Mathematical Analysis of Fractal-Fractional Mathematical Model of COVID-19

In this work, we modified a dynamical system that addresses COVID-19 infection under a fractal-fractional-order derivative. The model investigates the psychological effects of the disease on humans. We establish global and local stability results for the model under the aforementioned derivative. Additionally, we compute the fundamental reproduction number, which helps predict the transmission of the disease in the community. Using the Carlos Castillo-Chavez method, we derive some adequate results about the bifurcation analysis of the proposed model. We also investigate sensitivity analysis to the given model using the criteria of Chitnis and his co-authors. Furthermore, we formulate the characterization of optimal control strategies by utilizing Pontryagin's maximum principle. We simulate the model for different fractal-fractional orders subject to various parameter values using Adam Bashforth's numerical method. All numerical findings are presented graphically. © 2023 by the authors.

The inspiratory activity of respiratory center and respiratory muscles strength after COVID-19.

The respiratory pump that provides pulmonary ventilation includes the respiratory center, peripheral nervous system, chest and respiratory muscles. The aim of this study was to evaluate the activity of the respiratory center and the respiratory muscles strength after COVID-19 (COronaVIrus Disease 2019). Methods. The observational retrospective cross-sectional study included 74 post-COVID-19 patients (56 (76%) men, median age - 48 years). Spirometry, body plethysmography, measurement of lung diffusing capacity (DLCO), maximal inspiratory and expiratory pressures (MIP and MEP), and airway occlusion pressure after 0.1 sec (P0.1) were performed. In addition, dyspnea was assessed in 31 patients using the mMRC scale and muscle strength was assessed in 27 of those patients using MRC Weakness scale. Results. The median time from the COVID-19 onset to pulmonary function tests (PFTs) was 120 days. The total sample was divided into 2 subgroups: 1 - P0.1 <= 0.15 kPa (norm), 2 - > 0.15 kPa. The lung volumes, airway resistance, MIP, and MEP were within normal values in most patients, whereas DLCO was reduced in 59% of cases in both the total sample and the subgroups. Mild dyspnea and a slight decrease in muscle strength were also detected. Statistically significant differences between the subgroups were found in the lung volumes (lower) and airway resistance (higher) in subgroup 2. Correlation analysis revealed moderate negative correlations between P0.1 and ventilation parameters. Conclusion. Measurement of P0.1 is a simple and non-invasive method for assessing pulmonary function. In our study, an increase in P0.1 was detected in 45% of post-COVID-19 cases, possibly due to impaired pulmonary mechanics despite the preserved pulmonary ventilation as well as normal MIP and MEP values.Copyright © Savushkina O.I. et al., 2023.

Oncolytic virus TG6002 safety and activity after intrahepatic artery administration in patients with liverdominant metastatic colorectal cancer

The TG6002.03 trial is a dose-escalation phase 1 clinical trial of TG6002 infusion via the hepatic artery in patients with liver-dominant colorectal cancer metastases. TG6002 is an engineered Copenhagen strain oncolytic Vaccinia virus, deleted of thymidine kinase and ribonucleotide reductase to enhance tumor selective viral replication and expressing FCU1, an enzyme converting the non-cytotoxic prodrug 5-fluorocytosine (5-FC) into the chemotherapeutic compound 5-fluorouracil (5-FU). In this trial, patients with advanced unresectable liver-dominant metastatic colorectal cancer who had failed previous oxaliplatin and irinotecan-based chemotherapy were treated with up to 2 cycles of TG6002 infusion 6 weeks apart via the hepatic artery on day 1 combined with oral 5-FC on days 5 to 14 (where day 1 = TG6002 infusion). TG6002 infusion was performed over 30 minutes via selective catheterization of the hepatic artery proper. 5-FC oral dosing was 50mg/kg x4 daily. Blood was sampled for TG6002 pharmacokinetics and 5-FC and 5-FU measurements. Sampling of liver metastases was performed at screening and on day 4 or day 8 for virus detection and 5-FC and 5-FU quantification. In total, 15 patients (median age 61 years, range 37-78) were treated in 1 UK centre and 2 centres in France and received a dose of TG6002 of 1 x 106 (n=3), 1 x 107 (n=3), 1 x 108 (n=3), or 1 x 109 pfu (n=6). Fourteen of the 15 patients received a single cycle of treatment, including one patient who did not received 5-FC, and one patient received two cycles. TG6002 was transiently detected in plasma following administration, suggesting a strong tissue selectivity for viral replication. In the highest dose cohort, a virus rebound was observed on day 8, concordant with replication time of the virus. In serum samples, 5-FU was present on day 8 in all patients with a high variability ranging from 0.8 to 1072 ng/mL and was measurable over several days after initiation of therapy. Seven of the 9 patients evaluable showed the biodistribution of the virus in liver lesions by PCR testing on day 4 or day 8. Translational blood samples showed evidence for T-cell activation and immune checkpoint receptor-ligand expression. At 1 x 109 pfu, there was evidence for T-cell proliferation and activation against tumour-associated antigens by ELISpot and for immunogenic cell death. In terms of safety, a total of 34 TG6002-related adverse events were reported, of which 32 were grade 1-2 and 2 were grade 3. The maximum tolerated dose was not reached, and a single dose-limiting toxicity was observed consisting of a myocardial infarction in a context of recent Covid-19 infection in a 78-year-old patient. These results indicate that TG6002 infused via the hepatic artery in combination with oral 5-FC was well tolerated, effectively localized and replicated in the tumor tissues, expressed its therapeutic payload and showed anti-tumoral immunological activity.

