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1.
J Clin Invest ; 132(12)2022 Jun 15.
Article in English | MEDLINE | ID: covidwho-2053515

ABSTRACT

BACKGROUNDNeutralizing antibodies are considered a key correlate of protection by current SARS-CoV-2 vaccines. The manner in which human infections respond to therapeutic SARS-CoV-2 antibodies, including convalescent plasma therapy, remains to be fully elucidated.METHODSWe conducted a proof-of-principle study of convalescent plasma therapy based on a phase I trial in 30 hospitalized COVID-19 patients with a median interval between onset of symptoms and first transfusion of 9 days (IQR, 7-11.8 days). Comprehensive longitudinal monitoring of the virological, serological, and disease status of recipients allowed deciphering of parameters on which plasma therapy efficacy depends.RESULTSIn this trial, convalescent plasma therapy was safe as evidenced by the absence of transfusion-related adverse events and low mortality (3.3%). Treatment with highly neutralizing plasma was significantly associated with faster virus clearance, as demonstrated by Kaplan-Meier analysis (P = 0.034) and confirmed in a parametric survival model including viral load and comorbidity (adjusted hazard ratio, 3.0; 95% CI, 1.1-8.1; P = 0.026). The onset of endogenous neutralization affected viral clearance, but even after adjustment for their pretransfusion endogenous neutralization status, recipients benefitted from plasma therapy with high neutralizing antibodies (hazard ratio, 3.5; 95% CI, 1.1-11; P = 0.034).CONCLUSIONOur data demonstrate a clear impact of exogenous antibody therapy on the rapid clearance of viremia before and after onset of the endogenous neutralizing response, and point beyond antibody-based interventions to critical laboratory parameters for improved evaluation of current and future SARS-CoV-2 therapies.TRIAL REGISTRATIONClinicalTrials.gov NCT04869072.FUNDINGThis study was funded via an Innovation Pool project by the University Hospital Zurich; the Swiss Red Cross Glückskette Corona Funding; Pandemiefonds of the UZH Foundation; and the Clinical Research Priority Program "Comprehensive Genomic Pathogen Detection" of the University of Zurich.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , Antibody Formation , COVID-19/therapy , COVID-19 Vaccines , Humans , Immunization, Passive/adverse effects , Proof of Concept Study
2.
Int J Environ Res Public Health ; 19(16)2022 08 21.
Article in English | MEDLINE | ID: covidwho-2023677

ABSTRACT

The aim of this study was to assess the acceptability and feasibility of offering risk-based breast cancer screening and its integration into regular clinical practice. A single-arm proof-of-concept trial was conducted with a sample of 387 women aged 40-50 years residing in the city of Lleida (Spain). The study intervention consisted of breast cancer risk estimation, risk communication and screening recommendations, and a follow-up. A polygenic risk score with 83 single nucleotide polymorphisms was used to update the Breast Cancer Surveillance Consortium risk model and estimate the 5-year absolute risk of breast cancer. The women expressed a positive attitude towards varying the frequency of breast screening according to individual risk and, especially, more frequently inviting women at higher-than-average risk. A lower intensity screening for women at lower risk was not as welcome, although half of the participants would accept it. Knowledge of the benefits and harms of breast screening was low, especially with regard to false positives and overdiagnosis. The women expressed a high understanding of individual risk and screening recommendations. The participants' intention to participate in risk-based screening and satisfaction at 1-year were very high.


Subject(s)
Breast Neoplasms , Early Detection of Cancer , Breast Neoplasms/diagnosis , Breast Neoplasms/genetics , Feasibility Studies , Female , Humans , Mammography , Mass Screening , Proof of Concept Study
3.
Int J Infect Dis ; 123: 97-103, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-1983206

