Identification of diphenylurea derivatives as novel endocytosis inhibitors that demonstrate broad-spectrum activity against SARS-CoV-2 and influenza A virus both in vitro and in vivo.

Rapid evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus (IAV) poses enormous challenge in the development of broad-spectrum antivirals that are effective against the existing and emerging viral strains. Virus entry through endocytosis represents an attractive target for drug development, as inhibition of this early infection step should block downstream infection processes, and potentially inhibit viruses sharing the same entry route. In this study, we report the identification of 1,3-diphenylurea (DPU) derivatives (DPUDs) as a new class of endocytosis inhibitors, which broadly restricted entry and replication of several SARS-CoV-2 and IAV strains. Importantly, the DPUDs did not induce any significant cytotoxicity at concentrations effective against the viral infections. Examining the uptake of cargoes specific to different endocytic pathways, we found that DPUDs majorly affected clathrin-mediated endocytosis, which both SARS-CoV-2 and IAV utilize for cellular entry. In the DPUD-treated cells, although virus binding on the cell surface was unaffected, internalization of both the viruses was drastically reduced. Since compounds similar to the DPUDs were previously reported to transport anions including chloride (Cl-) across lipid membrane and since intracellular Cl- concentration plays a critical role in regulating vesicular trafficking, we hypothesized that the observed defect in endocytosis by the DPUDs could be due to altered Cl- gradient across the cell membrane. Using in vitro assays we demonstrated that the DPUDs transported Cl- into the cell and led to intracellular Cl- accumulation, which possibly affected the endocytic machinery by perturbing intracellular Cl- homeostasis. Finally, we tested the DPUDs in mice challenged with IAV and mouse-adapted SARS-CoV-2 (MA 10). Treatment of the infected mice with the DPUDs led to remarkable body weight recovery, improved survival and significantly reduced lung viral load, highlighting their potential for development as broad-spectrum antivirals.

Microbiological blood profile among COVID-19 patients hospitalized in a tertiary care hospital: An observational study

Background: Bacterial coinfection contributes to increase morbidity and morbidity of viral respiratory infections and may lead to fatal outcome during its course of illness. Aims and Objectives: The main objective of this study was to determine the bacteriological profile of COVID-19 patients admitted in hospital, their antibiotic susceptibility, and their association with severity. Materials and Methods: The present study was retrospective observational cross-sectional study of all patients admitted for COVID-19 at Gandhi Medical College and Hamidia Hospital, Bhopal (MP) between (March 2020 and December 2020). Demographic, comorbid conditions, and microbiological data were compared HBD and intensive care unit (ICU) admissions and role secondary coinfection in severity and mortality. Results: Thirty percentages of percent of patients showed bacterial growth, Staphylococcus aureus was most common, followed by Pseudomonas aeruginosa. Mean±SD of age was 43.6±21.6. Antibiotic resistance of cefoxitin, cotrimoxazole, and azithromycin was seen in maximum Gram-positive growth, whereas sensitivity for linezolid and gentamicin was present in 10--16% cases. Highest antibiotic resistance in Gram-negative growth was seen for ceftozidime, amikacin, imipenem, and meropenem, whereas sensitivity of colistin antibiotic was highest in Gram-negative growth. Conclusion: Coinfection rates increase in patients admitted to the ICU, despite frequent prescription of broad-spectrum antibiotics. Infectious diseases practitioners carry the burden of life-saving and provide for societal trust that is effective antibiotic therapy in the face of these changes. With a growing body of evidence supporting short-course, antimicrobial therapy "Shorter Is Better" should be the new mantra. [ABSTRACT FROM AUTHOR] Copyright of Asian Journal of Medical Sciences is the property of Manipal Colleges of Medical Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Pulmonary cavitation in follow-up COVID 2019 cases: An etiological perspective.

Background: The current COVID-19 pandemic is an ongoing global healthcare challenge that has caused morbidity and mortality at unprecedented levels. Since the post-COVID pulmonary complications are evolving and challenging, a study was carried out to assess pulmonary cavitation in follow-up COVID cases from an etiological perspective. The aim of this study was to assess the incidence of pulmonary cavitation and describe its etiology and evolution in moderate and severe post-COVID pneumonia patients. Methods: A prospective observational study of all patients admitted to our institution with moderate or severe COVID pneumonia was carried out. Some of these patients again became symptomatic after discharge and developed pulmonary cavitation on imaging. Results: 6.2% (n = 37) out of 589 patients admitted to our institution with moderate or severe COVID pneumonia developed pulmonary cavitation on follow-up. We describe the imaging characteristics of post-COVID cavitation and present these patients' clinical, laboratory, and microbiological parameters. Conclusion: Cavitary lung disease in patients with moderate to severe COVID-19 disease is not uncommon, and an etiological workup is necessary to institute timely and correct therapy.

