scholarly journals SARS-CoV-2: Possible recombination and emergence of potentially more virulent strains

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0251368
Author(s):  
Dania Haddad ◽  
Sumi Elsa John ◽  
Anwar Mohammad ◽  
Maha M. Hammad ◽  
Prashantha Hebbar ◽  
...  
Keyword(s):  
North America ◽  
Viral Entry ◽  
Haplotype Block ◽  
Current Treatment ◽  
Missense Mutations ◽  
Death Rates ◽  
Treatment Regimens ◽  
Variant Frequency ◽  
Different Strains ◽  
Genomic Recombination

COVID-19 is challenging healthcare preparedness, world economies, and livelihoods. The infection and death rates associated with this pandemic are strikingly variable in different countries. To elucidate this discrepancy, we analyzed 2431 early spread SARS-CoV-2 sequences from GISAID. We estimated continental-wise admixture proportions, assessed haplotype block estimation, and tested for the presence or absence of strains’ recombination. Herein, we identified 1010 unique missense mutations and seven different SARS-CoV-2 clusters. In samples from Asia, a small haplotype block was identified, whereas samples from Europe and North America harbored large and different haplotype blocks with nonsynonymous variants. Variant frequency and linkage disequilibrium varied among continents, especially in North America. Recombination between different strains was only observed in North American and European sequences. In addition, we structurally modelled the two most common mutations, Spike_D614G and Nsp12_P314L, which suggested that these linked mutations may enhance viral entry and replication, respectively. Overall, we propose that genomic recombination between different strains may contribute to SARS-CoV-2 virulence and COVID-19 severity and may present additional challenges for current treatment regimens and countermeasures. Furthermore, our study provides a possible explanation for the substantial second wave of COVID-19 presented with higher infection and death rates in many countries.

scholarly journals SARS-CoV-2: Proof of recombination between strains and emergence of possibly more virulent ones

2020 ◽  
Author(s):  
Dania Haddad ◽  
Sumi Elsa John ◽  
Anwar Mohammad ◽  
Maha M Hammad ◽  
Prashantha Hebbar ◽  
...  
Keyword(s):  
North America ◽  
Viral Entry ◽  
Haplotype Block ◽  
Vaccine Development ◽  
Current Treatment ◽  
Missense Mutations ◽  
Treatment Regimens ◽  
Variant Frequency ◽  
Different Strains ◽  
Genomic Recombination

AbstractCOVID-19 is challenging healthcare preparedness, world economies, and livelihoods. The infection and death rates associated with this pandemic are strikingly variable in different countries. To elucidate this discrepancy, we analyzed 2431 early spread SARS-CoV-2 sequences from GISAID. We estimated continental-wise admixture proportions, assessed haplotype block estimation, and tested for the presence or absence of strains recombination. Herein, we identified 1010 unique missense mutations and seven different SARS-CoV-2 clusters. In samples from Asia, a small haplotype block was identified; whereas, samples from Europe and North America harbored large and different haplotype blocks with nonsynonymous variants. Variant frequency and linkage disequilibrium varied among continents, especially in North America. Recombination between different strains was only observed in North American and European sequences. Additionally, we structurally modeled the two most common mutations D614G and P314L which suggested that these linked mutations may enhance viral entry and stability. Overall, we propose that COVID-19 virulence may be more severe in Europe and North America due to coinfection with different SARS-CoV-2 strains leading to genomic recombination which might be challenging for current treatment regimens and vaccine development. Furthermore, our study provides a possible explanation for the more severe second wave of COVID-19 that many countries are currently experiencing presented as higher rates of infection and death.

scholarly journals Cancer missense mutations in the BRC repeats of BRCA2 protein disrupt RAD51 binding and activity leading to chemotherapeutic sensitivity