Isometric thumb extension exercise as part of a multimodal intervention for de Quervain's syndrome: A randomised feasibility trial

Introduction: de Quervain's syndrome is a painful condition commonly presented to hand therapists. Exercise is utilised as an intervention, but isometric exercise has not been investigated. We aimed to assess the feasibility and safety of isometric thumb extension exercise for de Quervain's syndrome and to explore differences between high-load and low-load isometric exercise. Method(s): This parallel-group randomised clinical feasibility trial included individuals with de Quervain's syndrome. All participants underwent a 2 week washout period where they received an orthosis, education, and range of motion exercises. Eligible participants were then randomised to receive high or low-load isometric thumb extension exercises, performed daily for 4 weeks. Feasibility and safety were assessed by recruitment and drop-out rates, adherence, adverse events, and participant feedback via semi-structured interviews. Secondary outcomes included patient-reported outcomes for pain and function, and blinded assessment of range of motion and strength. Result(s): Twenty-eight participants were randomised. There were no drop-outs after randomisation, and no serious adverse events. Adherence to exercise was 86.7%, with 84% of participants stating they would choose to participate again. There were clinically and statistically significant improvements in pain and function over time (p < 0.001) but not in range of motion or strength. There were no statistically significant between-group differences. Conclusion(s): Isometric thumb extension exercise within a multimodal approach appears a safe and feasible intervention for people with de Quervain's syndrome. A large multi-centre trial would be required to compare high- and low-load isometric exercises. Further research investigating exercise and multimodal interventions in this population is warranted.Copyright © The Author(s) 2023.

A review on drawdown risk measures and their implications for risk management

As highlighted by the recent market turmoil following COVID‐19, markets can experience significant retracements or drawdowns. While these recent market moves have definitely been large, significant drawdowns have been around since the start of financial markets. Various risk metrics such as Value at Risk and volatility are used to describe risk. The intuitive drawdown risk measure, which is often used in practice alongside the above metrics, is receiving more and more academic attention. In this article we provide a systematic review of the literature on the drawdown risk measures. We describe two different methodologies for calculating drawdowns and analyze drawdown based risk measures used in risk management, portfolio construction and optimization. Finally we discuss the statistical properties related to drawdowns. Based on the research done so far, we identify several areas for further research.

Online Phylogenetics with matOptimize Produces Equivalent Trees and is Dramatically More Efficient for Large SARS-CoV-2 Phylogenies than de novo and Maximum-Likelihood Implementations.

Phylogenetics has been foundational to SARS-CoV-2 research and public health policy, assisting in genomic surveillance, contact tracing, and assessing emergence and spread of new variants. However, phylogenetic analyses of SARS-CoV-2 have often relied on tools designed for de novo phylogenetic inference, in which all data are collected before any analysis is performed and the phylogeny is inferred once from scratch. SARS-CoV-2 datasets do not fit this mold. There are currently over 14 million sequenced SARS-CoV-2 genomes in online databases, with tens of thousands of new genomes added every day. Continuous data collection, combined with the public health relevance of SARS-CoV-2, invites an "online" approach to phylogenetics, in which new samples are added to existing phylogenetic trees every day. The extremely dense sampling of SARS-CoV-2 genomes also invites a comparison between likelihood and parsimony approaches to phylogenetic inference. Maximum likelihood (ML) and pseudo-ML methods may be more accurate when there are multiple changes at a single site on a single branch, but this accuracy comes at a large computational cost, and the dense sampling of SARS-CoV-2 genomes means that these instances will be extremely rare because each internal branch is expected to be extremely short. Therefore, it may be that approaches based on maximum parsimony (MP) are sufficiently accurate for reconstructing phylogenies of SARS-CoV-2, and their simplicity means that they can be applied to much larger datasets. Here, we evaluate the performance of de novo and online phylogenetic approaches, as well as ML, pseudo-ML, and MP frameworks for inferring large and dense SARS-CoV-2 phylogenies. Overall, we find that online phylogenetics produces similar phylogenetic trees to de novo analyses for SARS-CoV-2, and that MP optimization with UShER and matOptimize produces equivalent SARS-CoV-2 phylogenies to some of the most popular ML and pseudo-ML inference tools. MP optimization with UShER and matOptimize is thousands of times faster than presently available implementations of ML and online phylogenetics is faster than de novo inference. Our results therefore suggest that parsimony-based methods like UShER and matOptimize represent an accurate and more practical alternative to established maximum likelihood implementations for large SARS-CoV-2 phylogenies and could be successfully applied to other similar datasets with particularly dense sampling and short branch lengths.

