COVID-19 patients' clinical profile and outcome with respect to their vaccination status: A prospective observational multicentre cohort study during third wave in Western India.

PURPOSE: To understand the benefits of COVID-19 vaccination (Covishield, Covaxin) on clinical features and outcome of COVID-19 during the third wave in India. MATERIALS AND METHODS: The primary study aim was to describe the clinical profile and outcome of COVID-19 regarding their vaccination and to identify risk factors for disease progression in vaccinated patients. This was a prospective observational multicentric study of COVID-19 attended by Infectious Disease physicians during January 15, 2022 to February 15, 2022. Adult patients with positive RT-PCR or rapid antigen test for COVID-19 were enrolled. Patient received treatment as per local institutional protocol. Chi square test for categorical and Mann Whitney test for continuous variables were applied for the analysis. Logistic regression was used to calculate adjusted odds ratios. RESULTS: A total of 788 patients were included in analysis out of 883 enrolled patients from 13 centers across Gujarat. By the end of two weeks' follow up, 22 patients (2.8%) had expired. The Median age of subjects was 54 years, with a (55.8%) male. 90% of the subjects were vaccinated, majority (77%) of them had received 2 doses of vaccine with Covishield (659, 93%). Mortality among the non-vaccinated was significantly (11.4%) higher than vaccinated (1.8%). Logistic regression analysis showed numbers of comorbidities (p â€‹= â€‹0.027), baseline higher WBC count (p â€‹= â€‹0.02), higher NLR (p â€‹= â€‹0.016), and Ct value (p â€‹= â€‹0.046) were associated with mortality while vaccination was associated with survival (p â€‹= â€‹0.001). The factors associated with mortality among vaccinated were age, comorbidities, baseline higher WBC, NLR, and CRP. CONCLUSIONS: Omicron variant was associated with mild symptoms. Clinical and laboratory risk factors for getting severe disease with Omicron variant were the same with previous SARS CoV-2 strain. Two doses of vaccine protect people against severe disease and death. Age, comorbidities, baseline leucocytosis, high NLR, elevated CRP are the risk factors for poor outcome in vaccinated patients.

Benchmark datasets for SARS-CoV-2 surveillance bioinformatics.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has spread globally and is being surveilled with an international genome sequencing effort. Surveillance consists of sample acquisition, library preparation, and whole genome sequencing. This has necessitated a classification scheme detailing Variants of Concern (VOC) and Variants of Interest (VOI), and the rapid expansion of bioinformatics tools for sequence analysis. These bioinformatic tools are means for major actionable results: maintaining quality assurance and checks, defining population structure, performing genomic epidemiology, and inferring lineage to allow reliable and actionable identification and classification. Additionally, the pandemic has required public health laboratories to reach high throughput proficiency in sequencing library preparation and downstream data analysis rapidly. However, both processes can be limited by a lack of a standardized sequence dataset. Methods: We identified six SARS-CoV-2 sequence datasets from recent publications, public databases and internal resources. In addition, we created a method to mine public databases to identify representative genomes for these datasets. Using this novel method, we identified several genomes as either VOI/VOC representatives or non-VOI/VOC representatives. To describe each dataset, we utilized a previously published datasets format, which describes accession information and whole dataset information. Additionally, a script from the same publication has been enhanced to download and verify all data from this study. Results: The benchmark datasets focus on the two most widely used sequencing platforms: long read sequencing data from the Oxford Nanopore Technologies platform and short read sequencing data from the Illumina platform. There are six datasets: three were derived from recent publications; two were derived from data mining public databases to answer common questions not covered by published datasets; one unique dataset representing common sequence failures was obtained by rigorously scrutinizing data that did not pass quality checks. The dataset summary table, data mining script and quality control (QC) values for all sequence data are publicly available on GitHub: https://github.com/CDCgov/datasets-sars-cov-2. Discussion: The datasets presented here were generated to help public health laboratories build sequencing and bioinformatics capacity, benchmark different workflows and pipelines, and calibrate QC thresholds to ensure sequencing quality. Together, improvements in these areas support accurate and timely outbreak investigation and surveillance, providing actionable data for pandemic management. Furthermore, these publicly available and standardized benchmark data will facilitate the development and adjudication of new pipelines.

Risk factors for COVID-19 associated mucormycosis in India: A case control study.