2021 ◽  
Author(s):  
Judit Jimenez-Sainz ◽  
Joshua Mathew ◽  
Jennifer Garbarino ◽  
Joseph P Eder ◽  
Ryan B Jensen
Keyword(s):  
Genome Stability ◽  
Treatment Options ◽  
Suppressor Gene ◽  
Current Treatment ◽  
Missense Mutations ◽  
Dna Double Strand Breaks ◽  
Clinical Databases ◽  
Brca2 Protein ◽  
Hypomorphic Alleles ◽  
The Impact

BRCA2 is a tumor suppressor gene that maintains genome stability by mediating the high fidelity repair of DNA double-strand breaks (DSBs) through homology-directed repair (HDR). Pathogenic mutations in BRCA2 predispose to breast, ovarian, pancreatic, prostate, and other cancers. Mutations in BRCA2 leading to severe protein truncation predict pathogenicity, however, missense mutations with unknown functional consequences, designated Variants of Uncertain Significance (VUS), comprise 60% of BRCA2 sequence changes deposited in clinical databases. Classifying BRCA2 VUS correctly is critical for relaying clinically actionable information to patients concerning future cancer risk or current treatment options. In this study, we identified and biochemically characterized three BRCA2 VUS located in BRC repeats to determine the impact on canonical HDR functions. Two of the germline variants, S1221P and T1980I, map to conserved residues in BRC2 and BRC7, disrupt RAD51 binding, and are diminished in their ability to stabilize RAD51-ssDNA complexes. We provide supporting cellular evidence that S1221P and T1980I are significantly compromised in their response to chemotherapeutics and ionizing radiation. The third variant, T1346I, lies within the spacer region between BRC2 and BRC3 but remains fully functional. We conclude that T1346I has a neutral impact on BRCA2 function, while S1221P and T1980I are hypomorphic alleles that disrupt the ability of BRCA2 to fully engage and stabilize RAD51 nucleoprotein filaments.

Perspectives for Potential Therapies for SARS-CoV-2

2021 ◽  
Vol 6 (4) ◽  
pp. 1-24
Author(s):  
Preeti Suman Saxena ◽  
Kirti Singh ◽  
Poonam Jangir ◽  
Manish Nath Tripathi ◽  
Vimal Singh ◽  
...  
Keyword(s):  
Therapeutic Agents ◽  
Current Treatment ◽  
Third Wave ◽  
Biological Targets ◽  
Treatment Regimens ◽  
Current Review ◽  
Corona Virus ◽  
Current Treatment Strategy ◽  
Ongoing Development ◽  
Corona Viruses

The current pandemic, novel corona virus 19 disease (COVID-19), has created havoc across the world. Now a third wave is possible, and we have already crossed two waves. The current review article presents recent reports about the COVID-19, the ways of treatments, and prevention. In view of the potential threats of a pandemic, various scientists have been trying to understand the pathophysiology of this disease to uncover possible treatment regimens and discover effective therapeutic agents and vaccines. To add further information to support the ongoing current research and development against SARS-CoV-2, the authors have provided the basics of pathophysiology, possible targets, and current treatment strategy for corona viruses. The current review highlights the antiviral strategies involving small molecules and different biological targets involved in corona virus infection and replication. The information included in this article provides a strong intellectual foundation for the ongoing development of therapeutic agents and vaccines.

Ponatinib, Lestaurtinib and mTOR/PI3K inhibitors are promising repurposing candidates against Entamoeba histolytica

2021 ◽  
Author(s):  
Monica M. Kangussu-Marcolino ◽  
Upinder Singh
Keyword(s):  
Entamoeba Histolytica ◽  
Current Treatment ◽  
Clinical Development ◽  
New Drugs ◽  
Phase Iii ◽  
Significant Advance ◽  
Pi3k Inhibitors ◽  
Treatment Regimens ◽  
Clinical Resistance ◽  
Tk Inhibitors

