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SARS-CoV-2 has infected more than 600 million people worldwide over the last 2.5 years. So far, there efficacy of many antiviral drugs against COVID-19 has been evaluated only in small studies conducted in different countries. Objective. To assess the efficacy of umifenovir in patients with COVID-19. Materials and methods. We performed systematic search of publications in the PubMed and Google Scholar databases. Sixteen studies with a total of 1,843 patients were included in the analysis. The following endpoints were evaluated: frequencies of negative PCR test on days 7 and 14;mortality in patients with mild, moderate, and severe disease;and frequency of fever resolution on day 7. Results. We found that patients receiving umifenovir demonstrated a significantly higher frequency of negative PCR test on day 7 than patients who received no causal therapy or other antiviral drugs (odds ratio (OR) 1.69, 95% confidence interval (CI): 1.09-2.62, p = 0.02, I2 = 13%). This difference was even more significant among patients with mild to moderate COVID-19 (OR: 2.03, 95% CI: 1.24-3.32, p = 0.005, I2 = 0%), as well as on day 14 (OR: 2.02, 95% CI: 1.35-3.94, p = 0.0007, I2 = 50%). We also observed a reduced risk of death in the studies that included only patients with mild and moderate disease (JR: 0.53, 95% CI: 0.33-0.83, p = 0.006, I2 = 0). Umifenovir therapy did not affect the frequency of fever resolution by day 7 (OR: 0.87, 95% CI: 0.49-1.56, p = 0.64, I2 = 0%). Conclusion. Umifenovir significantly accelerated virus elimination by days 7 and 14 among patients with mild to moderate COVID-19. Umifenovir also reduced the risk of death compared to other antiviral drugs.Copyright © 2022, Dynasty Publishing House. All rights reserved.
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The Covid 19 pandemic remains a serious public health problem until effective drugs and/or vaccines are available. Can we explain why so many people remain asymptomatic but nevertheless highly contagious explaining the speed with which the pandemic has spread around the world? Can we explain why the acute respiratory distress syndrome (ARDS) appears late but can so quickly have a fatal outcome? In the lung, mucociliary clearance (CMC) and alveolar clearance (CA) depend on the transport of sodium through the plasma membrane of epithelial cells. This transport is mediated by a highly selective sodium channel (Epithelial Sodium Channel = ENaC) which could be a key element in the pulmonary pathophysiology of SARS-CoV-2 infection.Copyright © 2020 Editions Medecine et Hygiene. All rights reserved.
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Problem: COVID-19 placentitis is a rare complication of maternal SARS-CoV-2 respiratory infection associated with serious adverse obstetric outcomes, including intra-uterine death. The precise role of SARS-CoV-2 in COVID-19 placentitis is uncertain, as trophoblast infection is only observed in around one-half of the affected placenta. Method of Study: Through multi-omic spatial profiling, including Nanostring GeoMX digital spatial profiling and Lunaphore COMET multiplex IHC, we provide a deep characterization of the immunopathology of placentitis from obstetrically complicated maternal COVID-19 infection. Result(s):We show that SARS-CoV-2 infection of placental trophoblasts is associated with a distinct innate and adaptive immune cell infiltrate, florid cytokine expression and upregulation of viral restriction factors. Quantitative spatial analyses reveal a unique microenvironment surrounding virus-infected trophoblasts characterizedd by multiple immune evasion mechanisms, including immune checkpoint expression, cytotoxic T-cell exclusion, and interferon blunting. Placental viral loads inversely correlated with the duration of maternal infection consistent with progressive virus clearance, potentially explaining the absence of virus in some cases. Conclusion(s): Our results demonstrate a central role for placental SARS-CoV-2 infection in driving the unique immunopathology of COVID-19 placentitis.