The coronavirus disease 2019 (COVID-19) pandemic had led to an increase in a surge of mucormycosis in COVID-19 patients, especially in India. Diabetes and irrational usage of corticosteroids to treat COVID-19 were some of the factors implicated for COVID-19-associated mucormycosis (CAM). We designed this case-control study to identify risk factors for mucormycosis in COVID-19 patients. The study was conducted at a private tertiary care center in western India. Data were extracted from records of COVID 19 patients (January-May 2021) and divided into two groups: Those with proven or probable mucormycosis, and those without mucormycosis with a ratio of 1:3. A binary logistic regression analysis was done to assess potential risk factors for CAM. A total of 64 CAM and 205 controls were included in the analysis. Age and sex distribution were similar in cases and controls with the majority of males in both the groups (69.9%) and the mean age was 56.4 (±13.5) years. We compared the comorbidities and treatment received during acute COVID-19, specifically the place of admission, pharmacotherapy (steroids, tocilizumab, remdesivir), and the requirement of oxygen as a risk factor for CAM. In a multivariate analysis, risk factors associated with increased odds of CAM were new-onset diabetes (vs. non-diabetics, adjusted odds ratio [OR] 48.66, 95% confidence interval [CI] 14.3-166), pre-existing diabetes (vs. non-diabetics, aOR 2.93, 95%CI 1.4-6.1), corticosteroid therapy (aOR 3.64, 95%CI 1.2-10.9) and home isolation (vs. ward admission, aOR 4.8, 95%CI 2-11.3). Diabetes, especially new-onset, along with corticosteroid usage and home isolation were the predominant risk factors for CAM. LAY SUMMARY: This study revealed new-onset diabetes, pre-existing diabetes, corticosteroid therapy, and home isolation as risk factors for COVID-19-associated mucormycosis. Avoiding the use of corticosteroids in non-severe COVID-19 disease coupled with proper blood sugar monitoring and control will help to reduce the CAM burden.

Pulmonary function test and computed tomography features during follow-up after SARS, MERS and COVID-19: a systematic review and meta-analysis.

Background: The COVID-19 pandemic follows severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronavirus epidemics. Some survivors of COVID-19 infection experience persistent respiratory symptoms, yet their cause and natural history remain unclear. Follow-up after SARS and MERS may provide a model for predicting the long-term pulmonary consequences of COVID-19. Methods: This systematic review and meta-analysis aims to describe and compare the longitudinal pulmonary function test (PFT) and computed tomography (CT) features of patients recovering from SARS, MERS and COVID-19. Meta-analysis of PFT parameters (DerSimonian and Laird random-effects model) and proportion of CT features (Freeman-Tukey transformation random-effects model) were performed. Findings: Persistent reduction in the diffusing capacity for carbon monoxide following SARS and COVID-19 infection is seen at 6 months follow-up, and 12 months after MERS. Other PFT parameters recover in this time. 6 months after SARS and COVID-19, ground-glass opacity, linear opacities and reticulation persist in over 30% of patients; honeycombing and traction dilatation are reported less often. Severe/critical COVID-19 infection leads to greater CT and PFT abnormality compared to mild/moderate infection. Interpretation: Persistent diffusion defects suggestive of parenchymal lung injury occur after SARS, MERS and COVID-19 infection, but improve over time. After COVID-19 infection, CT features are suggestive of persistent parenchymal lung injury, in keeping with a post-COVID-19 interstitial lung syndrome. It is yet to be determined if this is a regressive or progressive disease.

Aversion liquid-filled drug releasing capsule (3D-RECAL): A novel technology for the development of immediate release abuse deterrent formulations using a fused deposition modelling (FDM) 3D printer.

COVID19 has caused a significant socioeconomic burden worldwide. Opioid crisis was further intensified with the increasing number of opioid overdose/misuse related deaths in last two years. Abusers have adopted newer/efficient methods for manipulating and abusing commercial opioid formulations. Food and Drug Administration (FDA) has been strategizing tirelessly to prevent misuse/abuse of prescription opioids. One of the strategies is to develop an abuse deterrent formulation (ADF). The current study aims to develop a novel 3D printed drug-releasing capsule shell filled with an aversion liquid (3D-RECAL). Primarily, metformin hydrochloride (MT, model drug) loaded printable filaments of polyvinyl alcohol was prepared using hot melt extrusion. Following extrusion, a 3D printed capsule shell was designed and fabricated using a single nozzle fuse deposition modelling 3D printer. An aversion liquid to be filled in 3D-RECAL capsules was prepared by combining sudan black and sodium polyacrylamide starch in oil base. Mechanical analysis of extruded filaments suggested that the filaments with 20%w/w MT had a higher mechanical strength compared to other drug loadings. Instantaneous gelling and large black non-snortable particles were formed during solvent extraction and physical manipulation studies, respectively. Due to the drug being embedded in the capsule shell, MT release was immediately started with >85% of MT release within 45 mins in 0.1 N HCl. Due to the everlasting need for the newer efficient ADF technologies, 3D-RECAL can be a step in the right direction towards saving lives, providing safe and effective measures to deterring abusers.

SARS-CoV-2 Breakthrough Infections among US Embassy Staff Members, Uganda, May-June 2021.