COVID-19 SIR model: Bifurcation analysis and optimal control

This paper proposes a SIR epidemic model with vital dynamics to control or eliminate the spread of the COVID-19 epidemic considering the constant population, saturated treatment, and direct-indirect transmission rate of the model. We demonstrate positivity, boundness and calculate the disease-free equilibrium point and basic reproduction number from the model. We use the Jacobian matrix and the Lyapunov function to analyze the local and global stability, respectively. It is observed that indirect infection increases the basic reproduction number and gives rise to multiple endemic diseases. We perform transcritical, forward, backward, and Hopf bifurcation analyses. We propose two control parameters (Use of face mask, hand sanitizer, social distancing, and vaccination) to minimize the spread of the coronavirus. We use Pontryagin's maximum principle to solve the optimal control problem and demonstrate the results numerically.

INTERIM RESULTS OF THE PML-16, PML-19 PROTOCOLS FOR PRIMARY MEDIASTINAL LARGE B-CELL LYMPHOMA THERAPY

Introduction. Primary mediastinal lymphoma (PML) is an aggressive lymphoid tumor treatment success of which is determined by induction therapy. To date, none of the standard chemotherapy regimens (CT) have demonstrated an advantage in efficacy. Intensive therapy programs are associated with high toxicity. Aim - to evaluate the efficacy and toxicity of two pilot prospective treatment protocols PML-16 and PML-19 as well as the possibility of using the analysis of freely circulating tumor DNA (ctDNA) to assess MRD in patients with PML. Materials and methods. From January 2016 to January 2022, 34 previously untreated PML patients were included in the study;average age - 32;stage > I - in 60 %;extramediastinal lesions - in 14.7 %;bulky disease - in 73.5 % of patients. Positron emission tomography combined with computed tomography (PET-CT) was performed;ctDNA was determined to assess the completeness of remission. Results. Eighteen patients received treatment according to the PML-16 protocol (6 courses of chemotherapy;2 blocks of RmNHL-BFM-90 + 4 courses of R-EPOCH). After the end of therapy, all 18 patients achieved PET-negative remission. The next 16 patients received treatment according to the PML-19 protocol (4 courses of chemotherapy;2 blocks of R-mNHL-BFM-90 + 2 courses of R-EPOCH) in combination with lenalidomide. After the end of therapy, 9 (56 %) patients achieved PET-negative remission;7 (44 %) retained pathological activity (D4-5 points). After 3 and 6 months 15 (94 %) patients achieved normalization of metabolic activity. Considering the high frequency of false-positive results in patients with PML, a ctDNA study was performed to determine the depth of remission in 15 patients. After the end of therapy, all 15 patients had complete elimination of ctDNA. Of these, 5 (33 %) remained PET-positive at the end of treatment. During further observation, after 3-6 months, in 4 patients the level of metabolic activity decreased to physiological without the use of consolidating therapy. After the end of therapy, one patient suffered the new coronavirus infection, COVID-19. A month later, residual formation of SUVmax 14.2 remained in the mediastinum. The patient is currently under observation. With a median follow-up of 36 months (9 to 76 months) all 34 patients are in remission. Conclusion. The effectiveness of PML-16 made it possible to abandon the consolidation therapy and refuted the idea of the need for 6 courses of CT. The combination of programs based on the application of the principle of high-dose short-pulse induction of remission (R-mNHL-BFM-90) in combination with the prolonged administration of medium doses (R-EPOCH) was crucial in achieving a successful result. The inclusion of lenalidomide in the "PML-19" program made it possible to achieve complete remission in 100 % of cases after 4 courses. The possibility of using DNA analysis to assess MRD in patients with PML was shown.Copyright © 2022 Izdatel'stvo Meditsina. All rights reserved.

Hypermetabolic ipsilateral supraclavicular and axillary lymphadenopathy: Optimal time point for performing 18F-FDG PET/CT after COVID-19 vaccination