ABSTRACT

OBJECTIVES: Severe COVID-19 is associated with immune dysregulation and hyperinflammation (lymphocyte exhaustion and elevated interleukin 6. Pembrolizumab (P; immune-activating anti-programmed cell death-1 antibody) plus tocilizumab (TCZ; anti- interleukin 6 receptor antibody) might interrupt the hyperinflammation and restore cellular immunocompetence. We assessed the efficacy and safety of P + TCZ + standard of care (SOC) in high-risk, hospitalized patients with COVID-19 pneumonia without mechanical ventilation. METHODS: Randomized, controlled, open-label, phase II trial in patients with severe SARS-CoV-2 infection to assess the hospitalization period to discharge. RESULTS: A total of 12 patients were randomized (P + TCZ + SOC, n = 7; SOC, n = 5). Nine (75%) were males, with a median age of 68 (41-79) years. The median time to discharge for P + TCZ + SOC and SOC was 10 and 47.5 days (P = 0.03), with zero (n = 1 patient had P-related grade 5 myositis) and two COVID-19-related deaths, respectively. CONCLUSION: The addition of P and TCZ to SOC reduced the hospitalization period, with higher and faster discharges without sequelae than SOC alone.


Subject(s)
COVID-19 , Aged , Antibodies, Monoclonal, Humanized , COVID-19/drug therapy , Female , Humans , Interleukin-6 , Male , Proof of Concept Study , Receptors, Interleukin-6 , SARS-CoV-2 , Treatment Outcome
4.
Front Public Health ; 10: 852083, 2022.
Article in English | MEDLINE | ID: covidwho-1834649

ABSTRACT

Polymerase chain reaction (PCR) remains the gold standard in disease diagnostics due to its extreme sensitivity and specificity. However, PCR tests are expensive and complex, require skilled personnel and specialized equipment to conduct the tests, and have long turnaround times. On the other hand, lateral flow immunoassay-based antigen tests are rapid, relatively inexpensive, and can be performed by untrained personnel at the point of care or even in the home. However, rapid antigen tests are less sensitive than PCR since they lack the inherent target amplification of PCR. It has been argued that rapid antigen tests are better indicators of infection in public health decision-making processes to test, trace, and isolate infected people to curtail further transmission. Hence, there is a critical need to increase the sensitivity of rapid antigen tests and create innovative solutions to achieve that goal. Herein, we report the development of a low-cost diagnostic platform, enabling rapid detection of SARS-CoV-2 under field or at-home conditions. This platform (Halo™) is a small, highly accurate, consumer-friendly diagnostic reader paired with fluorescently labeled lateral flow assays and custom software for collection and reporting of results. The focus of this study is to compare the analytical performance of HaloTM against comparable tests that use either colloidal gold nanoparticles or fluorescence-based reporters in simulated nasal matrix and not in clinical samples. Live virus data has demonstrated limit of detection performance of 1.9 TCID50/test in simulated nasal matrix for the delta variant, suggesting that single-assay detection of asymptomatic SARS-CoV-2 infections may be feasible. Performance of the system against all tested SARS CoV-2 virus variants showed comparable sensitivities indicating mutations in SARS-CoV-2 variants do not negatively impact the assay.


Subject(s)
COVID-19 , Metal Nanoparticles , COVID-19/diagnosis , Gold , Humans , Proof of Concept Study , SARS-CoV-2
6.
Sci Rep ; 12(1): 2356, 2022 02 18.
Article in English | MEDLINE | ID: covidwho-1706307

ABSTRACT

Effective testing is essential to control the coronavirus disease 2019 (COVID-19) transmission. Here we report a-proof-of-concept study on hyperspectral image analysis in the visible and near-infrared range for primary screening at the point-of-care of SARS-CoV-2. We apply spectral feature descriptors, partial least square-discriminant analysis, and artificial intelligence to extract information from optical diffuse reflectance measurements from 5 µL fluid samples at pixel, droplet, and patient levels. We discern preparations of engineered lentiviral particles pseudotyped with the spike protein of the SARS-CoV-2 from those with the G protein of the vesicular stomatitis virus in saline solution and artificial saliva. We report a quantitative analysis of 72 samples of nasopharyngeal exudate in a range of SARS-CoV-2 viral loads, and a descriptive study of another 32 fresh human saliva samples. Sensitivity for classification of exudates was 100% with peak specificity of 87.5% for discernment from PCR-negative but symptomatic cases. Proposed technology is reagent-free, fast, and scalable, and could substantially reduce the number of molecular tests currently required for COVID-19 mass screening strategies even in resource-limited settings.