Dysentery caused by Entamoeba histolytica affects millions of people annually. Current treatment regimens are based on metronidazole to treat invasive parasites combined with paromomycin for luminal parasites. Issues with treatment include significant side effects, inability to easily treat breastfeeding and pregnant women, the use of two sequential agents, and concern that all therapy is based on nitroimidazole agents with no alternatives if clinical resistance emerges. Thus, the need for new drugs against amebiasis is urgent. To identify new therapeutic candidates, we screened the ReFRAME library (11,948 compounds assembled for Repurposing, Focused Rescue, and Accelerated Medchem) against E. histolytica trophozoites. We identified 159 hits in the primary screen at 10 μM and 46 compounds were confirmed in secondary assays. Overall, 26 were selected as priority molecules for further investigation including 6 FDA approved, 5 orphan designation, and 15 which are currently in clinical trials (3 phase III, 7 phase II and 5 phase I). We found that all 26 compounds are active against metronidazole resistant E. histolytica and 24 are able to block parasite recrudescence after drug removal. Additionally, 14 are able to inhibit encystation and 2 (lestaurtinib and LY-2874455) are active against mature cysts. Two classes of compounds are most interesting for further investigations: the Bcr-Abl TK inhibitors, with the ponatinib (EC 50 0.39) as most potent and mTOR or PI3K inhibitors with 8 compounds in clinical development, of which 4 have nanomolar potency. Overall, these are promising candidates and represent a significant advance for drug development against E. histolytica .

scholarly journals Epidemiology, classification, treatment and mortality of distal radius fractures in adults: an observational study of 23,394 fractures from the national Swedish fracture register

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Johanna Rundgren ◽  
Alicja Bojan ◽  
Cecilia Mellstrand Navarro ◽  
Anders Enocson
Keyword(s):  
Observational Study ◽  
Distal Radius Fracture ◽  
Distal Radius ◽  
Current Treatment ◽  
Distal Radius Fractures ◽  
Radius Fracture ◽  
Fracture Classification ◽  
Radius Fractures ◽  
Treatment Regimens ◽  
Fracture Register

Abstract Background Distal radius fractures are the most common of all fractures. Optimal treatment is still debated. Previous studies report substantial changes in treatment trends in recent decades. Few nation-wide studies on distal radius fracture epidemiology and treatment exist, none of which provide detailed data on patient and injury characteristics, fracture pattern and mortality. The aim of this study was to describe the epidemiology, fracture classification, current treatment regimens and mortality of distal radius fractures in adults within the context of a large national register study. Methods We performed a descriptive study using prospectively registered data from the Swedish fracture register. Included were all non-pathological distal radius fractures registered between January 1st 2015 and December 31st 2017 in patients aged 18 years and above. Nominal variables were presented as proportions of all registered fractures. Results A total of 23,394 distal radius fractures in 22,962 patients were identified. The mean age was 62.7 ± 17.6 years for all, 65.4 ± 16.0 for women and 53.6 ± 20.0 for men. A simple fall was the most common cause of injury (75%, n = 17,643/23,394). One third (33%, n = 7783/21,723) of all fractures occurred at the patients’ residence. 65% (n = 15,178/23,394) of all fractures were classified as extra-articular AO-23-A, 12% (n = 2770/23,394) as partially intra-articular AO-23-B and 23% (n = 5446/23,394) as intra-articular AO-23-C. The primary treatment was non-surgical for 74% (n = 17,358/23,369) and surgical for 26% (n = 6011/23,369) of all fractures. Only 18% of the AO-23-A fractures were treated surgically, compared to 48% of the AO-23-C fractures. The most frequently used surgical method was plate fixation (82%, n = 4954/5972), followed by pin/wire fixation (8.2%, n = 490/5972), external fixation (4.8%, n = 289/5972) and other methods (4.0%, n = 239/5972). The overall 30-day mortality was 0.4% (n = 98/23,394) and the 1-year mortality 2.9% (n = 679/23,394). Conclusion This nation-wide observational study provides comprehensive data on the epidemiology, fracture classification and current treatment regimens of distal radius fractures in a western European setting. The most common patient was an eldery woman who sustained a distal radius fracture through a simple fall in her own residence, and whose fracture was extra-articluar and treated non-surgically.