A Preliminary Genomic Analysis of the Omicron Variants of SARS-CoV-2 in Central India During the third wave of the COVID-19 Pandemic.

BACKGROUND: Omicron was detected in South Africa for the first time at the month of November 2021, from then it expanded swiftly over the world, outcompeting other SARS-CoV-2 variants such as Delta. The toxicity, resistance to antiviral medicines, transmissibility, and vaccine-induced immunity of newly developed SARS-CoV-2 variants are major worldwide health concerns. AIM OF STUDY: This study investigates the comprehensive explanation of all mutations and their evolutionary linkages between the Omicron variant and recently discovered SARS-CoV-2 variants. METHOD: On Illumina MiniSeq Machine, 31 RNA isolates from clinical specimens were sequenced utilizing next-generation sequencing technique. Different bioinformatics tools have been used to analyze the mutations in omicron variant. A phylogenetic tree was constructed to determine Omicron's evolutionary relationships with other variants. RESULTS: In our investigation, we discovered 79 distinct types of mutations in 31 fully vaccinated COVID-19 positive samples. Mostly mutations were found in non-spike region. According to the NJ approach of phylogenetic tree revels, the nearest variants were in the order listed, based on sequence identity: Omicron, Gamma, Alpha, Delta, Mu and Beta. On the other hand as per UPGMA approach, the Omicron variation creates a novel monophyletic clade that is distinct from previous SARS-CoV-2 variants. CONCLUSION: Despite the fact that some of the mutations are prevalent in Omicron and other VOCs, there are several unique mutations that have been connected to the virus's transmissibility and immune evasion, indicating a substantial shift in SARS-CoV-2 evolution.

Vitamin D: The Missing Nutrient Behind the Two Deadly Pandemics, COVID-19 and Cardiovascular Diseases.

The coronavirus (COVID-19) pandemic is claiming millions of lives and creating an additional burden on health care, which is already affected by the rise of non-communicable diseases (NCDs). The scientific community, on the other side, is enormously engaged with studies to best identify the characteristics of the virus and minimize its effect while supporting the fight to contain NCDs, mainly cardiovascular diseases (CVDs), which are contributing hugely to the global death toll. Hence, the roles of vitamin D in COVID-19 immunity and cardiovascular health are gaining traction recently.  This literature review will mainly focus on summarizing pertinent studies and scientific publications which highlight the association of vitamin D levels with the various outcomes of COVID-19 and CVDs. It will also address how low vitamin D correlates with the epidemiology of CVDs and the inflammatory mechanisms attributed to COVID-19 severity. We believe that our review may open up hindsight perspectives and further discussions among the physicians in tapping the potential of vitamin D supplementation to tackle the morbidity, mortality, and health care cost of the two deadly diseases, COVID-19 and CVDs.

Human genetic factors associated with pneumonia risk, a cue for COVID-19 susceptibility.

Pneumonia, an acute respiratory tract infection, is one of the major causes of mortality worldwide. Depending on the site of acquisition, pneumonia can be community acquired pneumonia (CAP) or nosocomial pneumonia (NP). The risk of pneumonia, is partially driven by host genetics. CYP1A1 is a widely studied pulmonary CYP family gene primarily expressed in peripheral airway epithelium. The CYP1A1 genetic variants, included in this study, alter the gene activity and are known to contribute in lung inflammation, which may cause pneumonia pathogenesis. In this study, we performed a meta-analysis to establish the possible contribution of CYP1A1 gene, and its three variants (rs2606345, rs1048943 and rs4646903) towards the genetic etiology of pneumonia risk. Using PRISMA guidelines, we systematically reviewed and meta-analysed case-control studies, evaluating risk of pneumonia in patients carrying the risk alleles of CYP1A1 variants. Heterogeneity across the studies was evaluated using I2 statistics. Based on heterogeneity, a random-effect (using maximum likelihood) or fixed-effect (using inverse variance) model was applied to estimate the effect size. Pooled odds ratio (OR) was calculated to estimate the overall effect of the risk allele association with pneumonia susceptibility. Egger's regression test and funnel plot were used to assess publication bias. Subgroup analysis was performed based on pneumonia type (CAP and NP), population, as well as age group. A total of ten articles were identified as eligible studies, which included 3049 cases and 2249 healthy controls. The meta-analysis findings revealed CYP1A1 variants, rs2606345 [T vs G; OR = 1.12 (0.75-1.50); p = 0.02; I2 = 84.89%], and rs1048943 [G vs T; OR = 1.19 (0.76-1.61); p = 0.02; I2 = 0.00%] as risk markers whereas rs4646903 showed no statistical significance for susceptibility to pneumonia. On subgroup analysis, both the genetic variants showed significant association with CAP but not with NP. We additionally performed a spatial analysis to identify the key factors possibly explaining the variability across countries in the prevalence of the coronavirus disease 2019 (COVID-19), a viral pneumonia. We observed a significant association between the risk allele of rs2606345 and rs1048943, with a higher COVID-19 prevalence worldwide, providing us important links in understanding the variability in COVID-19 prevalence.