Subject(s)
Exudates and Transudates/virology , Mass Screening/methods , SARS-CoV-2/isolation & purification , Saliva/virology , Spectroscopy, Near-Infrared , Humans , Point-of-Care Testing , Proof of Concept Study
7.
ACS Appl Mater Interfaces ; 14(8): 10844-10855, 2022 Mar 02.
Article in English | MEDLINE | ID: covidwho-1692677

ABSTRACT

The widespread and long-lasting effect of the COVID-19 pandemic has called attention to the significance of technological advances in the rapid diagnosis of SARS-CoV-2 virus. This study reports the use of a highly stable buffer-based zinc oxide/reduced graphene oxide (bbZnO/rGO) nanocomposite coated on carbon screen-printed electrodes for electrochemical immuno-biosensing of SARS-CoV-2 nuelocapsid (N-) protein antigens in spiked and clinical samples. The incorporation of a salt-based (ionic) matrix for uniform dispersion of the nanomixture eliminates multistep nanomaterial synthesis on the surface of the electrode and enables a stable single-step sensor nanocoating. The immuno-biosensor provides a limit of detection of 21 fg/mL over a linear range of 1-10 000 pg/mL and exhibits a sensitivity of 32.07 ohms·mL/pg·mm2 for detection of N-protein in spiked samples. The N-protein biosensor is successful in discriminating positive and negative clinical samples within 15 min, demonstrating its proof of concept used as a COVID-19 rapid antigen test.


Subject(s)
Antigens, Viral/analysis , COVID-19/diagnosis , Coronavirus Nucleocapsid Proteins/analysis , Graphite/chemistry , Nanocomposites/chemistry , Zinc Oxide/chemistry , Antibodies, Immobilized/immunology , Antigens, Viral/immunology , Biosensing Techniques/instrumentation , Biosensing Techniques/methods , Coronavirus Nucleocapsid Proteins/immunology , Electrochemical Techniques/instrumentation , Electrochemical Techniques/methods , Electrodes , Humans , Immunoassay/instrumentation , Immunoassay/methods , Limit of Detection , Phosphoproteins/analysis , Phosphoproteins/immunology , Proof of Concept Study , SARS-CoV-2/chemistry
8.
J Bras Pneumol ; 48(1): e20210349, 2022.
Article in English, Portuguese | MEDLINE | ID: covidwho-1687896

ABSTRACT

OBJECTIVE: To assess the feasibility of using a new helmet interface for CPAP, designated ELMO, to treat COVID-19-related acute hypoxemic respiratory failure (AHRF) outside the ICU. METHODS: This was a proof-of-concept study involving patients with moderate to severe AHRF secondary to COVID-19 admitted to the general ward of a public hospital. The intervention consisted of applying CPAP via the ELMO interface integrated with oxygen and compressed air flow meters (30 L/min each) and a PEEP valve (CPAP levels = 8-10 cmH2O), forming the ELMOcpap system. The patients were monitored for cardiorespiratory parameters, adverse events, and comfort. RESULTS: Ten patients completed the study protocol. The ELMOcpap system was well tolerated, with no relevant adverse effects. Its use was feasible outside the ICU for a prolonged amount of time and was shown to be successful in 60% of the patients. A CPAP of 10 cmH2O with a total gas flow of 56-60 L/min improved oxygenation after 30-to 60-min ELMOcpap sessions, allowing a significant decrease in estimated FIO2 (p = 0.014) and an increase in estimated PaO2/FIO2 ratio (p = 0.008) within the first hour without CO2 rebreathing. CONCLUSIONS: The use of ELMOcpap has proven to be feasible and effective in delivering high-flow CPAP to patients with COVID-19-related AHRF outside the ICU. There were no major adverse effects, and ELMO was considered comfortable. ELMOcpap sessions significantly improved oxygenation, reducing FIO2 without CO2 rebreathing. The overall success rate was 60% in this pilot study, and further clinical trials should be carried out in the future.(ClinicalTrials.gov identifier: NCT04470258 [http://www.clinicaltrials.gov/]).