Ziel/Aim We aimed at evaluating the incidence of SARS-CoV2 vaccine-related axillary and supraclavicular hypermetabolic lymphadenopathy (HLA) and evaluate which timepoint produces the least number of false-positive findings in HLA. Methodik/Methods For this retrospective, multi-center imaging study patients with any form of SARS-CoV2 vaccination prior to 18F-FDG-PET/CT between January 2021 and December 2021 were included. Patients were divided into six groups according to the timepoint of vaccination prior to 18F-FDG-PET/CT imaging: Group 1 (0-6 Days), Group 2 (7-13 Days), Group 3 (14-20 Days), Group 4 (21-27 Days), Group 5 (28-34 Days) and Group 6 (35-80 Days). As reference SUVmax of mediastinal blood pool (MBP) and SUVmax contralateral reference lymph node (RL) were determined. For each group, the following parameters were assessed. A) absolute SUVmax of HLA B) incidence of HLA [defined as the ratio of SUVmaxHLA/ SUVmax Mediastinal Blood Pool (rHLA/MBP)] greater than 1,5 C) rHLA/MBP D) ratio SUVmax HLA vs. SUVmax contralateral reference lymph node (rHLA/RL). Ergebnisse/Results HLA showed the highest incidence in Group 1(day 0-6) 16/23 (70 %). Similarly, SUVmax HLA and rHLA/MBP were highest in this group, SUVmax 4.97 +/- 4.1 and 2.58 +/- 2.1 respectively. The incidence of HLA, SUVmax HLA, and rHLA/MBP were higher in Group 3 (14-20 days) than in Group 2 (7- 13days);57 % vs 44 %;5.05 +/- 4.33vs 3.9 +/- 2.81 (p = 0.723 and 2.32 +/- 1.8 vs 1.83 +/- 1.38(p = 0.788). All parameters for HLA dropped markedly after at least 21 days of vaccination. There were no significant differences in SUVmax HLA, rHLA/MBP and rHLA/RL in group 4 (21-27 days), group 5 (28-34 days) and group 6 (35-80 Days). [1] Schlussfolgerungen/Conclusions It is crucial for diagnostic physicians to assess the recent history of COVID-19 vaccination prior to FDG-PET/CT scan to reduce the risk of false-positive calls. If feasible, FDG PET should be postponed by at least 3 weeks after SARS-CoV2 vaccination especially if an accurate evaluation of axillary status is required.

Optimal control analysis of Monkeypox disease with the impact of environmental transmission

Monkeypox is an emerging zoonotic viral disease resembling that of smallpox, although it is clinically less severe. Following the COVID-19 outbreak, monkeypox is an additional global health concern. The present study aims to formulate a novel mathematical model to examine various epidemiological aspects and to suggest optimized control strategies for the ongoing outbreak. The environmental viral concentration plays an important role in disease incidence. Therefore, in this study, we consider the impact of the environmental viral concentration on disease dynamics and control. The model is first constructed with constant control measures.The basic mathematical properties including equilibria, stability, and reproduction number of the monkeypox model are presented. Furthermore, using the nonlinear least square method, we estimate the model parameters from the actual cases reported in the USA during a recent outbreak in 2022. Normalized sensitivity analysis is performed to develop the optimal control problem. Based on the sensitivity indices of the model parameters, the model is reformulated by introducing six control variables. Based on theoretical and simulation results, we conclude that considering all suggested control measures simultaneously is the effective and optimal strategy to curtail the infection. We believe that the outcomes of this study will be helpful in understanding the dynamics and prevention of upcoming monkeypox outbreaks. © 2023 the Author(s), licensee AIMS Press.

The inspiratory activity of respiratory center and respiratory muscles strength after COVID-19

The respiratory pump that provides pulmonary ventilation includes the respiratory center, peripheral nervous system, chest and respiratory muscles. The aim of this study was to evaluate the activity of the respiratory center and the respiratory muscles strength after COVID-19 (COronaVIrus Disease 2019). Methods. The observational retrospective cross-sectional study included 74 post-COVID-19 patients (56 (76%) men, median age – 48 years). Spirometry, body plethysmography, measurement of lung diffusing capacity (DLCO), maximal inspiratory and expiratory pressures (MIP and MEP), and airway occlusion pressure after 0.1 sec (P0.1) were performed. In addition, dyspnea was assessed in 31 patients using the mMRC scale and muscle strength was assessed in 27 of those patients using MRC Weakness scale. Results. The median time from the COVID-19 onset to pulmonary function tests (PFTs) was 120 days. The total sample was divided into 2 subgroups: 1 – P0.1 ≤ 0.15 kPa (norm), 2 – > 0.15 kPa. The lung volumes, airway resistance, MIP, and MEP were within normal values in most patients, whereas DLCO was reduced in 59% of cases in both the total sample and the subgroups. Mild dyspnea and a slight decrease in muscle strength were also detected. Statistically significant differences between the subgroups were found in the lung volumes (lower) and airway resistance (higher) in subgroup 2. Correlation analysis revealed moderate negative correlations between P0.1 and ventilation parameters. Conclusion. Measurement of P0.1 is a simple and non-invasive method for assessing pulmonary function. In our study, an increase in P0.1 was detected in 45% of post-COVID-19 cases, possibly due to impaired pulmonary mechanics despite the preserved pulmonary ventilation as well as normal MIP and MEP values. © Savushkina O.I. et al., 2023.