The SARS-CoV-2 Delta variant emerged shortly after COVID-19 vaccines became available in 2021. We describe SARS-CoV-2 breakthrough infections in a highly vaccinated, well-monitored US Embassy community in Kampala, Uganda. Defining breakthrough infection rates in highly vaccinated populations can help determine public health messaging, guidance, and policy globally.

Cannabidiol Inhibits In Vitro Human Liver Microsomal Metabolism of Remdesivir: A Promising Adjuvant for COVID-19 Treatment.

Introduction: The year 2020 began with the world being flounced with a wave of novel coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) disease, named COVID-19. Based on promising pre-clinical and clinical data, remdesivir (RDV) was the first drug to receive FDA approval and so far, it is the most common therapy for treatment of SARS-CoV-2/MERS-CoV. However, following intravenous administration, RDV metabolizes majorly by human liver carboxylesterase 1 (CES1) and marginally by the CYP3A4 enzyme in merely less than an hour. Its resultant active metabolite is a hydrophilic nucleoside with very limited accumulation within lung tissues. Therefore, there is a need to investigate strategies to overcome such premature metabolism issues and improve the antiviral efficacy of RDV at the target site. Objective: Considering the major CES1-mediated metabolism of RDV on systemic administration, we intend to explore the remarkable CES1 plus CYP3A4 inhibitory activity of cannabidiol (CBD) against in vitro microsomal metabolism of RDV to indicate its therapeutic potential as an adjuvant to RDV in the treatment and management of COVID-19. Methods: We investigated the in vitro human liver microsomal metabolism of RDV in the presence of two potential CES1 inhibitors-CBD and nelfinavir, and two standard CYP3A4 inhibitors-ritonavir (RITO) and cyclosporin A. The microsomal metabolism assay was further validated by using a well-characterized CYP3A4-selective substrate, midazolam (MDZ), in the presence of CBD and RITO. Results: Our findings depicted that RDV was rapidly and completely metabolized by human liver microsomes within 60 min. Coincubation with CBD substantially reduced microsomal metabolism of RDV and prolonged its in vitro half-life from 8.93 to 31.07 min. CBD showed significantly higher inhibition of RDV compared with known CES1 and CYP3A4 inhibitors. Inhibition of MDZ metabolism by CBD and RITO further validated the assay. Conclusions: The current study strongly suggests that CBD significantly inhibits human liver microsomal metabolism of RDV and extends its in vitro half-life. Thus, concomitant administration of CBD with RDV intravenous injection could be a promising strategy to prevent premature metabolism in COVID-19 patients.

Therapeutic drug monitoring of posaconazole delayed release tablet while managing COVID-19-associated mucormycosis in a real-life setting.

BACKGROUND: Along with COVID-19 pandemic, India has faced an outbreak of COVID-19-associated mucormycosis (CAM). Due to restricted availability of amphotericin B during this outbreak, clinicians were forced to use posaconazole or isavuconazole preparations as first-line or alternate therapy in many patients. We planned an early monitoring of posaconazole trough level while using delayed release (DR) tablet as first-line or alternate therapy. OBJECTIVES: Primary objective of the study was to determine percentage of patients achieving arbitrarily decided therapeutic posaconazole levels (≥1.2 µg/ml) after using standard dosages of posaconazole. Secondary objective was to identify potential factors associated with sub-therapeutic posaconazole levels. METHODS: We performed retrospective chart review of the hospitalised patients, who received posaconazole DR tablet as first-line or alternate therapy to treat CAM during outbreak period (March 1 to May 31, 2021). High-performance liquid chromatographic (HPLC) method was used to measure trough level of posaconazole. RESULTS: Posaconazole serum levels of 29 patients were analysed, who received posaconazole DR tablet. Majority (n = 23) were male with the median (range) age 53 (24-86) years. The mean (SD) posaconazole level was 1.66 (0.76) µg/ml. Sub-therapeutic posaconazole trough level was observed in 7 (24.1%) patients. Relatively younger patients were associated with lower posaconazole level (p = .046). Except two patients, all the patients tolerated posaconazole well. CONCLUSIONS: The study supports the posaconazole trough level measurement on day 4 while using posaconazole DR tablet as first-line or alternate therapy to treat mucormycosis during limited supply of amphotericin B.

SARS-CoV-2 viral sepsis with meningoencephalitis.

SARS-CoV-2 predominantly involves the lungs producing acute lung injury, but it can also give rise to a variety of complications involving the central nervous system, gastrointestinal system, kidney and also viral sepsis. With this case report, we are discussing unusual series of complication from acute lung injury, followed by viral sepsis then encephalitis, followed by progressive macrophage activation syndrome.

Aerosolized nanoliposomal carrier of remdesivir: an effective alternative for COVID-19 treatment in vitro.