Subject(s)
COVID-19 , Respiratory Insufficiency , Feasibility Studies , Humans , Intensive Care Units , Pilot Projects , Proof of Concept Study , Respiratory Insufficiency/therapy , SARS-CoV-2
9.
Sci Rep ; 11(1): 24507, 2021 12 30.
Article in English | MEDLINE | ID: covidwho-1597358

ABSTRACT

Diagnostic tests that detect antibodies (AB) against SARS-CoV-2 for evaluation of seroprevalence and guidance of health care measures are important tools for managing the COVID-19 pandemic. Current tests have certain limitations with regard to turnaround time, costs and availability, particularly in point-of-care (POC) settings. We established a hemagglutination-based AB test that is based on bi-specific proteins which contain a dromedary-derived antibody (nanobody) binding red blood cells (RBD) and a SARS-CoV-2-derived antigen, such as the receptor-binding domain of the Spike protein (Spike-RBD). While the nanobody mediates swift binding to RBC, the antigen moiety directs instantaneous, visually apparent hemagglutination in the presence of SARS-CoV-2-specific AB generated in COVID-19 patients or vaccinated individuals. Method comparison studies with assays cleared by emergency use authorization demonstrate high specificity and sensitivity. To further increase objectivity of test interpretation, we developed an image analysis tool based on digital image acquisition (via a cell phone) and a machine learning algorithm based on defined sample-training and -validation datasets. Preliminary data, including a small clinical study, provides proof of principle for test performance in a POC setting. Together, the data support the interpretation that this AB test format, which we refer to as 'NanoSpot.ai', is suitable for POC testing, can be manufactured at very low costs and, based on its generic mode of action, can likely be adapted to a variety of other pathogens.


Subject(s)
Antibodies, Viral/blood , COVID-19 Serological Testing/methods , Diagnostic Tests, Routine/methods , Hemagglutination Tests/methods , Point-of-Care Testing , Spike Glycoprotein, Coronavirus/immunology , Humans , Proof of Concept Study
10.
PLoS One ; 16(11): e0260247, 2021.
Article in English | MEDLINE | ID: covidwho-1542186

ABSTRACT

BACKGROUND: Countries are increasingly defining health benefits packages (HBPs) as a way of progressing towards Universal Health Coverage (UHC). Resources for health are commonly constrained, so it is imperative to allocate funds as efficiently as possible. We conducted allocative efficiency analyses using the Health Interventions Prioritization tool (HIPtool) to estimate the cost and impact of potential HBPs in three countries. These analyses explore the usefulness of allocative efficiency analysis and HIPtool in particular, in contributing to priority setting discussions. METHODS AND FINDINGS: HIPtool is an open-access and open-source allocative efficiency modelling tool. It is preloaded with publicly available data, including data on the 218 cost-effective interventions comprising the Essential UHC package identified in the 3rd Edition of Disease Control Priorities, and global burden of disease data from the Institute for Health Metrics and Evaluation. For these analyses, the data were adapted to the health systems of Armenia, Côte d'Ivoire and Zimbabwe. Local data replaced global data where possible. Optimized resource allocations were then estimated using the optimization algorithm. In Armenia, optimized spending on UHC interventions could avert 26% more disability-adjusted life years (DALYs), but even highly cost-effective interventions are not funded without an increase in the current health budget. In Côte d'Ivoire, surgical interventions, maternal and child health and health promotion interventions are scaled up under optimized spending with an estimated 22% increase in DALYs averted-mostly at the primary care level. In Zimbabwe, the estimated gain was even higher at 49% of additional DALYs averted through optimized spending. CONCLUSIONS: HIPtool applications can assist discussions around spending prioritization, HBP design and primary health care transformation. The analyses provided actionable policy recommendations regarding spending allocations across specific delivery platforms, disease programs and interventions. Resource constraints exacerbated by the COVID-19 pandemic increase the need for formal planning of resource allocation to maximize health benefits.