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Objectives Human leukocyte antigens (HLA) are highly diverse transmembrane proteins that present viral peptides to T cells and launch pathogen-specific immune responses. We aim to investigate the correlation between HLA evolutionary divergence (HED), a surrogate for the capacity to present different peptides, and the outcomes of SARS-CoV-2 infection in a cohort from the St. Louis Metropolitan area. Methods We enrolled adult patients with SARS-CoV-2 infection confirmed by RT-PCR who were hospitalized at two tertiary hospitals in St. Louis between March and July 2020. Genomic DNA was extracted from peripheral blood and genotyped by next-generation sequencing (NGS). HLA alleles were assigned based on key-exon sequences (G group) and limited to the 2-field resolution. HED was calculated by Grantham distance, which considers the difference in composition, polarity, and molecular volume between each pair of amino acids from maternal and paternal HLA. The HED score was obtained for HLA class I (HLA-A, -B, and -C) genotypes using the HLAdivR package in R. Clinical data were collected retrospectively from electronic medical records. A poor outcome was defined as an admission to the intensive care unit (ICU), a need for mechanical ventilation, or death. A favorable outcome was defined as the absence of the above poor outcomes. Results A total of 234 patients were enrolled in this study, 96 being females (41%). The median age and BMI were 66 years old and 28.30 kg/m2, respectively. African Americans comprised 71.4% of the cohort. Only 19 patients (8.1%) presented with no comorbidity;the rest had one or more comorbidities, with cardiovascular diseases being the most common. A total of 137 (58.5%) patients had poor outcomes from SARS-CoV-2 infection, while 97 (41.5%) patients had a favorable outcome. We detected a significant association between higher HLA-B HED and favorable outcomes, with each 1-point increase in HLA-B HED associated with 8% increased probability for the composite endpoint (OR 1.08, 95% CI=1.01-1.16, P = 0.04). The HED scores calculated for HLA-A or HLA-C were not significantly different between patients with favorable or poor outcomes. In a multivariate logistic regression analysis, increased HLA-B HED score, younger age, and no comorbidity were independently associated with favorable outcomes (P = 0.02, P = 0.01, and P = 0.05, respectively). Conclusion Our study shows a significant correlation between lower HLA-B HED scores and poor outcomes after SARS-CoV-2 infection. This finding suggests that maximizing the presentation of diverse SARS-CoV-2 peptides by HLA-B alleles may improve the clearance of SARS-CoV-2. Further studies are warranted to understand the functional and mechanistic implications of this finding.
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Background & Aim: Despite the successful implementation of vaccines worldwide, COVID-19 remains a risk in patients with a compromised immune system. Emerging viral variants have also reduced the effectiveness of monoclonal antibody therapies in these patients. New treatment options are therefore required to improve clinical outcomes. Methods, Results & Conclusion(s): T cell immunotherapy has proven effective for the treatment of a number of refractory viral diseases in patients with a compromised immune system. We have now completed the manufacture of a bank of SARS-CoV-2 specific T cells and commenced an open-label phase I clinical trial at the Royal Brisbane and Women's Hospital, Australia. Patients enrolled in the study receive two doses of partially HLA-matched allogeneic T cells at a fortnightly interval. We have thus far recruited and treated three immune compromised patients with SARS-CoV-2 T cells. In two of the three patients treated thus far, the administration of T cell therapy was coincident with the clearance of viral load after 28 days. Viral clearance in these patients was also associated with an increase in circulating SARS-CoV-2 specific T cells. Our preliminary observations suggest that SARS-CoV-2 specific T cell therapy is well tolerated and has the potential to impact viral control in immune compromised patients.Copyright © 2023 International Society for Cell & Gene Therapy
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Breast cancer is the most common form of cancer and the second cancer-causing death in females. Although remission rates are high if detected early, survival rates drop substantially when breast cancer becomes metastatic. The most common sites of metastatic breast cancer are bone, liver and lung. Respiratory viral infections inflict illnesses on countless people. The latest pandemic caused by the respiratory virus, SARS-CoV-2, has infected more than 600 million worldwide, with documented COVID-related death upward of 1 million in the United States alone. Respiratory viral infections result in increased inflammation with immune cell influx and expansion to facilitate viral clearance. Prior studies have shown that inflammation, including through neutrophils, can contribute to dormant cancer cells reawakening and outgrowth. Moreover, inhibition of IL6 has been shown to decrease breast cancer lung metastasis in mouse models. However, how respiratory viral infections contribute to breast cancer lung metastasis remains to be unraveled. Using MMTV/PyMT and MMTV/NEU mouse models of breast cancer lung metastasis and influenza A virus as a model respiratory virus, we demonstrated that acute influenza infection and the accompanying inflammation and immune cell influx awakens and dramatically increased proliferation and expansion of dormant disseminated cancer cells (DCC) in the lungs. Acute influenza infection leads to immune influx and expansion, including neutrophils and macrophages, with increased proportion of MHCII+ macrophages in early time points, and a sustained decrease in CD206+ macrophages starting 6 days post-infection until 28 days after the initial infection. Additionally, we observed a sustained accumulation of CD4+ T cells around expanding tumor cells for as long as 28 days after the infection. Notably, neutrophil depletion or IL6 knockout reversed the flu-induced dormant cell expansion in the lung. Finally, awakened DCC exhibited downregulation of vimentin immunoreactivity, suggesting a role for phenotypic plasticity in DCC outgrowth following viral infection. In conclusion, we show that respiratory viral infections awaken and increase proliferation of dormant breast cancer cells in the lung, and that depletion of neutrophils or blocking IL6 reverses influenza-induced dormant cell awakening and proliferation.