Novel role of 18F- FDG PET/CT in rhinosinonasal mucormycosis in the era of covid-19 infection

Objectives: In the Covid-19 era, there was a surge in the cases of a life-threatening infection of rhinosinonasal mucormycosis. Mucormycosis, popularly known as black fungus, is an infection caused by mycetes mucorales, an aseptate hyphae. Presently, computed tomography (CT) and magnetic resonance imaging (MRI) are commonly used imaging modalities for the management of patients with rhinosinonasal mucormycosis. The present study was aimed to evaluate the role of 18F- FDG PET/CT in the detection of recurrent or residual disease in post-surgical or post antifungal therapy in these patients for further management. Method(s): A total of 10 patients were included in this pilot study of Covid-19 positive patients and histologically proven mucormycosis (by KOH mount). 18F- FDG PET/CT was performed to assess the disease status in 6 postoperative/ post debridement patients and response to antifungal therapy in 4 patients, at an interval of 40 (range = 27-66) days post intervention. Result(s): The mean age of the patients was 45.0 +/- 11.65 years. The male: female ratio was 9:1. The common clinical presentation was ipsilateral facial or orbital pain and swelling. Covid-19 infection was positive in all the patients except one who had CT finding with HRCT score of 10/25 and hence was considered as post Covid-19 infection. Six out of 10 patients were diabetic on oral hypoglycaemic agents or insulin. All patients had a baseline CT/MRI for staging the initial extent of the disease. Surgical debridement was done in 6 out of the 10 patients followed by antifungal therapy (Liposomal Amphotericin B and Pozaconazole). Remaining four patients were treated with antifungal therapy. PET/CTwas performed after an average of 40 days of surgical/medical intervention, in whom clinical symptoms persisted or worsened even on antifungal therapy. 18F-FDG PET/CT showed metabolically active residual disease in all the patients with a mean SUVmax of 9.78 +/- 4.03. Conclusion(s): In the era of ongoing Covid-19 infection, black fungus has been a debilitating disease with high mortality and morbidity. Present study demonstrated that 18F-FDG PET/CT can be an efficient imaging tool for an early surgical/ medical treatment response assessment and restaging.

High Dose Ivig in Multisystem Inflammatory Syndrome in Children and Response to Treatment

Purpose of Study: In February 2022, the American College of Rheumatology (ACR) updated its guidance for multisystem inflammatory syndrome in children (MIS-C). The treatment recommendation is to use intravenous immunoglobulin (IVIG) at 2 grams/kg with a maximum dose of 100 grams based on a moderate level of consensus among the task force members. To date, there are no studies comparing the response to doses of more than 100 grams in MIS-C. Methods Used: A retrospective review was conducted of patients admitted to Loma Linda University Children's Hospital for MIS-C from May 2020 to March 2021. Demographic, symptom, laboratory, and treatment data were systematically collected from the electronic medical record. The PRISM III score was calculated for all patients admitted to the PICU and used to control for severity of illness. Patients were designated non-responders if anakinra, or a second IVIG dose was given. A binomial logistic regression was used to model response to the IVIG dose in univariate and multivariate analysis with and without the PRISM III score and PICU length of stay. A Fisher's exact test was used to compare categorical variables. Summary of Results: There were 77 children treated for MIS-C. The median age was 118.5 months with a range of 3 to 254 months. There was a total of 30 patients who initially received at least 100 grams of IVIG of which 20 were in the PICU. All patients given at least 100 grams of IVIG received steroids concurrently. A univariate binomial regression using IVIG dose for patients admitted to the PICU showed an odds ratio of non-response was 0.98 (CI 0.94 - 1.02). The analysis is the same for all patients who received greater than 100 grams of IVIG. In a multivariate binomial regression, which included the PRISM III score, length of PICU stay and days of symptoms prior to admission, the odds ratio of non-response to IVIG was 0.98 (CI 0.92 - 1.03). Of the 10 patients who were not admitted to the PICU, only 1 failed to respond to IVIG and required anakinra. None of the patients who received more than 100 grams of IVIG were tested for hemolytic anemia but only 1 patient who received more than 1 dose of IVIG had a decline in hemoglobin. There was a median decline of 2.75 g/dL (range 1.6 - 6.7 g/dL) in all patients who had a decline in hemoglobin and received more than 100 grams of IVIG. Conclusion(s): In this single center cohort of patients who were admitted to the PICU for MIS-C who received more than 100 grams of IVIG initially, there was no relationship between higher doses of IVIG and halting inflammation. This study agrees with the ACR guidance regarding the dose of IVIG in MIS-C and adds evidence to give no more than 100 grams of IVIG.

