular composition of the human olfactory epithelium is similar to that of other vertebrates, its functional properties are largely unknown. We prepared acute slices of human olfactory epithelium from nasal biopsies and used the whole-cell patch-clamp technique to record electrical properties of cells. We measured voltage-gated currents in human olfactory sensory neurons and supporting cells, and action potentials in neurons. Additionally, inward currents and action potentials responses of neurons to a phosphodiesterase inhibitor indicated that the transduction cascade involves cAMP as a second messenger. Furthermore, responses to odorant mixtures demonstrated that the transduction cascade was intact in this preparation. This study provides the first electrophysiological characterization of olfactory sensory neurons in acute slices of the human olfactory epithelium, paving the way for future research to expand our knowledge of human olfactory physiology.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.03.27.534398v1" target="_blank">Shedding light on human olfaction: electrophysiological recordings from sensory neurons in acute slices of olfactory epithelium</a>
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<li><strong>A Complement Atlas identifies interleukin 6 dependent alternative pathway dysregulation as a key druggable feature of COVID-19</strong> -
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To improve COVID-19 therapy, it is essential to understand the mechanisms driving critical illness. The complement system is an essential part of innate host defense that can also contribute to injury. All complement pathways have been implicated in COVID-19 pathogenesis, however the upstream drivers and downstream consequences on tissue injury remain ill-defined. Here, we demonstrate that complement activation is mediated by the alternative pathway and we provide a comprehensive atlas of the alterations in complement around the time of respiratory deterioration. Proteome and single-cell sequencing mapping across cell types and tissues reveals a division of labor between lung epithelial, stromal and myeloid cells in the production of complement, in addition to liver-derived factors. Upstream, IL-6 drives complement responses, linking complement dysregulation to approved COVID-19 therapies. In an exploratory proteomic study, C5 inhibition improves epithelial damage and markers of disease severity. Collectively, these results identify complement dysregulation as a key druggable feature of COVID-19.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.03.25.23287712v1" target="_blank">A Complement Atlas identifies interleukin 6 dependent alternative pathway dysregulation as a key druggable feature of COVID-19</a>
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<li><strong>Sequential viral introductions and spread of BA.1 drove the Omicron wave across Pakistani provinces</strong> -
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Background: COVID-19 waves caused by specific SARS-CoV-2 variants have occurred globally at different times. We focused on Omicron variants to understand the genomic diversity and phylogenetic relatedness of SARS-CoV-2 strains in various regions of Pakistan. Methods: We studied 276,525 COVID-19 cases and 1,041 genomes sequenced from December 2021 to August 2022. Sequences were analyzed and visualized using phylogenetic trees. Results: The highest case numbers and deaths were recorded in Sindh and Punjab, the most populous provinces in Pakistan. Omicron variants comprised 95% of all genomes, with BA.2 (34.2%) and BA.5 (44.6%) predominating. The first Omicron wave was associated with the sequential identification of BA.1 in Sindh, then Islamabad Capital Territory, Punjab, Khyber Pakhtunkhwa (KP), Azad Jammu Kashmir (AJK), Gilgit-Baltistan (GB) and Balochistan. Phylogenetic analysis revealed Sindh to be the source of BA.1 and BA.2 introductions into Punjab and Balochistan during early 2022. BA.4 was first introduced in AJK and BA.5 in Punjab. Most recent common ancestor (MRCA) analysis revealed relatedness between the earliest BA.1 genome from Sindh with Balochistan, AJK, Punjab and ICT, and that of first BA.1 from Punjab with strains from KPK and GB. Conclusions: Phylogenetic analysis provides insights into the introduction and transmission dynamics of the Omicron variant in Pakistan, identifying Sindh as a hotspot for viral dissemination. Such data linked with public health efforts can help limit surges of new infections.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.03.25.23287718v1" target="_blank">Sequential viral introductions and spread of BA.1 drove the Omicron wave across Pakistani provinces</a>
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<li><strong>Facility-based and virtual cardiac rehabilitation in young patients with heart disease during the COVID-19 era</strong> -