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Background & Aim: Immunocompromised patients are susceptible to high-risk opportunistic infections and malignant diseases. If available, most antiviral and antifungal drugs are quite toxic, relatively ineffective, and induce resistance in the long term. Methods, Results & Conclusion(s): We have previously demonstrated the safety of adoptive cell therapy for COVID-19 patients with CD45RA negative cells containing SARS-CoV-2-specific T cells from a donor, chosen based on HLA compatibility and cellular response to SARS-CoV-2 peptide pools. After finishing a Phase 2 randomized multicenter clinical trial (RELEASE, NCT04578210), we concluded that the infusion is safe, effective, accelerates lymphocyte recovery and shows hallmarks of an immune response. To use adoptive cell therapy to treat COVID-19 it would be necessary to develop a biobank of living drugs. For that, we examined the immune evolution performing a longitudinal analysis from previously SARS-CoV-2 infected and infection- naive individuals covering 21 months from infection. Cellular responses were maintained over time while humoral responses increased after vaccination but were gradually lost. Therefore, the best donors would be recovered individuals and two months after vaccination. We also evaluated the effect of dexamethasone (current standard of care treatment for COVID-19 and other infections involving lymphopenia) and Interleukin-15 (cytokine involved in T-cell maintenance and survival) on CD45RA negative. Dexamethasone did not alter cell functionality, proliferation or phenotype at a clinical-practice concentration, while interleukin-15 increased the memory T-cell and T-regulatory cell activation state, and interferon gamma release. Furthermore, we applied the adoptive passive transfer of CD45RA negative cells containing pathogen-specific memory T-cells to other infectious diseases characterized by sustained lymphopenia. We infused six immunocompromised patients with Cytomegalovirus, BK virus, Aspergillus, and Epstein-Barr virus lymphoproliferative disease. Patients experienced pathogen clearance, resolution of symptoms and lymphocyte increase. Transient microchimerism was detected in three patients. The use of CD45RA negative cells containing specific memory T cells of a third-party donor for treating severe pathogenic diseases in immunocompromised patients is feasible, safe, and effective, and has an advantage over other cell therapies such as lower costs and a less complex regulatory environment.Copyright © 2023 International Society for Cell & Gene Therapy
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Background: Omicron is the recently emerged highly transmissible severe acute respiratory syndrome coronavirus 2 variant that has caused a dramatic increase in coronavirus disease-2019 infection cases worldwide. This study was to investigate the association between demographic and laboratory findings, and the duration of Omicron viral clearance. Methods: Approximately 278 Omicron cases at the Ruijin Hospital Luwan Branch, Shanghai Jiaotong University School of Medicine were retrospectively analyzed between August 11 and August 31, 2022. Demographic and laboratory data were also collected. The association between demographics, laboratory findings, and duration of Omicron viral clearance was analyzed using Pearson correlation analysis and univariate and multivariate logistic regression. Results: Univariate logistic regression analyses showed that a prolonged viral clearance time was significantly associated with older age and lower immunoglobulin (Ig) G and platelet (PLT) levels. Using multinomial logistic regression analyses, direct bilirubin, IgG, activated partial thromboplastin time (APTT), and PLT were independent factors for longer viral shedding duration. The model combining direct bilirubin, IgG, APTT, and PLT identifies patients infected with Omicron whose viral clearance time was ≥7 days with 62.7% sensitivity and 83.4% specificity. Conclusion: These findings suggest that direct bilirubin, IgG, PLT, and APTT are significant risk factors for a longer viral shedding duration in patients infected with Omicron. Measuring levels of direct bilirubin, IgG, PLT, and APTT is advantageous to identify patients infected with Omicron with longer viral shedding duration.