BEMNIFOSBUVIR HAS LOW POTENTIAL TO INHIBIT P-gp, BCRP, AND OATP1B1 MEDIATED TRANSPORT

Background: Bemnifosbuvir (BEM, AT-527) is a guanosine nucleotide prodrug candidate for the treatment of COVID-19 and chronic HCV. BEM was identified in vitro as an inhibitor of drug transporters P-glycoprotein, breast cancer resistant protein (BCRP) and organic anion transporting polypeptide 1B1 (OATP1B1). Ph 1 studies in healthy participants were conducted to assess the clinical implications of these results using digoxin (DIG) and rosuvastatin (ROSU) as P-gp and BCRP/ OATP1B1 index drugs, respectively. Method(s): Both studies employed a similar design with 2 groups of 14 healthy participants: Day 1/period 1, all participants received a single dose of DIG 0.25mg or ROSU 10mg alone. In period 2, participants received DIG 0.25mg or ROSU 10mg with BEM 1100mg, simultaneously (n=14) or staggered by 2h (n=14). Serial plasma samples were collected and quantitated for DIG or ROSU concentrations. Result(s): A single dose of BEM 1100mg simultaneously administered slightly increased the Cmax of DIG (78%), yet had no effect on its AUC, consistent with the transient nature of BEM plasma PK. When dosed staggered, BEM did not affect the PK of DIG. A single dose (simultaneous or staggered) of BEM 1100mg slightly increased the plasma exposure of ROSU (20%-40%). There was no effect on vital signs, ECG, and no SAEs or drug discontinuations. Conclusion(s): A single high dose of BEM 1100mg only slightly increased the plasma exposure of the P-gp and BCRP/OATP1B1 index drugs DIG and ROSU. BEM has low potential to exhibit clinical meaningful inhibition of these transporters. No dose adjustment will be needed for drugs that are sensitive substrates of P-gp or BCRP/OAT1B1 when co-administered with BEM, staggered dosing may lessen any DDI risk.

SARS-CoV-2 VARIANTS' TEMPORAL AND VL DISTRIBUTIONS IN IMMUNOCOMPROMISED PATIENTS

Background: The COVID-19 pandemic has been striking for three years and, despite the regular arise of new variants, populations are now widely immune and protected from severe symptoms. However, immunocompromised patients still have worse clinical outcomes, higher mortality and rarely develop effective immunity through vaccination or infection. Here, we studied the temporal distribution of infections, viral loads (VL) as well as the viral genetic diversity among an immunocompromised patient cohort, between January 2021 and September 2022. Method(s): Overall, 478 immunocompromised patients (solid organ transplant, HIV positive, cancer, autoimmune disease) and 234 controls (healthcare workers) from Pitie-Salpetriere and Bichat Claude-Bernard University hospitals (Paris, FRANCE) were diagnosed with SARS-CoV-2 infection by RT-qPCR. Whole genome sequencing was performed according to ARTIC protocol on Oxford Nanopore platform. All 712 full viral genomes were used to determine lineages and mapped to Wuhan-Hu-1 reference to produce a maximum likelihood phylogenetic tree (IQTree, 1000 bootstraps). Differences in temporal distributions of infections and VL were assessed using nonparametric statistical tests. Result(s): According to phylogenetic analysis, genomes from SARS-CoV- 2 infecting immunocompromised patients and those infecting healthy individuals are distributed in a similar way. No significant genetic differences can be observed between viral genomes from patients and controls within the different lineages. Temporal distribution of COVID-19 infections were also similar between immunocompromised patients and controls, with the exception of BA.2 variant for which controls were infected earlier (p< 0.001). VL were significantly lower in immunocompromised patients infected with Omicron variants (p=0.04). No differences in VL were observed for Alpha and Delta variants. Conclusion(s): At diagnosis, no intrinsic genetic divergence was observed in virus infecting immunocompromised patients compared to those circulating in the general population. Similarities in temporal distribution of infections between controls and patients suggest that these different groups become infected concomitantly. VL appeared to be lower for Omicron variants in immunocompromised patients. An earlier VL peak of Omicron and a testing of immunocompromised patients hospitalized once severe symptoms have appeared could indicate a delayed testing in these patients, once the replicative phase over. (Figure Presented).