Subject(s)
Clinical Decision-Making , Proof of Concept Study , Resource Allocation , Universal Health Insurance , Armenia , Humans , Public Policy , Zimbabwe
11.
Adv Mater ; 34(3): e2104608, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1499211

ABSTRACT

Solid-state transistor sensors that can detect biomolecules in real time are highly attractive for emerging bioanalytical applications. However, combining upscalable manufacturing with the required performance remains challenging. Here, an alternative biosensor transistor concept is developed, which relies on a solution-processed In2 O3 /ZnO semiconducting heterojunction featuring a geometrically engineered tri-channel architecture for the rapid, real-time detection of important biomolecules. The sensor combines a high electron mobility channel, attributed to the electronic properties of the In2 O3 /ZnO heterointerface, in close proximity to a sensing surface featuring tethered analyte receptors. The unusual tri-channel design enables strong coupling between the buried electron channel and electrostatic perturbations occurring during receptor-analyte interactions allowing for robust, real-time detection of biomolecules down to attomolar (am) concentrations. The experimental findings are corroborated by extensive device simulations, highlighting the unique advantages of the heterojunction tri-channel design. By functionalizing the surface of the geometrically engineered channel with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody receptors, real-time detection of the SARS-CoV-2 spike S1 protein down to am concentrations is demonstrated in under 2 min in physiological relevant conditions.


Subject(s)
Biosensing Techniques/instrumentation , COVID-19/virology , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/analysis , Transistors, Electronic , Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Immobilized , Antibodies, Viral , Bioengineering , COVID-19/blood , COVID-19/diagnosis , COVID-19 Testing/instrumentation , COVID-19 Testing/methods , Computer Simulation , Computer Systems , DNA/analysis , Equipment Design , Humans , Indium , Microtechnology , Proof of Concept Study , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Zinc Oxide
13.
Proc Natl Acad Sci U S A ; 118(45)2021 11 09.
Article in English | MEDLINE | ID: covidwho-1475573

ABSTRACT

Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other pathogens with pandemic potential requires safe, protective, inexpensive, and easily accessible vaccines that can be developed and manufactured rapidly at a large scale. DNA vaccines can achieve these criteria, but induction of strong immune responses has often required bulky, expensive electroporation devices. Here, we report an ultra-low-cost (<1 USD), handheld (<50 g) electroporation system utilizing a microneedle electrode array ("ePatch") for DNA vaccination against SARS-CoV-2. The low cost and small size are achieved by combining a thumb-operated piezoelectric pulser derived from a common household stove lighter that emits microsecond, bipolar, oscillatory electric pulses and a microneedle electrode array that targets delivery of high electric field strength pulses to the skin's epidermis. Antibody responses against SARS-CoV-2 induced by this electroporation system in mice were strong and enabled at least 10-fold dose sparing compared to conventional intramuscular or intradermal injection of the DNA vaccine. Vaccination was well tolerated with mild, transient effects on the skin. This ePatch system is easily portable, without any battery or other power source supply, offering an attractive, inexpensive approach for rapid and accessible DNA vaccination to combat COVID-19, as well as other epidemics.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/immunology , COVID-19/prevention & control , Electroporation/instrumentation , SARS-CoV-2 , Vaccines, DNA/administration & dosage , Animals , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , Costs and Cost Analysis , Electroporation/economics , Electroporation/methods , Equipment Design , Female , Genes, Reporter , Humans , Mice , Mice, Inbred BALB C , Microelectrodes , Needles , Pandemics/prevention & control , Proof of Concept Study , Rats , Rats, Wistar , Skin/immunology , Skin/metabolism , Transfection , Vaccination/economics , Vaccination/instrumentation , Vaccination/methods , Vaccines, DNA/genetics , Vaccines, DNA/immunology
14.
Sci Rep ; 11(1): 20143, 2021 10 11.
Article in English | MEDLINE | ID: covidwho-1462040

ABSTRACT

Rapid, high-throughput diagnostic tests are essential to decelerate the spread of the novel coronavirus disease 2019 (COVID-19) pandemic. While RT-PCR tests performed in centralized laboratories remain the gold standard, rapid point-of-care antigen tests might provide faster results. However, they are associated with markedly reduced sensitivity. Bedside breath gas analysis of volatile organic compounds detected by ion mobility spectrometry (IMS) may enable a quick and sensitive point-of-care testing alternative. In this proof-of-concept study, we investigated whether gas analysis by IMS can discriminate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from other respiratory viruses in an experimental set-up. Repeated gas analyses of air samples collected from the headspace of virus-infected in vitro cultures were performed for 5 days. A three-step decision tree using the intensities of four spectrometry peaks correlating to unidentified volatile organic compounds allowed the correct classification of SARS-CoV-2, human coronavirus-NL63, and influenza A virus H1N1 without misassignment when the calculation was performed with data 3 days post infection. The forward selection assignment model allowed the identification of SARS-CoV-2 with high sensitivity and specificity, with only one of 231 measurements (0.43%) being misclassified. Thus, volatile organic compound analysis by IMS allows highly accurate differentiation of SARS-CoV-2 from other respiratory viruses in an experimental set-up, supporting further research and evaluation in clinical studies.