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Background: Cardiac rehabilitation (CR) is an important tool for improving fitness and quality of life in those with heart disease (HD). Few pediatric centers use CR to care for these patients, and virtual CR is rarely used. Additionally, it is unclear how the COVID-19 era has changed CR outcomes. Objectives: This study assessed fitness improvements in young HD patients participating in both facility-based and virtual CR during the COVID-19 pandemic. Methods: This retrospective single-center cohort study included new patients who completed CR from March 2020 through July 2022. CR outcomes included physical, performance, and psychosocial measures. Comparison between serial testing was performed with a paired t-test with P<0.05 was considered significant. Data are reported as mean±standard deviation. Results: There were 47 patients (19±7.3 years-old; 49% male) who completed CR. Improvements were seen in peak oxygen consumption (VO2, 62.3±16.1 v 71±18.2% of predicted, p=0.0007), 6-minute walk (6MW) distance (401±163.8 v 480.7±119.2 meters, p=<0.0001), sit to stand (16.2±4.9 v 22.1±6.6 repetitions; p=<0.0001), Patient Health Questionnaire-9 (PHQ-9) (5.9±4.3 v 4.4± 4.2; p=0.002), and Physical Component Score (39.9±10.1 v 44.9± 8.8; p=0.002). Facility-based CR enrollees were less likely to complete CR than virtual patients (60%, 33/55 v 80%, 12/15; p=0.005). Increases in peak VO2 (60±15.3 v 70.2±17.8 % of predicted; p=0.002) were seen among those that completed facility-based CR; this was not observed in the virtual group. Both groups demonstrated improvement in 6MW distance, sit-to-stand repetitions, and sit-and-reach distance. Conclusions: Completion of a CR program resulted in fitness improvements during the COVID-19 era regardless of location.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.03.24.23287722v1" target="_blank">Facility-based and virtual cardiac rehabilitation in young patients with heart disease during the COVID-19 era</a>
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<h1 data-aos="fade-right" id="from-clinical-trials">From Clinical Trials</h1>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Clinical Performance Evaluation of the CareSuperb™ COVID-19 Antigen Home Test</strong> - <b>Condition</b>: COVID-19<br/><b>Intervention</b>: Device: CareSuperb COVID-19 Antigen Home Test Kit<br/><b>Sponsor</b>: AccessBio, Inc.<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Evaluation of Safety & Efficacy of MIR 19 ® Inhalation Solution in Patients With Mild COVID-19</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Drug: MIR 19 ®; Combination Product: Standard therapy<br/><b>Sponsor</b>: National Research Center - Institute of Immunology Federal Medical-Biological Agency of Russia<br/><b>Completed</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>LACTYFERRIN™ Forte and ZINC Defense™ and Standard of Care (SOC) vs SOC in the Treatment of Non-hospitalized Patients With COVID-19</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Drug: Sesderma LACTYFERRIN™ Forte and Sesderma ZINC Defense™; Drug: Placebo<br/><b>Sponsors</b>: Jose David Suarez, MD; Sesderma S.L.; Westchester General Hospital Inc. DBA Keralty Hospital Miami; MGM Technology Corp<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>MP0420 for Inpatients With COVID-19 (An ACTIV-3/TICO Treatment Trial)</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Drug: MP0420; Drug: Placebo; Biological: Remdesivir<br/><b>Sponsors</b>: National Institute of Allergy and Infectious Diseases (NIAID); International Network for Strategic Initiatives in Global HIV Trials (INSIGHT); University of Copenhagen; Medical Research Council; Kirby Institute; Washington D.C. Veterans Affairs Medical Center; AIDS Clinical Trials Group; National Heart, Lung, and Blood Institute (NHLBI); US Department of Veterans Affairs; Prevention and Early Treatment of Acute Lung Injury (PETAL); Cardiothoracic Surgical Trials Network (CTSN); Molecular Partners AG; University of Minnesota<br/><b>Active, not recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>AZD7442 for Inpatients With COVID-19 (An ACTIV-3/TICO Treatment Trial)</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Biological: AZD7442; Biological: Placebo; Biological: Remdesivir<br/><b>Sponsors</b>: National Institute of Allergy and Infectious Diseases (NIAID); International Network for Strategic Initiatives in Global HIV Trials (INSIGHT); University of Copenhagen; Medical Research Council; Kirby Institute; Washington D.C. Veterans Affairs Medical Center; AIDS Clinical Trials Group; National Heart, Lung, and Blood Institute (NHLBI); US Department of Veterans Affairs; Prevention and Early Treatment of Acute Lung Injury (PETAL); Cardiothoracic Surgical Trials Network (CTSN); AstraZeneca; University of Minnesota<br/><b>Active, not recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>VIR-7831 for Inpatients With COVID-19 (An ACTIV-3/TICO Treatment Trial)</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Biological: VIR-7831; Biological: Placebo; Biological: Remdesivir<br/><b>Sponsors</b>: National Institute of Allergy and Infectious Diseases (NIAID); International Network for Strategic Initiatives in Global HIV Trials (INSIGHT); University of