Evolution of Clusters Transmission Patterns in France during the Last Decade

Background: The recent transmission clusters (RTCs) identified through phylogenetic approaches allow to describe the main transmission networks. This render possible to describe potential shifts among HIV transmission routes and populations and, in some cases, to specifically target prevention measures. Here we describe the evolution of RTCs over the last decade in a specialized laboratory serving centers from the entire French territory. Method(s): We extracted all the HIV reverse transcriptase sequences available between 01/01/2013 and 31/08/2022. The sequences dataset was studied overall and divided into three equal time periods: 2013-15, 2016-18, 2019-2021. The first sequences available for each patient were aligned and the trees were reconstructed by maximum likelihood using IQtree software. Clusters, defined by a maximum genetic distance < 4.5% and a branch support >90%, were extracted using ClusterPicker. Result(s): Overall, 8591 sequences were included. Among them, 950 RTCs were identified including 2492 sequences (29%) and 68 large RTCs ( >4 sequences) with 475 (5.6%) sequences. The mean duration of large RTCs (from the first to the last sequences) was 5.1 years [IQR: 4.1-7.1] and 34 were still active (including at least one sequence during the last year of the study period). 3640, 2897 and 2157 sequences were included for the 2013-15, 2016-18 and 2019-2021 periods, respectively. We identified 298 RTCs (19.5% of sequences), 249 (20.4%) and 226 (27.5%) among those periods, respectively. While the number of sequence pairs decreased from 2013-15 to 2019-21, the number of large RTCs increased steadily (see Table 1). During the period 2019-21, including the largest clusters, patients belonging to a RTC were more often male (68 vs 58%, p< 0.001) and younger (average age: 39 vs 44 years, p< 0.001) than non-RTC patients. This observation was even more marked for very large RTCs (see Table 2). It should be noted that the largest cluster (14 patients) was mainly composed of women and located in French overseas territories. Conclusion(s): This study shows an evolution of the structure of HIV sequence clusters over time with a decreasing number of small RTCs but an increasing number of large RTCs. These trends can be explained by a better global control of transmission, due in part to TasP, but not preventing some super-transmitters networks, despite PrEP use and not only including MSM is some settings. The COVID period does not seem to have strongly prevented such large transmission networks.

Viral Suppression Trajectories Destabilized after Covid-19 among Us People with Hiv

Background: Disruptions in clinical services during the COVID-19 pandemic could compromise past progress towards meeting U.S. Ending the HIV Epidemic (EHE) goals. We examined changes in the proportion with virologic suppression (VS) before and since the onset of COVID-19 in a multi-site U.S. cohort of people with HIV (PWH) using an interrupted time series design. Method(s): We assessed VS (< 200 copies/mL) trajectories 1/1/2018-1/1/2022, comparing trends before and after March 21, 2020 at 8 HIV clinics within the U.S. Center for AIDS Research Network of Integrated Clinical Systems (CNICS'). Hierarchical mixed-effects logistic regression and interrupted time series analyses examined changes in the trend (i.e., slope) of VS over time, and maximum likelihood estimation was used to account for missing VS data among those lost to follow-up (LTFU) post-COVID-19. Analyses were adjusted for demographics, site, CDC transmission group, CD4 nadir, VS, time on ART. Result(s): Data from 17,999 participants were included, providing a total of 120,918 VS assessments. Median age was 53 (interquartile range 42-61);19% were female sex at birth;the mean time on ART was 9.5 years;18% were unsuppressed at any point;17.7% were LTFU. Among the overall population, prior gains in VS slowed during COVID-19 (adjusted odds ratio [AOR] 0.93 per quarter-year;95% CI: 0.88-0.98;p=0.004;Figure). Greater impacts occurred among women (AOR 0.90;95% CI 0.81-0.99;p=0.05), persons with a history of injection drug use (PWID) (AOR 0.77 95% CI: 0.66-0.90;p=0.001), and Black PWH (AOR 0.90;95% CI: 0.84-0.96;p=0.001) in whom prior positive VS trends plateaued or began to reverse (Figure). VS remained lower among those with unstable housing (AOR 0.44;95% CI: 0.40-0.50;p< 0.001) but stayed unchanged from the pre-pandemic period. Conclusion(s): Previous gains in VS slowed during the COVID-19 pandemic among PWH in a multi-site network of U.S. HIV clinics. Known disparities in VS according to housing status remain unchanged, but VS disparities worsened for PWH who were women, PWID, or Black. Changes in VS trends could be related to socioeconomic impacts of the pandemic, insurance lapses, reduction of in-person clinic services, fear of coming to clinics, or other factors. Renewed investment in HIV public health and clinical services will be vital to achieve the U.S. EHE goals following COVID-19, with additional targeted interventions to support key populations with persistent or worsening disparities needed.

The inspiratory activity of respiratory center and respiratory muscles strength after COVID-19.

The respiratory pump that provides pulmonary ventilation includes the respiratory center, peripheral nervous system, chest and respiratory muscles. The aim of this study was to evaluate the activity of the respiratory center and the respiratory muscles strength after COVID-19 (COronaVIrus Disease 2019). Methods. The observational retrospective cross-sectional study included 74 post-COVID-19 patients (56 (76%) men, median age - 48 years). Spirometry, body plethysmography, measurement of lung diffusing capacity (DLCO), maximal inspiratory and expiratory pressures (MIP and MEP), and airway occlusion pressure after 0.1 sec (P0.1) were performed. In addition, dyspnea was assessed in 31 patients using the mMRC scale and muscle strength was assessed in 27 of those patients using MRC Weakness scale. Results. The median time from the COVID-19 onset to pulmonary function tests (PFTs) was 120 days. The total sample was divided into 2 subgroups: 1 - P0.1 <= 0.15 kPa (norm), 2 - > 0.15 kPa. The lung volumes, airway resistance, MIP, and MEP were within normal values in most patients, whereas DLCO was reduced in 59% of cases in both the total sample and the subgroups. Mild dyspnea and a slight decrease in muscle strength were also detected. Statistically significant differences between the subgroups were found in the lung volumes (lower) and airway resistance (higher) in subgroup 2. Correlation analysis revealed moderate negative correlations between P0.1 and ventilation parameters. Conclusion. Measurement of P0.1 is a simple and non-invasive method for assessing pulmonary function. In our study, an increase in P0.1 was detected in 45% of post-COVID-19 cases, possibly due to impaired pulmonary mechanics despite the preserved pulmonary ventilation as well as normal MIP and MEP values.Copyright © Savushkina O.I. et al., 2023.