scholarly journals Emerging Treatment Options for Infections by Multidrug-Resistant Gram-Positive Microorganisms

2020 ◽  
Vol 8 (2) ◽  
pp. 191 ◽  
Author(s):  
Despoina Koulenti ◽  
Elena Xu ◽  
Andrew Song ◽  
Isaac Yin Sum Mok ◽  
Drosos E. Karageorgopoulos ◽  
...  
Keyword(s):  
Safety Profile ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Treatment Options ◽  
Multidrug Resistant ◽  
Current Treatment ◽  
Multi Drug Resistance ◽  
Gram Positive ◽  
Treatment Regimens ◽  
Gram Positive Bacteria

Antimicrobial agents are currently the mainstay of treatment for bacterial infections worldwide. However, due to the increased use of antimicrobials in both human and animal medicine, pathogens have now evolved to possess high levels of multi-drug resistance, leading to the persistence and spread of difficult-to-treat infections. Several current antibacterial agents active against Gram-positive bacteria will be rendered useless in the face of increasing resistance rates. There are several emerging antibiotics under development, some of which have been shown to be more effective with an improved safety profile than current treatment regimens against Gram-positive bacteria. We will extensively discuss these antibiotics under clinical development (phase I-III clinical trials) to combat Gram-positive bacteria, such as Staphylococcus aureus, Enterococcus faecium and Streptococcus pneumoniae. We will delve into the mechanism of actions, microbiological spectrum, and, where available, the pharmacokinetics, safety profile, and efficacy of these drugs, aiming to provide a comprehensive review to the involved stakeholders.

Immersive Virtual Environments, Avatars, and Agents for Health

2017 ◽  
Author(s):  
Sun Joo (Grace) Ahn ◽  
Jesse Fox
Keyword(s):  
Virtual Environments ◽  
Health Care Providers ◽  
Sensory Information ◽  
Physical World ◽  
Autism Spectrum ◽  
Current Treatment ◽  
Care Providers ◽  
Individual Level ◽  
Immersive Virtual Environments ◽  
Treatment Regimens

Immersive virtual environments (IVEs) are systems comprised of digital devices that simulate multiple layers of sensory information so that users experience sight, sound, and even touch like they do in the physical world. Users are typically represented in these environments in the form of virtual humans and may interact with other virtual representations such as health-care providers, coaches, future selves, or treatment stimuli (e.g., phobia triggers, such as crowds of people or spiders). These virtual representations can be controlled by humans (avatars) or computers algorithms (agents). Embodying avatars and interacting with agents, patients can experience sensory-rich simulations in the virtual world that may be difficult or even impossible to experience in the physical world but are sufficiently real to influence health attitudes and behaviors. Avatars and agents are infinitely customizable to tailor virtual experiences at the individual level, and IVEs are able to transcend the spatial and temporal boundaries of the physical world. Although still preliminary, a growing number of studies demonstrate IVEs’ potential as a health promotion and therapy tool, complementing and enhancing current treatment regimens. Attempts to incorporate IVEs into treatments and intervention programs have been made in a number of areas, including physical activity, nutrition, rehabilitation, exposure therapy, and autism spectrum disorders. Although further development and research is necessary, the increasing availability of consumer-grade IVE systems may allow clinicians and patients to consider IVE treatment as a routine part of their regimen in the near future.