Copenhagen; Medical Research Council; Kirby Institute; Washington D.C. Veterans Affairs Medical Center; AIDS Clinical Trials Group; National Heart, Lung, and Blood Institute (NHLBI); US Department of Veterans Affairs; Prevention and Early Treatment of Acute Lung Injury (PETAL); Cardiothoracic Surgical Trials Network (CTSN); Vir Biotechnology, Inc.; GlaxoSmithKline; University of Minnesota<br/><b>Completed</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>PF-07304814 for Inpatients With COVID-19 (An ACTIV-3/TICO Treatment Trial)</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Drug: PF-07304814; Drug: Placebo; Biological: Remdesivir<br/><b>Sponsors</b>: National Institute of Allergy and Infectious Diseases (NIAID); International Network for Strategic Initiatives in Global HIV Trials (INSIGHT); University of Copenhagen; Medical Research Council; Kirby Institute; Washington D.C. Veterans Affairs Medical Center; AIDS Clinical Trials Group; National Heart, Lung, and Blood Institute (NHLBI); US Department of Veterans Affairs; Prevention and Early Treatment of Acute Lung Injury (PETAL); Cardiothoracic Surgical Trials Network (CTSN); Pfizer; University of Minnesota<br/><b>Suspended</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>BRII-196/BRII-198 for Inpatients With COVID-19 (An ACTIV-3/TICO Treatment Trial)</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Biological: BRII-196; Biological: BRII-198; Biological: Placebo; Biological: Remdesivir<br/><b>Sponsors</b>: National Institute of Allergy and Infectious Diseases (NIAID); International Network for Strategic Initiatives in Global HIV Trials (INSIGHT); University of Copenhagen; Medical Research Council; Kirby Institute; Washington D.C. Veterans Affairs Medical Center; AIDS Clinical Trials Group; National Heart, Lung, and Blood Institute (NHLBI); US Department of Veterans Affairs; Prevention and Early Treatment of Acute Lung Injury (PETAL); Cardiothoracic Surgical Trials Network (CTSN); Brii Biosciences Limited; University of Minnesota<br/><b>Completed</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>LY3819253 (LY-CoV555) for Inpatients With COVID-19 (An ACTIV-3/TICO Treatment Trial)</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Biological: LY3819253; Biological: Placebo; Biological: Remdesivir<br/><b>Sponsors</b>: National Institute of Allergy and Infectious Diseases (NIAID); International Network for Strategic Initiatives in Global HIV Trials (INSIGHT); University of Copenhagen; Medical Research Council; Kirby Institute; Washington D.C. Veterans Affairs Medical Center; AIDS Clinical Trials Group; National Heart, Lung, and Blood Institute (NHLBI); US Department of Veterans Affairs; Prevention and Early Treatment of Acute Lung Injury (PETAL); Cardiothoracic Surgical Trials Network (CTSN); Eli Lilly and Company; University of Minnesota<br/><b>Completed</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Use of E-health Based Exercise Intervention After COVID-19</strong> - <b>Condition</b>: COVID-19<br/><b>Intervention</b>: Behavioral: Exercise training using an e-health tool<br/><b>Sponsors</b>: Norwegian University of Science and Technology; University of Oslo<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>RCT for Yinqiaosan-Maxingganshitang in the Treatment of COVID-19</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Drug: Chinese Herb; Diagnostic Test: Placebo<br/><b>Sponsor</b>: Chinese University of Hong Kong<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A Phase II Clinical Trial of Recombinant Variant COVID-19 Vaccine (Sf9 Cell) (WSK-V102)</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Biological: Recombinant variant COVID-19 vaccine (Sf9 cell); Biological: Recombinant COVID-19 vaccine (CHO cell); Biological: Recombinant COVID-19 vaccine (Sf9 cell)<br/><b>Sponsor</b>: WestVac Biopharma Co., Ltd.<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Short-term Effects of Transdermal Estradiol on Female COVID-19 Patients</strong> - <b>Conditions</b>: COVID-19; Hormone Replacement Therapy<br/><b>Interventions</b>: Drug: Climara 0.1Mg/24Hr Transdermal System; Other: Hydrogel patch<br/><b>Sponsors</b>: Istanbul University - Cerrahpasa (IUC); Turkish Menopause and Osteoporosis Society; Karakoy Rotary Club; Rebul Pharmacy<br/><b>Completed</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Effect of Kinesio Tape Versus Diaphragmatic Breathing Exercise In Post COVID-19</strong> - <b>Condition</b>: Post COVID-19 Condition<br/><b>Interventions</b>: Other: Pursed lip breathing; Other: Cognitive Behavior Therapy; Other: Diaphragmatic breathing exercise; Other: Kinesio tape<br/><b>Sponsor</b>: Cairo University<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Effect of a Health Pathway for People With Persistent Symptoms Covid-19</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Other: usual care and follow-up by a nurse; Other: Personalized Multifactorial Intervention (IMP)<br/><b>Sponsor</b>: Centre Hospitalier Universitaire de Saint Etienne<br/><b>Not yet recruiting</b></p></li>
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</ul>