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COVID-19 , Immunoglobulin G , Humans , SARS-CoV-2 , Partial Thromboplastin Time , Retrospective Studies , China , BilirubinABSTRACT
PEGylated lipid nanoparticle-based Covid-19 vaccines, including Pfizer's BNT162b2 and Moderna's mRNA-1273, have been shown to stimulate variable anti-PEG antibody production in humans. Anti-PEG antibodies have the potential to accelerate the plasma clearance of PEGylated therapeutics, such as PEGylated liposomes and proteins, and compromise their therapeutic efficacy. However, it is not yet clear whether antibody titers produced by PEGylated Covid-19 vaccines significantly affect the clearance of PEGylated therapeutics. This study examined how anti-PEG IgM levels affect the pharmacokinetics of PEGylated liposomal doxorubicin (PLD) and compared the immunogenicity of a lipid nanoparticle formulation of linear DNA (DNA-LNP) to standard PEG-HSPC liposomes. DNA-LNP was prepared using the same composition and approach as Pfizer's BNT162b2, except linear double-stranded DNA was used as the genetic material. PEGylated HSPC-based liposomes were formulated using the lipid rehydration and extrusion method. Nanoparticles were dosed IM to rats at 0.005-0.5 mg lipid/kg body weight 1 week before evaluating the plasma pharmacokinetics of clinically relevant doses of PLD (1 mg/kg, IV) or PEGylated interferon α2a (Pegasys, 5 µg/kg, SC). Plasma PEG IgM was compared between pre- and 1-week post-dose blood samples. The results showed that anti-PEG IgM production increased with increasing PEG-HSPC liposome dose and that IgM significantly correlated with the plasma half-life, clearance, volume of distribution, and area under the curve of a subsequent dose of PLD. The plasma exposure of Pegasys was also significantly reduced after initial delivery of 0.005 mg/ml PEG-HSPC liposome. However, a single 0.05 mg/kg IM dose of DNA-LNP did not significantly elevate PEG IgM and did not alter the IV pharmacokinetics of PLD. These data showed that PEGylated Covid-19 vaccines are less immunogenic compared to standard PEGylated HSPC liposomes and that there is an antibody threshold for accelerating the clearance of PEGylated therapeutics.
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COVID-19 , Nanoparticles , Rats , Humans , Animals , Liposomes , BNT162 Vaccine , COVID-19 Vaccines , Immunoglobulin M , Polyethylene Glycols/pharmacokinetics , DNA , PhosphatidylcholinesABSTRACT
HH-120, a recently developed IgM-like ACE2 fusion protein with broad-spectrum neutralizing activity against all ACE2-utilizing coronaviruses, has been developed as a nasal spray for use as an early treatment agent to reduce disease progression and airborne transmission. The objective of this study was to evaluate the safety and efficacy of the HH-120 nasal spray in SARS-CoV-2-infected subjects. Eligible symptomatic or asymptomatic SARS-CoV-2-infected participants were enrolled in a single-arm trial to receive the HH-120 nasal spray for no longer than 6 days or until viral clearance at a single hospital between August 3 and October 7, 2022. An external control was built from real-world data of SARS-CoV-2-infected subjects contemporaneously hospitalized in the same hospital using a propensity score matching (PSM) method. After PSM, 65 participants in the HH-120 group and 103 subjects with comparable baseline characteristics in the external control group were identified. The viral clearance time was significantly shorter in participants receiving the HH-120 nasal spray than that in subjects of the control group (median 8 days vs. 10 days, p < 0.001); the difference was more prominent in those subgroup subjects with higher baseline viral load (median 7.5 days vs. 10.5 days, p < 0.001). The incidence of treatment-emergent adverse events and treatment-related adverse events of HH-120 group were 35.1% (27/77) and 3.9% (3/77), respectively. All the adverse events observed were mild, being of CTCAE grade 1 or 2, and transient. The HH-120 nasal spray showed a favorable safety profile and promising antiviral efficacy in SARS-CoV-2-infected subjects. The results from this study warrant further assessment of the efficacy and safety of the HH-120 nasal spray in large-scale randomized controlled clinical trials.