Safety and Pharmacokinetics of a Novel Double Prodrug Asc10 in Healthy Subjects

Background: ASC10 is an oral double prodrug of the active antiviral ribonucleoside analog, ASC10-A (also known as beta-d-N4-hydroxycytidine), which is a potent inhibitor of SARS-CoV-2. ASC10 is rapidly metabolized into ASC10-A in vivo after oral dosing. Here, we report the results of the first-in-human, phase 1 study to determine the safety, tolerability, and pharmacokinetics (PK) of ASC10 in healthy subjects, and to assess the food effect on the pharmacokinetics. Method(s): This study included 2 parts. Part 1 (multiple-ascending-dose) consisted of 6 cohorts (8 or 12 subjects per cohort). Eligible subjects were randomized in a 3:1 ratio to receive either twice-daily (BID) doses of 50 to 800 mg ASC10 or placebo for 5.5 days, and were then followed for 7 days for safety. In Part 2 (food effect), 12 subjects were randomized in a 1:1 ratio to either 800 mg ASC10 in the fed state followed by 800 mg in the fasted state, or vice versa, with a 7-day washout period between doses. PK blood samples were collected and measured for ASC10-A along with ASC10 and molnupiravir. Safety assessments included monitoring of adverse events (AEs), measurement of vital signs, clinical laboratory tests, and physical examinations. Result(s): ASC10-A was the major circulating metabolite ( >99.94%) in subjects after oral dosing of ASC10. ASC10-A appeared rapidly in plasma, with a median Tmax of 1.00 to 2.00 h, and declined with a geometric t1/2 of approximately 1.10 to 3.04 h. After multiple dosing for 5.5 days, both Cmax and AUC of ASC10-A increased in a dose-proportional manner from doses of 50 to 800 mg BID without accumulation. of ASC10-A in the fed state occurred slightly later, with a median of 3.99 h postdose versus 2.00 h (fasted state). However, Cmax and AUC were very similar or the same between fed and fasted states. Thus, administration of ASC10 with food is unlikely to have an effect on exposure. The incidence of AEs was similar between subjects receiving ASC10 or placebo (both 66.7%) and 95.0% of AEs were mild. There were no serious adverse events as well as no clinically significant findings in clinical laboratory, vital signs, or electrocardiography. Conclusion(s): Results of this study showed that ASC10 was well tolerated, and the increase in plasma exposure of ASC10-A was dose proportional across the range of doses tested with no accumulation and no food effect. 800 mg ASC10 BID is selected for further studies in patients infected with SARS-CoV-2.

Simulation of pharmacokinetic drug-drug interaction and dosage regimens optimization of nelfinavir and cepharanthine as a potential combination against COVID-19

The pharmacokinetic (PK) drug-drug interactions (DDIs) of nelfinavir and cepharanthine combination is limited information in human. In addition, the dosage regimen of this combination is not available for COVID-19 treatment. The objective of this study was to perform in silico simulations using GastroPlusTM software to predict physicochemical properties, PK parameters using the physiologically based pharmacokinetic (PBPK) model of healthy adults in different dosage regimens. The DDIs analysis of nelfinavir and cepharanthine combination was carried out to optimize the dosage regimens as a potential against COVID-19. The Spatial Data File (SDF) format of nelfinavir and cepharanthine structures obtained from PubChem database were used to carry out in silico predictions for physicochemical properties and PK parameters using several aspects of modules such as ADMET Predictor, Metabolism and Transporter, PBPK model. Subsequently, all data were utilized in the DDIs simulations. The dynamic simulation feature was selected to calculate and investigate the Cmax, AUC0-120, AUC0-inf, Cmax ratio, AUC0-120 ratio, and AUC0-inf ratio. The victim or nelfinavir dosage regimens were used four oral administration regimens of 500 mg and 750 mg in every 8 and 12 hours for simulations. The perpetrator or cepharanthine oral dosage regimens were used in several regimens from 10 mg to 120 mg in every 8, 12, and 24 hours. From all predicted results, the dosage regimen as a potential combination against COVID-19 was nelfinavir 500 mg every 8 hours and cepharanthine 10 mg every 12 hours.Copyright © 2023 by Faculty of Pharmacy, Mahidol University, Thailand is licensed under CC BY-NC-ND 4.0. To view a copy of this license, visit https://www.creativecommons.org/licenses/by-nc-nd/4.0/.