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<h1 data-aos="fade-right" id="from-pubmed">From PubMed</h1>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Antiviral activity of curcumin and its analogs selected by an artificial intelligence-supported activity prediction system in SARS-CoV-2-infected VeroE6 cells</strong> - Curcumin has been reported to exert its anti-SARS-CoV-2 activity by inhibiting the binding of spike receptor-binding domain (RBD) to angiotensin-converting enzyme-2 (ACE2). To identify more potent compounds, we evaluated the antiviral activities of curcumin and its analogs in SARS-CoV-2-infected cells. An artificial intelligence-supported activity prediction system was used to select the compounds, and 116 of the 334 curcumin analogs were proposed to have spike RBD-ACE2 binding inhibitory…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Molecular modeling and simulations of some antiviral drugs, benzylisoquinoline alkaloid, and coumarin molecules to investigate the effects on Mpro main viral protease inhibition</strong> - CONCLUSION: In this study, we identify potent molecules that exhibit interactions with catalytical dyad HIS41 and CYS145 amino acids and unravel Coumarin-EM04 exhibited ΔG(bind) higher than Remdesivir against Mpro and thus may serve better antiviral agent against SARS-CoV-2.</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Chemical Profiling and Biological Properties of Essential Oils of <em>Lavandula stoechas</em> L. Collected from Three Moroccan Sites: In Vitro and In Silico Investigations</strong> - The aim of this study was the determination of the chemical compounds of Lavandula stoechas essential oil from Aknol (LSEO(A)), Khenifra (LSEO(K)), and Beni Mellal (LSEO(B)), and the in vitro investigation of their antibacterial, anticandidal, and antioxidant effects, and in silico anti-SARS-CoV-2 activity. The chemical profile of LSEO was determined using GC-MS-MS analysis, the results of which showed a qualitative and quantitative variation in the chemical composition of volatile compounds…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Recent Developments in Polyphenol Applications on Human Health: A Review with Current Knowledge</strong> - Polyphenol has been used in treatment for some health disorders due to their diverse health promoting properties. These compounds can reduce the impacts of oxidation on the human body, prevent the organs and cell structure against deterioration and protect their functional integrity. The health promoting abilities are attributed to their high bioactivity imparting them high antioxidative, antihypertensive, immunomodulatory, antimicrobial, and antiviral activity, as well as anticancer properties….</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>An Enhanced Dissolving Cyclosporin-A Inhalable Powder Efficiently Reduces SARS-CoV-2 Infection In Vitro</strong> - This work illustrates the development of a dry inhalation powder of cyclosporine-A for the prevention of rejection after lung transplantation and for the treatment of COVID-19. The influence of excipients on the spray-dried powder’s critical quality attributes was explored. The best-performing powder in terms of dissolution time and respirability was obtained starting from a concentration of ethanol of 45% (v/v) in the feedstock solution and 20% (w/w) of mannitol. This powder showed a faster…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Phenylpyrazolone-1,2,3-triazole Hybrids as Potent Antiviral Agents with Promising SARS-CoV-2 Main Protease Inhibition Potential</strong> - COVID-19 infection is now considered one of the leading causes of human death. As an attempt towards the discovery of novel medications for the COVID-19 pandemic, nineteen novel compounds containing 1,2,3-triazole side chains linked to phenylpyrazolone scaffold and terminal lipophilic aryl parts with prominent substituent functionalities were designed and synthesized via a click reaction based on our previous work. The novel compounds were assessed using an in vitro effect on the growth of…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Cardamonin as a p38 MAPK Signaling Pathway Activator Inhibits Human Coronavirus OC43 Infection in Human Lung Cells</strong> - A natural chalcone, cardamonin (2’,4’-dihydroxy-6’-methoxychalcone; CDN) was isolated from the seeds of Alpinia katsumadai Hayata, which has been traditionally used to treat stomach aches. CDN has been reported to possess various pharmacological properties, including anticancer and anti-inflammatory effects. This study evaluated the antiviral activity of CDN against human coronavirus HCoV-OC43 and determined the mode of action in HCoV-OC43-infected human lung cell lines (MRC-5 and A549 cells)….