Subject(s)
Antigens, Viral/isolation & purification , COVID-19 Serological Testing/methods , COVID-19/diagnosis , Point-of-Care Testing , SARS-CoV-2/isolation & purification , Animals , COVID-19/immunology , COVID-19/virology , COVID-19 Serological Testing/instrumentation , Chlorocebus aethiops , Coronavirus NL63, Human/immunology , Coronavirus NL63, Human/isolation & purification , Diagnosis, Differential , High-Throughput Screening Assays/instrumentation , High-Throughput Screening Assays/methods , Humans , Influenza A Virus, H1N1 Subtype/immunology , Influenza A Virus, H1N1 Subtype/isolation & purification , Ion Mobility Spectrometry , Proof of Concept Study , SARS-CoV-2/immunology , Vero Cells
15.
J Nanobiotechnology ; 19(1): 301, 2021 Oct 01.
Article in English | MEDLINE | ID: covidwho-1448238

ABSTRACT

BACKGROUND: In the past decades, different diseases and viruses, such as Ebola, MERS and COVID-19, impacted the human society and caused huge cost in different fields. With the increasing threat from the new or unknown diseases, the demand of rapid and sensitive assay method is more and more urgent. RESULTS: In this work, we developed a magneto-optical biochip based on the Cotton-Mouton effect of γ-Fe2O3@Au core/shell magnetic nanoparticles. We performed a proof-of-concept experiment for the detection of the spike glycoprotein S of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The assay was achieved by measuring the magneto-optical Cotton-Mouton effect of the biochip. This magneto-optical biochip can not only be used to detect SARS-CoV-2 but also can be easily modified for other diseases assay. CONCLUSION: The assay process is simple and the whole testing time takes only 50 min including 3 min for the CM rotation measurement. The detection limit of our method for the spike glycoprotein S of SARS-CoV-2 is estimated as low as 0.27 ng/mL (3.4 pM).


Subject(s)
Antibodies, Viral/immunology , COVID-19 Testing/methods , COVID-19/diagnosis , Magnetic Iron Oxide Nanoparticles/chemistry , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , COVID-19/virology , Ferric Compounds/chemistry , Gold/chemistry , Humans , Immunoassay , Limit of Detection , Proof of Concept Study , SARS-CoV-2/isolation & purification , Sensitivity and Specificity
16.
Cytokine ; 148: 155719, 2021 12.
Article in English | MEDLINE | ID: covidwho-1433128

ABSTRACT

Effective therapies for coronavirus disease 2019 (COVID-19) are urgently needed. Maladaptive hyperinflammation and excessive cytokine release underlie the disease severity, with antiinflammatory and cytokine inhibiting agents expected to exert therapeutic effects. A major present challenge is identification of appropriate phase of the illness for a given intervention to yield optimum outcomes. Considering its established disease biomarker and drug discovery potential, a compendious analysis of existing transcriptomic data is presented here toward addressing this gap. The analysis is based on COVID-19 data related to intensive care unit (ICU) and non-ICU admissions, discharged and deceased patients, ventilation and non-ventilation phases, and high oxygen supplementation. It integrates transcriptomic data related to the effects of, in various cellular treatment models, the COVID-19 randomized clinical trial (RCT) successful drug dexamethasone, and the failed drug, with a potential to harm, hydroxychloroquine/chloroquine. Similarly, effects of various COVID-19 candidate drugs/anticytokines as well as proinflammatory cytokines implicated in the illness are also examined. The underlying assumption was that compared to COVID-19, an effective drug/anticytokine and a disease aggravating agent would affect gene regulation in opposite and same direction, in that order. Remarkably, the assumption was supported with respect to both the RCT drugs. With this control validation, etanercept, followed by tofacitinib and adalimumab, showed transcriptomic effects predictive of benefits in both ventilation and non-ventilation ICU stages as well as in non-ICU phase. On the other hand, canakinumab showed potential for effectiveness in high oxygen supplementation phase. These findings may inform experimental and clinical studies toward drug repurposing in COVID-19.