Aim: To formulate an aerosolized nanoliposomal carrier for remdesivir (AL-Rem) against coronavirus disease 2019. Methods: AL-Rem was prepared using modified hydration technique. Cytotoxicity in lung adenocarcinoma cells, stability and aerodynamic characteristics of developed liposomes were evaluated. Results: AL-Rem showed high encapsulation efficiency of 99.79%, with hydrodynamic diameter of 71.46 ± 1.35 nm and surface charge of -32 mV. AL-Rem demonstrated minimal cytotoxicity in A549 cells and retained monolayer integrity of Calu-3 cells. AL-Rem showed sustained release, with complete drug release obtained within 50 h in simulated lung fluid. Long-term stability indicated >90% drug recovery at 4°C. Desirable aerosol performance, with mass median aerodynamic diameter of 4.56 ± 0.55 and fine particle fraction of 74.40 ± 2.96%, confirmed successful nebulization of AL-Rem. Conclusion: AL-Rem represents an effective alternative for coronavirus disease 2019 treatment.

Lay abstract Remdesivir is one of the first drugs approved for the treatment of coronavirus disease 2019. Currently, it is administered via an injection into the bloodstream. This means that the drug circulates around the entire body and only a limited amount reaches the diseased site ­ the lungs. Frequent dosing is therefore required, which needs expert personnel and multiple hospital visits and can result in serious side effects. In this study, the authors developed specialized, nanosized particles containing the drug remdesivir that can be administered directly into the lungs. This could drastically minimize side effects, enhance efficacy and allow easy self-administration at home. The results of the study are promising but require additional investigation.

Self-injectable extended release formulation of Remdesivir (SelfExRem): A potential formulation alternative for COVID-19 treatment.

There has been a growing and evolving research to find a treatment or a prevention against coronavirus 2019 (COVID-19). Though mass vaccination will certainly help in reducing number of COVID-19 patients, an effective therapeutic measure must be available too. Intravenous remdesivir (RDV) was the first drug receiving Food and Drug Administration (FDA) approval for the treatment of COVID-19. However, in a pandemic like COVID-19, it is essential that drug formulations are readily available, affordable and convenient to administer to every patient around the globe. In this study, we have developed a Self-injectable extended release subcutaneous injection of Remdesivir (SelfExRem) for the treatment of COVID-19. As opposed to intravenous injection, extended release subcutaneous injection has the benefits of reducing face-to-face contact, minimizing hospitalization, reducing dosing frequency and reducing overall health care cost. SelfExRem was developed using a biodegradable polymer, poly(lactic-co-glycolic acid) (PLGA), dissolved in a biocompatible vehicle. Six different batches were formulated using 2 different grades of low molecular weight PLGA and 3 different PLGA concentration. The force of injection of various polymeric solutions through 23-30-gauge needles were analyzed using a TA.XTplus texture analyzer. The time required for injection was evaluated both manually and by using an autoinjector. In vitro release of all the batches were carried out in 1% v/v tween 80 in phosphate buffer saline. The study indicated that SelfExRem developed with15% w/v PLGA(75:25) provided a steady release of drug for 48 h and may be a breakthrough approach for the treatment of COVID-19.

Safety and efficacy of tocilizumab in the treatment of severe acute respiratory syndrome coronavirus-2 pneumonia: A retrospective cohort study.

Background: Cytokine release storm (CRS) in severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) is thought to be the cause for organ damage and death which is independent of the actual viral burden. Tocilizumab (TCZ), an interleukin-6 receptor antagonist, is approved for the treatment of CRS. We describe the efficacy and safety of TCZ in SARS CoV-2 pneumonia. Methods: This retrospective study was conducted at a tertiary care hospital from April 20 2020 to May 21 2020. The primary endpoint was the cumulative incidence of a composite of either need for admission to the intensive care unit (ICU) with invasive mechanical ventilation or death. Safety outcomes included an increase in liver transaminases and/or evidence of infection. Results: A total of 20 patients received TCZ during the study period. The median age was 54 years (95% confidence interval [CI] 47-63). About 85% of the patients were male. Nearly 70% of the patients had at least one comorbidity. About 55% required ICU admission. The median duration of ICU stay was 11 days (95% CI: 3-13 days). The cumulative incidence of the requirement for mechanical ventilation, clinical improvement and mortality was 11% (95% CI: 0.03%-1%), 74% (95% CI 37%-89%) and 25% (95% CI: 11%-63%), respectively. There was no difference in outcomes according to age, gender or computed tomography severity score. Asymptomatic transaminitis was the most common drug reaction (55%), and one patient developed bacteraemia. Conclusions: TCZ is likely a safe and effective modality of treatment for improving clinical and laboratory parameters of SARS CoV-2 patients with a reduction in ICU stay and ventilatory care need.