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Angiotensin-Converting Enzyme 2 , COVID-19 , Humans , Nasal Sprays , SARS-CoV-2 , Cohort Studies , Propensity Score , Immunoglobulin MABSTRACT
Poly(ethylene glycol) (PEG) is widely applied to decorate nanocarriers due to its "long circulation” characteristics. However, the applications of linear PEG-modified nanocarriers have been hindered by severe adverse effects due to the accelerated blood clearance (ABC) phenomenon. It was universally known that anti-PEG antibodies (APAs) were main culprits in ABC phenomenon which induced the significant change in pharmacokinetics, biological distributions of the second injection and triggered complement activation-related pseudoallergies (CARPA). Recent studies have illustrated that APAs triggered the ABC phenomenon of PEGylated protein drug and even related to the CARPA of COVID-19 vaccine. Therefore, it is urgent to inhibit the generation of APAs and eliminate the ABC phenomenon. Here, "Y-type” PEG was chosen to replace linear PEG due to its weak immunogenicity. "Y-type” PEG-lipid derivatives [DSPE-mPEG2,n (n = 2, 10, and 20 kDa)]-modified doxorubicin liposomes (DOX-PL2,n) and topotecan liposomes (TP-PL2,n) induced lower levels of APAs and could avoid activating complement system. In further research, we found that liposomes decorated with DSPE-mPEG2,n could avoid the ABC phenomenon after duplicate injections. Furthermore, pharmacodynamic tests indicated that DOX-PL2,n and TP-PL2,n improved the curative effect of S180 tumor than DOX-PL2k and TP-PL2k (linear PEGylated liposomes). For the first time, DOX-PL2,n and TP-PL2,n were used for in vivo pharmacokinetic and pharmacodynamic experiments. Liposomes ornamented with "Y-type” PEG may provide new approaches to maintaining long blood circulation time, eliminating the ABC phenomenon of encapsulated active compounds, and also could weaken CARPA and improve tumor therapeutic effect. Our research aims to promote the research and development of "Y-type” PEG-decorated nanocarriers and provide a substantial academic basis for its clinical application.
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The article reflects the analysis of the state of the problem concerning the pathogenesis of COVID-19 (CoronaVirus Disease 2019), the epidemic of which began from the end of 2019 to the beginning of 2020, from the position of the bronchopulmonary system, which is associated with the main route of penetration of the virus of this infectious disease (SARS-CoV-1) with the development of severe pneumonia, often fatal. And if the study and results of the study of this problem are to a certain extent highlighted in the literature, then they concerned mainly the respiratory regions of the respiratory tract (RT), given that mainly complications leading to death are associated with them. At the same time, studies on conducting RT are reflected in a few foreign works, although there are data suggesting their not small contribution to the pathogenesis of COVID-19. In the domestic literature, studies of this kind have not been reflected. The aim of the work is to analyze, reflect and assess the role of possible morphological and functional regional changes in the mucous membrane of the RT in the pathogenesis of COVID-19. Methodologically, the analysis was carried out using a systematic approach based on the material of various databases of biomedical and biomedical scientific information, including such as Index Medicus, PubMed, EMBASE, Cochrane, and others for the period, mainly 2020. Results. An analysis of the mechanisms of influence on the morphofunctional state of the mucous membrane of the RT of coronavirus infection is given, depending on their departments, including conductive and respiratory. Methods and approaches to the study of such influence are reflected. The possible role of disturbances in the morphofunctional state and defense mechanisms of the lungs is shown, hypotheses and paradigms regarding the pathogenesis of coronavirus infection are presented. The results of the analysis indicate that there is a whole complex of morphological and functional disorders that determine the development of this pathology, its virulence. The fundamental role of the epithelium of the respiratory tract has been established and multicellular receptor tropism in the pathogenesis of COVID-19 is reflected. In conclusion, it is pointed out that the essential role of epithelial cells not only of the respiratory, but also of the conductive parts of the LTP, mainly ciliates, which are involved in the pathogenesis of COVID-19 not only from the position of functional receptors, but also in terms of violations of the earliest leading protective mechanism - mucociliary clearance aggravating the "vicious circle of pathogenesis" of this pathology.Copyright © 2021 Infectious Diseases: News, Opinions, Training. All rights reserved.