</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A Comprehensive Review of Natural Flavonoids with Anti-SARS-CoV-2 Activity</strong> - The COVID-19 pandemic caused by SARS-CoV-2 has majorly impacted public health and economies worldwide. Although several effective vaccines and drugs are now used to prevent and treat COVID-19, natural products, especially flavonoids, showed great therapeutic potential early in the pandemic and thus attracted particular attention. Quercetin, baicalein, baicalin, EGCG (epigallocatechin gallate), and luteolin are among the most studied flavonoids in this field. Flavonoids can directly or indirectly…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Unveiling the Inhibitory Potentials of Peptidomimetic Azanitriles and Pyridyl Esters towards SARS-CoV-2 Main Protease: A Molecular Modelling Investigation</strong> - The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for COVID-19, which was declared a global pandemic in March 2020 by the World Health Organization (WHO). Since SARS-CoV-2 main protease plays an essential role in the virus’s life cycle, the design of small drug molecules with lower molecular weight has been a promising development targeting its inhibition. Herein, we evaluated the novel peptidomimetic azatripeptide and azatetrapeptide nitriles against SARS-CoV-2…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Identification of a Synthetic Polyhydroxyphenolic Resveratrol Analogue, 3,3’,4,4’,5,5’-Hexahydroxy-<em>trans</em>-Stilbene with Anti-SARS-CoV-2 Activity</strong> - The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus has been causing the COVID-19 pandemic since December 2019, with over 600 million infected persons worldwide and over six million deaths. We investigated the anti-viral effects of polyphenolic green tea ingredients and the synthetic resveratrol analogue 3,3’,4,4’,5,5’-hexahydroxy-trans-stilbene (HHS), a compound with antioxidant, antitumor and anti-HIV properties. In the TCID(50) assay, four out of nine green tea constituents…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Identification of Z-Tyr-Ala-CHN<sub>2</sub>, a Cathepsin L Inhibitor with Broad-Spectrum Cell-Specific Activity against Coronaviruses, including SARS-CoV-2</strong> - The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is partly under control by vaccination. However, highly potent and safe antiviral drugs for SARS-CoV-2 are still needed to avoid development of severe COVID-19. We report the discovery of a small molecule, Z-Tyr-Ala-CHN(2), which was identified in a cell-based antiviral screen. The molecule exerts sub-micromolar antiviral activity against SARS-CoV-2, SARS-CoV-1, and human coronavirus 229E….</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Green Tea Consumption and the COVID-19 Omicron Pandemic Era: Pharmacology and Epidemiology</strong> - In spite of the development of numerous vaccines for the prevention of COVID-19 and the approval of several drugs for its treatment, there is still a great need for effective and inexpensive therapies against this disease. Previously, we showed that green tea and tea catechins interfere with coronavirus replication as well as coronavirus 3CL protease activity, and also showed lower COVID-19 morbidity and mortality in countries with higher green tea consumption. However, it is not clear whether…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>The Role of Folic Acid in SARS-CoV-2 Infection: An Intriguing Linkage under Investigation</strong> - CONCLUSIONS: Future randomized controlled trial studies, including the FA pharmacological group, are needed to better understand the role of FA as a potential protective or mortality risk indicator in COVID-19 patients.</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Prediction and Verification of Curcumin as a Potential Drug for Inhibition of PDCoV Replication in LLC-PK1 Cells</strong> - Porcine deltacoronavirus (PDCoV) is an emerging swine enteropathogenic coronavirus (CoV) that causes lethal watery diarrhea in neonatal pigs and poses economic and public health burdens. Currently, there are no effective antiviral agents against PDCoV. Curcumin is the active ingredient extracted from the rhizome of turmeric, which has a potential pharmacological value because it exhibits antiviral properties against several viruses. Here, we described the antiviral effect of curcumin against…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Direct Application of 3-Maleimido-PROXYL for Proving Hypoalbuminemia in Cases of SARS-CoV-2 Infection: The Potential Diagnostic Method of Determining Albumin Instability and Oxidized Protein Level in Severe COVID-19</strong> - Oxidative stress and the albumin oxidized form can lead to hypoalbuminemia, which is a predisposing factor for reduced treatment effectiveness and an increased mortality rate in severe COVID-19 patients. The aim of the study is to evaluate the application of free radical 3-Maleimido-PROXYL and SDSL-EPR spectroscopy in the in vitro determination of ox/red HSA in serum samples from patients with SARS-CoV-2 infection. Venous blood was collected from patients intubated (pO(2) < 90%) with a positive…</p></li>
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</ul>
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<h1 data-aos="fade-right" id="from-patent-search">From Patent Search</h1>
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