Heparin-induced Thrombocytopenia – Pathogenesis and Treatment

1999 ◽  
Vol 82 (S 01) ◽  
pp. 148-156 ◽  
Author(s):  
A. Greinacher
Keyword(s):  
Randomized Trials ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Thromboembolic Complications ◽  
Recombinant Hirudin ◽  
Heparin Induced Thrombocytopenia ◽  
Treatment Regimens ◽  
Immune Mediated ◽  
Therapeutic Concepts ◽  
Key Aspects

SummaryHeparin-induced thrombocytopenia (HIT) is now recognized as the most frequent immune-mediated adverse drug reaction. During the last decade, fundamental aspects of the pathogenesis of HIT have been resolved. The understanding of some the mechanisms underlying the development of new, paradox thromboembolic complications in HIT led to the concept that thrombin generation plays a key-role in clinically manifest HIT. Consequently new therapeutic concepts imply the use of drugs with either indirect of direct anti-thrombin activity such as donaparoid-sodium and the recombinant hirudin lepirudin. During the last years results of first prospective studies assessing various treatment regimens in HIT became available. Although data of randomized trials are still missing some treatment recommendations can already be drawn from these studies. This review summarizes key aspects of the pathogenesis of HIT and provides an overview of current treatment strategies.

scholarly journals Effect of Different Adjuvants on the Longevity and Strength of Humoral and Cellular Immune Responses to the HCV Envelope Glycoproteins

Vaccines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 204 ◽  
Author(s):  
Bassel Akache ◽  
Lise Deschatelets ◽  
Blair A. Harrison ◽  
Renu Dudani ◽  
Felicity C. Stark ◽  
...  
Keyword(s):  
T Cells ◽  
Neutralizing Antibodies ◽  
Lipid A ◽  
Cellular Responses ◽  
Current Treatment ◽  
Water Emulsion ◽  
Treatment Regimens ◽  
Immune Parameters ◽  
Monophosphoryl Lipid A ◽  
Oil In Water Emulsion

Infection by Hepatitis C virus (HCV) can lead to liver cirrhosis/hepatocellular carcinoma and remains a major cause of serious disease morbidity and mortality worldwide. However, current treatment regimens remain inaccessible to most patients, particularly in developing countries, and, therefore, the development of a novel vaccine capable of protecting subjects from chronic infection by HCV could greatly reduce the rates of HCV infection, subsequent liver pathogenesis, and in some cases death. Herein, we evaluated two different semi-synthetic archaeosome formulations as an adjuvant to the E1/E2 HCV envelope protein in a murine model and compared antigen-specific humoral (levels of anti-E1/E2 IgG and HCV pseudoparticle neutralization) and cellular responses (numbers of antigen-specific cytokine-producing T cells) to those generated with adjuvant formulations composed of mimetics of commercial adjuvants including a squalene oil-in-water emulsion, aluminum hydroxide/monophosphoryl lipid A (MPLA) and liposome/MPLA/QS-21. In addition, we measured the longevity of these responses, tracking humoral, and cellular responses up to 6 months following vaccination. Overall, we show that the strength and longevity of anti-HCV responses can be influenced by adjuvant selection. In particular, a simple admixed sulfated S-lactosylarchaeol (SLA) archaeosome formulation generated strong levels of HCV neutralizing antibodies and polyfunctional antigen-specific CD4 T cells producing multiple cytokines such as IFN-γ, TNF-α, and IL-2. While liposome/MPLA/QS-21 as adjuvant generated superior cellular responses, the SLA E1/E2 admixed formulation was superior or equivalent to the other tested formulations in all immune parameters tested.

Treatment of Common Childhood Malignancies

2002 ◽  
Vol 15 (1) ◽  
pp. 42-51 ◽  
Author(s):  
Betsy M. Bickert
Keyword(s):  
Clinical Trials ◽  
Cause Of Death ◽  
Pediatric Oncology ◽  
Systematic Approach ◽  
Current Treatment ◽  
Cooperative Group ◽  
Pediatric Malignancies ◽  
Treatment Regimens ◽  
Childhood Malignancies

Malignancy is the fourth leading cause of death in persons aged 1 to 19 years. The success of the pediatric oncology cooperative group clinical trials has allowed a systematic approach to the treatment of relatively rare malignancies. Each trial builds on previous results in terms of both survival and toxicity. This article will discuss the current treatment regimens for several of the more common pediatric malignancies and their long-term complications developed through this process.

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