Genomic characterization unravelling the causative role of SARS-CoV-2 Delta variant of lineage B.1.617.2 in 2nd wave of COVID-19 pandemic in Chhattisgarh, India.

COVID-19 pandemic 2nd wave catastrophic effect in the state of Chhattisgarh, India, from where no exclusive genomic data yet published, has prompted us to undertake this study to unearth the causative variant. Whole-genome sequencing of SARS-CoV-2 isolated from COVID-19 infected nine vaccinated healthcare workers (HCW), thirty mild/moderate, seventeen severe, and twenty-seven deceased patients, was performed. The significant predominance of the SARS-CoV-2 variant of concern (VOC), Delta (lineage B.1.617.2) identified in sixty-four (77.1%) cases in contrast to B.1 and its sublineage in eleven (13.2%), variant under monitoring (VUM), Kappa (lineage B.1.617.1) in five (6.0%) and another VOC Alpha (lineage B.1.1.7) in three (3.6%) cases respectively (p < 0.05, χ2 = 162.49). 88.8% vaccine breakthrough, 60% mild/moderate, 94.4% severe and 81.5% dead patients were infected by Delta. Kappa presents exclusively in mild/moderate, Alpha in vaccine breakthrough, mild/moderate, and dead patient and B.1 and its sublineages in mild, severe, and dead patient categories. Delta variant spike mutation of T19R, G142D, E156G, L452R, and deletion (F157 and R158) helps in escaping antibody response, T478K and D614G enhance viral affinity with ACE2 receptor while P681R and D950N result in higher replication and transmissibility by cleaving S1/S2 at furin site. We conclude that Delta variant predominant role along with co-occurrence of Kappa, Alpha, and B.1 variant during COVID-19 2nd wave pandemic in Chhattisgarh may pose a potential threat of future outbreak through hybrid variant evolution. Thus, intensive genomic surveillance for monitoring variant evolution and a more efficacious vaccine against the Delta and Alpha variants are required.

Can Zoom video conferencing tool be misused for real‐time cybercrime?

Video conferencing tool Zoom has boomed during this COVID pandemic situation. Although Zoom has been very useful for facilitating work‐from‐home and study‐from‐home arrangements, its misuse can result in cybercrime cases. The world has already seen the adverse effect of a Zoom‐related cybercrime, Zoombombing. In this article, we discuss how Zoom can also be misused for launching real‐time cybercrime, such as piracy and real‐time pornography. The end‐to‐end encryption proposed to be used by Zoom can further complicate these cybercrime issues. The existing mechanisms may not be sufficient in dealing with these real‐time issues. New mechanisms need to be found.This article is categorized under:Digital and Multimedia Science > Multimedia Forensics

Genomic characterization and epidemiology of an emerging SARS-CoV-2 variant in Delhi, India.

Delhi, the national capital of India, experienced multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreaks in 2020 and reached population seropositivity of >50% by 2021. During April 2021, the city became overwhelmed by COVID-19 cases and fatalities, as a new variant, B.1.617.2 (Delta), replaced B.1.1.7 (Alpha). A Bayesian model explains the growth advantage of Delta through a combination of increased transmissibility and reduced sensitivity to immune responses generated against earlier variants (median estimates: 1.5-fold greater transmissibility and 20% reduction in sensitivity). Seropositivity of an employee and family cohort increased from 42% to 87.5% between March and July 2021, with 27% reinfections, as judged by increased antibody concentration after a previous decline. The likely high transmissibility and partial evasion of immunity by the Delta variant contributed to an overwhelming surge in Delhi.