Subject(s)
COVID-19/drug therapy , COVID-19/genetics , Gene Expression Profiling , COVID-19/physiopathology , Humans , Intensive Care Units , Oxygen/therapeutic use , Patient Discharge , Proof of Concept Study , Respiration, Artificial
17.
Eur J Med Chem ; 215: 113286, 2021 Apr 05.
Article in English | MEDLINE | ID: covidwho-1385487

ABSTRACT

Covalent drugs have been intensively studied in some very important fields such as anti-tumor and anti-virus, including the currently global-spread SARS-CoV-2. However, these drugs may interact with a variety of biological macromolecules and cause serious toxicology, so how to reactivate the inhibited targets seems to be imperative in the near future. Organophosphate was an extreme example, which could form a covalent bound easily with acetylcholinesterase and irreversibly inhibited the enzyme, causing high toxicology. Some nucleophilic oxime reactivators for organophosphate poisoned acetylcholinesterase had been developed, but the reactivation process was still less understanding. Herein, we proposed there should be a pre-reactivated pose during the reactivating process and compounds whose binding pose was easy to transfer to the pre-reactivated pose might be efficient reactivators. Then we refined the previous reactivators based on the molecular dynamic simulation results, the resulting compounds L7R3 and L7R5 were proven as much more efficient reactivators for organophosphate inhibited acetylcholinesterase than currently used oximes. This work might provide some insights for constructing reactivators of covalently inhibited targets by using computational methods.


Subject(s)
Acetylcholinesterase/chemistry , Cholinesterase Reactivators/chemistry , Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/chemistry , Cholinesterase Reactivators/metabolism , Humans , Kinetics , Molecular Dynamics Simulation , Organophosphorus Compounds/chemistry , Proof of Concept Study , Protein Binding
18.
ACS Appl Mater Interfaces ; 13(35): 41445-41453, 2021 Sep 08.
Article in English | MEDLINE | ID: covidwho-1371587

ABSTRACT

Airborne transmission of exhaled virus can rapidly spread, thereby increasing disease progression from local incidents to pandemics. Due to the COVID-19 pandemic, states and local governments have enforced the use of protective masks in public and work areas to minimize the disease spread. Here, we have leveraged the function of protective face coverings toward COVID-19 diagnosis. We developed a user-friendly, affordable, and wearable collector. This noninvasive platform is integrated into protective masks toward collecting airborne virus in the exhaled breath over the wearing period. A viral sample was sprayed into the collector to model airborne dispersion, and then the enriched pathogen was extracted from the collector for further analytical evaluation. To validate this design, qualitative colorimetric loop-mediated isothermal amplification, quantitative reverse transcription polymerase chain reaction, and antibody-based dot blot assays were performed to detect the presence of SARS-CoV-2. We envision that this platform will facilitate sampling of current SARS-CoV-2 and is potentially broadly applicable to other airborne diseases for future emerging pandemics.


Subject(s)
Breath Tests/instrumentation , COVID-19 Testing/instrumentation , Masks , SARS-CoV-2/isolation & purification , Air Microbiology , Antibodies, Viral/immunology , Breath Tests/methods , COVID-19 Testing/methods , Collodion/chemistry , Colorimetry/methods , Molecular Diagnostic Techniques/methods , Nucleic Acid Amplification Techniques/methods , Polycarboxylate Cement/chemistry , Porosity , Proof of Concept Study , RNA, Viral/analysis , Real-Time Polymerase Chain Reaction/methods , SARS-CoV-2/chemistry , Viral Proteins/analysis , Viral Proteins/immunology
19.
Ann Rheum Dis ; 80(9): 1158-1167, 2021 09.
Article in English | MEDLINE | ID: covidwho-1356912