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Given the actual risk of poliomyelitis outbreaks in the region due to poliovirus derived from the Sabin vaccine or the importation of wild poliovirus, the Latin American Society of Pediatric Infectious Diseases commissioned an ad hoc group of experts from the institution's Vaccines and Biologicals Committee, to draft an official position paper on the urgent need to increase immunization levels against the disease in the region and incorporate inactivated polio vaccine exclusive schedules in all national immunization programs. This publication discusses the main conclusions and recommendations generated as a result of such activity.Copyright © 2022, Sociedad Chilena de Infectologia. All rights reserved.
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Intro: Background: Obesity affects drug delivery and clearance owing to the patient's altered pharmacokinetics. In treating infection, this presents as a conundrum antibiotic dosing to achieve optimal antibiotic concentration at the same time avoiding drug toxicity. Particularly in the case of antimicrobial agents, underdosing may lead to antibiotic resistance. Method(s): Case description: We report a case of a morbidly obese (BMI=58) COVID-19 patient infected with carbapenem-sensitive multi-drug resistant (MDR) Enterobacter cloacae bacteremia, treated with ertapenem 1g twice daily and intravenous polymyxin E 9MU stat and 4.5MU twice daily for MDR Acinetobacter baumanii co-infection. He had infected huge grade IV sacral sore one month later in which intraoperative tissue culture grew phenotypically heterogeneous colonies of MDR Enterobacter cloacae with carbapenem-sensitive and carbapenem-intermediate-resistant non-carbapenemase producing colonies. He responded well clinically and biochemically with an increased dose of intravenous ciprofloxacin 800mg BD based on his actual body weight. He was discharged with oral ciprofloxacin 750mg BD for a total of six weeks. Finding(s): Discussion: Obesity is a public health crisis that has reached epidemic proportions. Obesity affects the volume distribution and renal clearance of many drugs including antibiotics. Obese patients are shown to have higher drug clearance than normal-weighted patients resulting in inadequate systemic exposure. This puts patients at risk of developing antibiotic resistant organisms. Our patient, weighing 162kg was given three different beta-lactam antibiotics to treat his infection including ertapenem in which a standard adult dose was given without body weight consideration. Possible underdosing contributed to the conversion of carbapenem susceptibility from sensitive to resistant strain. Conclusion(s): Obese individuals may need a larger ertapenem dose than their non-obese counterparts. Clinical and laboratory assessment may help in monitoring treatment response in this group of patients.Copyright © 2023
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Background: Oseltamivir has been used as adjunctive therapy in the management of patients with COVID-19. However, the evidence about using oseltamivir in critically ill patients with severe COVID-19 remains scarce. This study aims to evaluate the effectiveness and safety of oseltamivir in critically ill patients with COVID-19. Methods: This multicenter, retrospective cohort study includes critically ill adult patients with COVID-19 admitted to the intensive care unit (ICU). Patients were categorized into two groups based on oseltamivir use within 48 hours of ICU admission (Oseltamivir vs. Control). The primary endpoint was viral load clearance. Results: A total of 226 patients were matched into two groups based on their propensity score. The time to COVID-19 viral load clearance was shorter in patients who received oseltamivir (11 vs. 16 days, p = 0.042; beta coefficient: -0.84, 95%CI: (-1.33, 0.34), p = 0.0009). Mechanical ventilation (MV) duration was also shorter in patients who received oseltamivir (6.5 vs. 8.5 days, p = 0.02; beta coefficient: -0.27, 95% CI: [-0.55,0.02], P = 0.06). In addition, patients who received oseltamivir had lower odds of hospital/ventilator-acquired pneumonia (OR:0.49, 95% CI:(0.283,0.861), p = 0.01). On the other hand, there were no significant differences between the groups in the 30-day and in-hospital mortality. Conclusion: Oseltamivir was associated with faster viral clearance and shorter MV duration without safety concerns in critically ill COVID-19 patients.
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Koutsakos et al. have recently published an article showing that SARS-CoV-2 breakthrough infection results in robust naïve and memory T cell activation, and the activity of CD8 T cells strongly correlates with viral clearance.