Near complete resolution of COVID-19 pneumonia lesions in a patient of carcinoma lung treated with volumetric modulated arc therapy.

A 49-year-old male presented with non-small cell lung cancer in right upper lobe lung with solitary brain metastasis. He developed COVID-19 infection and received domiciliary treatment for 3 weeks. Three weeks after testing negative for RT-PCR test, he received stereotactic radiosurgery (SRS) to brain metastasis. He then presented in emergency with pain in the epigastrium and was detected with amoebic liver abscess. Subsequently, he developed recurrent hemoptysis for which he was planned for palliative radiation to right lung mass. Planning CT scan showed COVID-19 pneumonia lesions involving bilateral lungs in addition to right upper lobe tumour. Palliative radiation 8 Gy/1 fraction was delivered to lung tumour with VMAT technique. He showed near total resolution of COVID-19 lesions with low-dose scatter radiation and relief of haemoptysis.

COVID-19 Outbreak Management and Vaccination Strategy in The United States of America.

Four months after the first case of COVID-19 was reported in the United States, the SARS-CoV-2 virus had spread to more than 90% of all counties. Although the transmission of the virus can be grossly mitigated through non-pharmaceutical interventions and public health measures, risks of future outbreaks, emergence of more infectious variants, and disruptions to socio-economic life will probably remain until effective vaccines are administered to large portions of the global population. An exceptional collaboration between governments and the scientific community has led to the authorization of eight vaccines globally for full use, four of which were funded and developed in the United States. In this paper, we contextualize epidemiological, political, and economic impacts of the COVID-19 vaccination strategy in the United States of America between 20 January 2020, to 5 May 2021, with a key focus on vaccine hesitancy and public-private partnerships.

Correction: Comparative analysis of various clinical specimens in detection of SARS-CoV-2 using rRT-PCR in new and follow up cases of COVID-19 infection: Quest for the best choice.

[This corrects the article DOI: 10.1371/journal.pone.0249408.].

Highly Accurate Chip-Based Resequencing of SARS-CoV-2 Clinical Samples.

SARS-CoV-2 has infected over 128 million people worldwide, and until a vaccine is developed and widely disseminated, vigilant testing and contact tracing are the most effective ways to slow the spread of COVID-19. Typical clinical testing only confirms the presence or absence of the virus, but rather, a simple and rapid testing procedure that sequences the entire genome would be impactful and allow for tracing the spread of the virus and variants, as well as the appearance of new variants. However, traditional short read sequencing methods are time consuming and expensive. Herein, we describe a tiled genome array that we developed for rapid and inexpensive full viral genome resequencing, and we have applied our SARS-CoV-2-specific genome tiling array to rapidly and accurately resequence the viral genome from eight clinical samples. We have resequenced eight samples acquired from patients in Wyoming that tested positive for SARS-CoV-2. We were ultimately able to sequence over 95% of the genome of each sample with greater than 99.9% average accuracy.

Comparative analysis of various clinical specimens in detection of SARS-CoV-2 using rRT-PCR in new and follow up cases of COVID-19 infection: Quest for the best choice.

BACKGROUND: An appropriate specimen is of paramount importance in Real Time reverse transcription-polymerase chain reaction (rRT-PCR) based diagnosis of novel coronavirus (nCoV) disease (COVID-19). Thus, it's pertinent to evaluate various diversified clinical specimens' diagnostic utility in both diagnosis and follow-up of COVID-19. METHODS: A total of 924 initial specimens from 130 COVID-19 symptomatic cases before initiation of treatment and 665 follow up specimens from 15 randomly selected cases comprising of equal number of nasopharyngeal swab (NPS), oropharyngeal swab (OPS), combined NPS and OPS (Combined swab), sputum, plasma, serum and urine were evaluated by rRT-PCR. RESULTS: Demographic analysis showed males (86) twice more affected by COVID-19 than females (44) (p = 0.00001). Combined swabs showed a positivity rate of 100% followed by NPS (91.5%), OPS (72.3%), sputum (63%), while nCoV was found undetected in urine, plasma and serum specimens. The lowest cycle threshold (Ct) values of targeted genes E, ORF1b and RdRP are 10.56, 10.14 and 12.26 respectively and their lowest average Ct values were found in combined swab which indicates high viral load in combined swab among all other specimen types. Analysis of 665 follow-up multi-varied specimens also showed combined swab as the last specimen among all specimen types to become negative, after an average 6.6 (range 4-10) days post-treatment, having lowest (15.48) and average (29.96) Ct values of ORF1b respectively indicating posterior nasopharyngeal tract as primary nCoV afflicted site with high viral load. CONCLUSION: The combined swab may be recommended as a more appropriate specimen for both diagnosis and monitoring of COVID-19 treatment by rRT-PCR for assessing virus clearance to help physicians in taking evidence-based decision before discharging patients. Implementing combined swabs globally will definitely help in management and control of the pandemic, as it is the need of the hour.