ABSTRACT

OBJECTIVES: Although causality remains to be established, targeting dysbiosis of the intestinal microbiota by faecal microbiota transplantation (FMT) has been proposed as a novel treatment for inflammatory diseases. In this exploratory, proof-of-concept study, we evaluated the safety and efficacy of FMT in psoriatic arthritis (PsA). METHODS: In this double-blind, parallel-group, placebo-controlled, superiority trial, we randomly allocated (1:1) adults with active peripheral PsA (≥3 swollen joints) despite ongoing treatment with methotrexate to one gastroscopic-guided FMT or sham transplantation into the duodenum. Safety was monitored throughout the trial. The primary efficacy endpoint was the proportion of participants experiencing treatment failure (ie, needing treatment intensification) through 26 weeks. Key secondary endpoints were change in Health Assessment Questionnaire Disability Index (HAQ-DI) and American College of Rheumatology (ACR20) response at week 26. RESULTS: Of 97 screened, 31 (32%) underwent randomisation (15 allocated to FMT) and 30 (97%) completed the 26-week clinical evaluation. No serious adverse events were observed. Treatment failure occurred more frequently in the FMT group than in the sham group (9 (60%) vs 3 (19%); risk ratio, 3.20; 95% CI 1.06 to 9.62; p=0.018). Improvement in HAQ-DI differed between groups (0.07 vs 0.30) by 0.23 points (95% CI 0.02 to 0.44; p=0.031) in favour of sham. There was no difference in the proportion of ACR20 responders between groups (7 of 15 (47%) vs 8 of 16 (50%)). CONCLUSIONS: In this first preliminary, interventional randomised controlled trial of FMT in immune-mediated arthritis, we did not observe any serious adverse events. Overall, FMT appeared to be inferior to sham in treating active peripheral PsA. TRIAL REGISTRATION NUMBER: NCT03058900.


Subject(s)
Arthritis, Psoriatic/therapy , Dysbiosis/therapy , Fecal Microbiota Transplantation/methods , Adult , Antirheumatic Agents/therapeutic use , Arthritis, Psoriatic/microbiology , Female , Humans , Male , Methotrexate/therapeutic use , Middle Aged , Proof of Concept Study , Treatment Outcome
20.
Antiviral Res ; 194: 105162, 2021 10.
Article in English | MEDLINE | ID: covidwho-1347485

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has infected over 200 million people throughout the world as of August 2021. There are currently no approved treatments providing high chance of recovery from a severe case of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, and the beneficial effect of Remdesivir and passive immunization therapies may only be seen when administered early on disease onset. The emergence of variants is also raising concerns regarding the efficacy of antibody therapies, antivirals, and vaccines. Therefore, there is still a need to develop new antivirals. Here, we investigated the suitability of primary human epithelial cells from the trachea/bronchia (NHBE) and small airway (SAEC) as lung models of SARS-CoV-2 infection to determine, whether the microbicide polyphenylene carboxymethylene (PPCM) has antiviral activity against SARS-CoV-2. Both NHBE and SAEC expressed proteins required for virus entry in lung epithelial cells. However, these cells were only low to moderately permissive to SARS-CoV-2 as titers increased at best by 2.5 log10 during an 8-day kinetic. Levels of replication in SAEC, unlike in NHBE, were consistent with data from other studies using human normal tissues or air-liquid interface cultures, suggesting that SAEC may be more relevant to use than NHBE for drug screening. PPCM EC50 against SARS-CoV-2 was between 32 and 132 µg/ml with a selectivity index between 12 and 41, depending on the cell type and the infective dose used. PPCM doses were consistent with those previously showing effect against other human viruses. Finally, PPCM antiviral effect observed in SAEC was in line with reduction of inflammatory markers observed overly expressed in severe COVID-19 patients. Altogether, our data support the fact that PPCM should be further evaluated in vivo for toxicity and antiviral activity against SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , Epithelial Cells/virology , Polymers/pharmacology , SARS-CoV-2/drug effects , Antiviral Agents/chemistry , COVID-19/prevention & control , COVID-19/transmission , Epithelial Cells/drug effects , Humans , Lung/cytology , Lung/virology , Polymers/chemistry , Proof of Concept Study , SARS-CoV-2/genetics , Virus Internalization/drug effects , Virus Replication/drug effects
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