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Background: To assess the safety, tolerability, and pharmacokinetic (PK) profile in humans of the novel inhaled epithelial sodium channel blocker ETD001. Method(s): Inhaled ETD001 or placebo, delivered via nebulizer, have been administered in a 3:1 ratio to 96 healthy subjects in a blinded, first-inhuman clinical trial (ClinicalTrials.gov Identifier: NCT04926701). The study consisted of two parts. Part A evaluated single ascending doses (SADs) up to 10.8 mg, and Part B evaluated multiple ascending doses (MADs) up to 3.1 mg once daily (QD) for 7 days and 4.65 mg twice daily (BID) for 14 days. Safety was assessed by monitoring for adverse events (AEs), laboratory safety tests (including blood potassium monitoring), vital signs, 12-lead electrocardiogram (ECG), and spirometry. Systemic exposurewas assessed using serial pharmacokinetic blood draws. Result(s): Therewere no serious AEs. Twenty-four subjects reported 38 AEs, all of mild to moderate intensity and all resolved. There were no clinically relevant changes in laboratory safety tests, vital signs, ECGs, or spirometry measurements. All blood potassium assessments were within normal range at all doses. Three subjects withdrew in Part B;all withdrawals were considered unrelated to study drug: one on day 6 from the 3.1-mg QD cohort for personal reasons, one after the first dose of the 3.1-mg BID cohort because of vasovagal syncope at time of venipuncture triggering atrial fibrillation that spontaneously resolved, and one on Day 4 of the 3.1- mg BID cohort because of a positive COVID-19 test. Pharmacokinetic parameters were approximately dose proportional in Part A, with peak concentrations 1 to 2 hours after dose and exposure out to 12 to 24 hours at all doses, indicating good lung retention. Part B plasma concentrations displayed dose-independent kinetics and showed minimal accumulation, with a mean of 1.11-fold observed over 14 days. Conclusion(s): ETD001 was well tolerated at single doses up to 10.8 mg and multiple doses of 3.1 mg QD for 7 days and 4.65 mg BID for 14 days. The wide safety margin is predicted to enable doses capable of durable target engagement in the lung, which are expected to enhance mucociliary clearance in people with cystic fibrosis.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved
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Background: A 5-day course of nirmatrelvir-ritonavir (N/R) can significantly reduce the hospitalization and death rates and the duration of infectiousness in high-risk SARS-CoV-2 patients. However, in a fraction of treated individuals virus rebounds following an initial recovery after treatment. The mechanism driving rebound is not well understood. We hypothesize that treatment with N/R near the time of symptom onset halts the depletion of target cells, but does not fully eliminate the virus, and thus can lead to viral rebound. Method(s): Previously, we and others have developed viral dynamic models and successfully used them to fit data on SARS-CoV-2 infection. Here we expand these models and incorporate N/R pharmacokinetic and pharmacodynamic effects and an adaptive immune response. Result(s): We fit this model to the data presented in Charness et al., NEJM (2022) where longitudinal quantitative PCR data is available for 3 individuals who experienced viral rebounds after taking N/R. We found that the model fit the data well. By varying model parameters from their best-fit values, we show the occurrence of viral rebound is sensitive to model parameters, and the time treatment is initiated, which may explain why only a fraction of individuals rebound. Finally, the model with its best-fit parameter values was used to test the therapeutic effects of treatment extended to 10 days or a second 5-day course of N/R initiated one day after symptoms reoccur. Conclusion(s): Our model fits predicted that virus is not fully eliminated during N/R treatment and supported our initial hypothesis that at the end of treatment target cells are available to allow viral resurgence. Simulating the effect of starting treatment later, we find the probability of viral rebound occurring decreases, suggesting that delaying treatment may be a strategy to reduce viral rebound. However, N/R treatment accelerates viral clearance and hence potentially can reduce viral transmission. Thus, delaying treatment may have a detrimental effect on public health and could also have impact on the severity of disease in the high-risk patients for whom N/R is recommended. Increasing treatment from 5 to 10 days continues to preserve target cells and thus may still allow viral rebound if viable virus is present at the end of treatment and sufficient adaptive immunity has not developed. Simulating giving a second course of treatment one day after symptoms reappear, did not prevent rebound.