Acute Coronary Syndrome and COVID-19: A Case Report of Refractory Hypercoagulability.

Novel coronavirus disease 2019 (COVID-19) is known to cause severe bilateral pneumonia and acute respiratory distress syndrome (ARDS), leading to difficulty breathing requiring mechanical ventilation and ICU management. In many patients, it has been found to cause severe hypercoagulability. We present a case of COVID-19 positive patient who developed myocardial infarction (MI) despite being on multiple anticoagulants. A 51-year-old, Middle-Eastern male diabetic patient presented to the emergency room with complaints of sudden onset left leg pain, paresthesias, and swelling for one day. On physical examination, the left leg was cool to touch from forefoot to mid-calf, with noticeable mottling over the forefoot and a nonpalpable dorsalis pedis. The patient was started on therapeutic enoxaparin and diltiazem in ED. Chest X-ray showed bilateral pulmonary infiltrates beginning peripherally and COVID-19 pneumonitis. The patient underwent a mechanical thrombectomy and was loaded with aspirin/clopidogrel, heparin drip, and enoxaparin. Despite being on triple anticoagulation, the patient had new-onset STEMI and elevated troponin levels. On angiography, the patient was found to have occluded mid-left anterior descending, most likely from acute on chronic thrombosis related to the patient's COVID-19 status. As flow could not be re-established, the patient was kept on long-term protective anticoagulation-triple therapy (an oral anticoagulant and dual antiplatelet therapy) and received pulmonary care for COVID-19 infection. The patient was discharged on long-term triple anticoagulation and COVID-19 precautions with scheduled retesting and follow-up.

Integrated genomic view of SARS-CoV-2 in India.

Background: India first detected SARS-CoV-2, causal agent of COVID-19 in late January 2020, imported from Wuhan, China. From March 2020 onwards, the importation of cases from countries in the rest of the world followed by seeding of local transmission triggered further outbreaks in India. Methods: We used ARTIC protocol-based tiling amplicon sequencing of SARS-CoV-2 (n=104) from different states of India using a combination of MinION and MinIT sequencing from Oxford Nanopore Technology to understand how introduction and local transmission occurred. Results: The analyses revealed multiple introductions of SARS-CoV-2 genomes, including the A2a cluster from Europe and the USA, A3 cluster from Middle East and A4 cluster (haplotype redefined) from Southeast Asia (Indonesia, Thailand and Malaysia) and Central Asia (Kyrgyzstan). The local transmission and persistence of genomes A4, A2a and A3 was also observed in the studied locations. The most prevalent genomes with patterns of variance (confined in a cluster) remain unclassified, and are here proposed as A4-clade based on its divergence within the A cluster. Conclusions: The viral haplotypes may link their persistence to geo-climatic conditions and host response. Multipronged strategies including molecular surveillance based on real-time viral genomic data is of paramount importance for a timely management of the pandemic.

A rapid and sensitive method to detect SARS-CoV-2 virus using targeted-mass spectrometry.

In the last few months, there has been a global catastrophic outbreak of severe acute respiratory syndrome disease caused by the novel coronavirus SARS-CoV-2 affecting millions of people worldwide. Early diagnosis and isolation are key to contain the rapid spread of the virus. Towards this goal, we report a simple, sensitive and rapid method to detect the virus using a targeted mass spectrometric approach, which can directly detect the presence of virus from naso-oropharyngeal swabs. Using a multiple reaction monitoring we can detect the presence of two peptides specific to SARS-CoV-2 in a 2.3 min gradient run with 100% specificity and 90.5% sensitivity when compared to RT-PCR. Importantly, we further show that these peptides could be detected even in the patients who have recovered from the symptoms and have tested negative for the virus by RT-PCR highlighting the sensitivity of the technique. This method has the translational potential of in terms of the rapid diagnostics of symptomatic and asymptomatic COVID-19 and can augment current methods available for diagnosis of SARS-CoV-2.