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Introduction: Diabetic patients with end-stage renal disease (ESRD) treated with insulin or any other diabetic agent show high variations in their glucose metabolism, lower insulin clearance level, and uncertain accuracy of glycemic control measurements. Therefore, these patients are at a greater risk of developing hypoglycemia. Diazoxide use in the treatment of spontaneous and refractory hypoglycemia in this population has not been well documented. We report a case of a young diabetic male that has been successfully treated with diazoxide for his asymptomatic refractory hypoglycemic episodes. Case Description: A young man with type 2 diabetes mellitus complicated by diabetic nephropathy, on hemodialysis for ESRD, presented with shortness of breath due to COVID pneumonia. After resolution of his infection, he was noted to have recurrent asymptomatic hypoglycemic episodes, although he has been off his diabetes medications for the past few years due to worsening of his kidney function. His oral intake was adequate and there was no concern for malnutrition, or any substance use. From the testing performed, we were able to exclude exogenous insulin or insulin secretagogues use and the presence of insulin antibodies. Insulin and noninsulin (insulin-like growth factor) mediated mechanisms were also ruled out. Since he was having recurrent and refractory asymptomatic hypoglycemic episodes and to minimize the need for supplemental dextrose containing fluids, he was started on diazoxide at 3 mg/kg/day. Knowing the risk of fluid retention with diazoxide, this patient on hemodialysis tolerated it well. Diazoxide helped reduce his episodes of hypoglycemia and he was then safely discharged on it. Discussion(s): In ESRD, hypoglycemia can be explained by the impaired contribution of the kidneys to gluconeogenesis and glucose release, as well as the higher insulin levels caused by insulin resistance and decrease in insulin clearance. When his hypoglycemia persisted even after the resolution of his infection, further testing and work-up was done and other causes of hypoglycemia were ruled out. Generally, diazoxide is used as a treatment to manage the symptoms of hypoglycemia in congenital hyperinsulinism, insulinomas and post bariatric surgery cases of hyperinsulinemic hypoglycemia. However, it has not been the optimal treatment when it comes to treating hypoglycemia in ESRD patients because of its side effects;specifically, fluid retention, and electrolyte imbalances. In our case, the patient was treated with diazoxide as a last resort, despite its known side effects and the limited documentation of its use in ESRD patients. Actually, a few other case reports, have also shown promising results with the use of diazoxide for that purpose with no or minimal side effects. However, there are not enough studies that have shown the benefits or risks of long-term treatment of diazoxide in ESRD patients, an area of growing interest.Copyright © 2023
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Background: Evolution evidence of Coronavirus disease 2019 (COVID-19) and viral clearance time remains limited in tropical settings. Understanding this is crucial for public health control measures at community-level. We evaluated the viral dynamics of SARS-CoV-2 infection and factors associated with positivity duration in COVID-19 cases in Cameroon. Method(s): We conducted a prospective cohort-study of SARS-CoV-2 positive cases from the first to third wave (March 2020-October 2021) in Yaounde- Cameroon. RT-PCR was performed on nasopharyngeal swabs. SARS-CoV-2 positivity duration was evaluated from the first to last positive test before a negative result. Epi-info V.7.0 was used for data analyses with p< 0.05 considered statistically significant Results: A total of 282 participants were enrolled. The mean age was 41+/-14 years, with male predominant (62.1%). We had 15.6% symptomatic cases and cough most common (59.09%). The overall median positivity duration was 15[IQR: 9-23] days with 15[ IQR: 13-16] in the first, 17[ IQR: 11-26] in the second and 8[ IQR: 4-12] in the third wave (p= 0.007). Positivity duration was significantly higher in males (16 versus 14 days, p=0.03) and people aged >40 years (15 versus 14 days, p=0.02). Positivity duration was not affected by presence or absence of symptoms (p=0.80). No significant correlation was found with viral load (r=0.03;p=0.61). Considering baseline (24.7+/-7.2Ct) and last viral load (29.3+/-5.9 Ct), the DELTACt (4.6+/-1.3) and positivity duration (15 days) revealed a kinetic in viral decay of 0.3+/-0.087 Ct/day. Conclusion(s): A median positivity duration of 15 days is in accordance with viral clearance around 2 weeks for optimal confinement at community-level. Men and/or the elderly stand at higher risk of prolonged infection. Given the viral decay (0.3 Ct daily), we suggest personalized confinement periods. The variability of positivity duration according to phases could be function of strains which could be a factor of positivity duration.