Tag Archives: Children

Exploring nutritional factors during pregnancy and in infancy to find clues for childhood tooth decay

23 May, 2023 Admin Leave a comment

Reviewed by Danielle Ellis, B.Sc.May 23 2023

Researchers from Rochester Institute of Technology and the University of Rochester Medical Center are taking a closer look at nutritional factors during pregnancy and in infancy associated with severe tooth decay in young children.

Brenda Abu, assistant professor in RIT’s Wegmans School of Health and Nutrition and a researcher in maternal and child health, is collaborating on a study to investigate the Oral Microbiome in Early Infancy (OMEI) and Nutrition. Perinatal oral health expert Dr. Jin Xiao, associate professor at the Eastman Institute for Oral Health, is leading a large project funded by the National Institutes of Health’s Dental and Craniofacial Research.

The researchers will examine relationships between perinatal nutritive behavior-;such as dietary iron intake-;and nonnutritive behavior-;such as pica-;and the oral microbiome during pregnancy and early life. Abu and Xiao will assess the impact on infants’ early-life oral yeast colonization and infection and explore microbial compositions of pica substances. A two-year $380,000 award from the NIH supports Abu’s collaboration.

Pica is the compulsive eating of items lacking nutritional value. The behavior occurs most often in women and children, and substances consumed include seemingly harmless items, such as ice, or dangerous materials, such as dried paint, clay, soil, or metal. Pica may cause infections and deplete iron stores in pregnant women. The results can be devastating on maternal health and fetal development and carry long-lasting consequences, according to Abu.

People who have iron deficiency crave the taste and smell of non-food substances that make iron deficiency worse. Pregnant women who develop iron deficiency anemia have increased risk of miscarriages, low-birthweight babies, and other poor-birth outcomes.”

Brenda Abu, Assistant Professor, RIT’s Wegmans School of Health and Nutrition

Other risk factors revealed from this study could inform prenatal counseling for underserved women and predict and prevent “Early Childhood Caries,” or severe tooth decay in young children. Xiao’s research among underserved racial and ethnic minority groups has shown that the presence of certain bacteria and yeast in the mother’s mouth increases the child’s likelihood of developing the condition.

“The OMEI + Nutrition is the first study that examines the relationship between nutritive and nonnutritive factors on perinatal oral microbiome among underserved U.S. pregnant women and their children,” said Dr. Xiao. “The data generated will strengthen the understanding of children’s oral microbiome development and their association to tooth decay.”

Abu’s collaboration with Xiao and other URMC researchers began with an earlier study assessing pica practice, oral health, and oral microbiome during pregnancy. The NIH award supports Abu’s career development and complements her international research focused on micronutrient nutrition and consequences among women and children living in Ghana. Findings from the current study exploring maternal nutrition and the oral microbiome in early infancy will influence the scope of Abu’s international research.

“With my training and expertise in nutrition, my long-term career goal is to bridge gaps in nutritional and oral research and generate groundbreaking interventions for early warning, early detections, and prevention of oral disease and iron deficiency among underserved mothers and young children,” Abu said.

Dr. Eli Eliav, professor and director of the UR’s Eastman Institute for Oral Health, is the adviser for the OMEI + Nutrition research. UR team members who will play key roles on the project include Steven Gill, professor of microbiology and immunology; Tong Tong Wu, associate professor of biostatistics and computational biology; and Dr. Kevin Fiscella, professor of family medicine. The entire team is listed online.

Source:

Rochester Institute of Technology

Microbiology

Novel gene-editing strategy harnesses an unusual protective ability to eliminate HIV-1 infection

19 May, 2023 Admin Leave a comment

Reviewed by Danielle Ellis, B.Sc.May 19 2023

Genetic alterations that give rise to a rare, fatal disorder known as MOGS-CDG paradoxically also protect cells against infection by viruses. Now, scientists at the Lewis Katz School of Medicine at Temple University have harnessed this unusual protective ability in a novel gene-editing strategy aimed at eliminating HIV-1 infection with no adverse effects on cell mortality.

The new approach, described online April 28 in the journal Molecular Therapy – Nucleic Acids, is based on a combination of two gene-editing constructs, one that targets HIV-1 DNA and one that targets a gene called MOGS – defects in which cause MOGS-CDG. In cells from persons infected with HIV-1, the Temple researchers show that disrupting the virus’s DNA while also deliberately altering MOGS blocks the production of infectious HIV-1 particles. The discovery opens up new avenues in the development of a cure for HIV/AIDS.

Proper MOGS function is essential for glycosylation, a process by which some cellular proteins synthesized in the body are modified to make them stable and functional. Glycosylation, however, is leveraged by certain kinds of infectious viruses. In particular, viruses like HIV, influenza, SARS-CoV-2, and hepatitis C, which are surrounded by a viral envelope, rely on glycosylated proteins to enter host cells.

In the new study, lead investigators Kamel Khalili, PhD, Laura H. Carnell Professor and Chair of the Department of Microbiology, Immunology, and Inflammation, Director of the Center for Neurovirology and Gene Editing, and Director of the Comprehensive NeuroAIDS Center at the Lewis Katz School of Medicine, and Rafal Kaminski, PhD, Assistant Professor at the Center for Neurovirology and Gene Editing at the Lewis Katz School of Medicine designed a genetic approach to exclusively turn on CRISPR to impede MOGS gene expression through DNA editing within immune cells that harbor replication competent, HIV-1. Their novel approach is expected to avoid any impact on the health of uninfected cells that retain normal MOGS gene function. Stimulation of the apparatus in HIV-1 infected cells disrupted the glycan structure of the HIV-1 envelope protein, culminating in the production of non-infectious virus particles.

“This approach is conceptually very interesting,” said Dr. Khalili, who is also senior investigator on the new study. “By mitigating the ability of the virus to enter cells, which requires glycosylation, MOGS may offer another target, in addition to the integrated viral DNA for developing the next generation of CRISPR gene-editing technology for HIV elimination.”

Dr. Kaminski, Dr. Khalili, and Tricia H. Burdo, PhD, Professor and Vice Chair in the Department of Microbiology, Immunology, and Inflammation and the Center for Neurovirology and Gene Editing at Temple and an expert in the use of non-human primate models for HIV-1, have been working together to further assess the efficacy and safety of CRISPR-MOGS strategy in preclinical studies. In previous work, the team demonstrated that CRISPR-based technology can successfully remove viral DNA from the cells of infected non-human primates.

Other researchers who contributed to the study include Hong Liu, Chen Chen, Shuren Liao, and Shohreh Amini, Department of Microbiology, Immunology, and Inflammation, Center for Neurovirology and Gene Editing, Lewis Katz School of Medicine at Temple University; Danielle K. Sohaii, Conrad R.Y. Cruz, and Catherine M. Bollard, Center for Cancer and Immunology Research, Children’s National Health System, The George Washington University; Thomas J. Cradick and Jennifer Gordon, Excision Biotherapeutics, San Francisco, CA; Anand Mehta, Stephane Grauzam, and James Dressman, Department of Cell and Molecular Pharmacology, Medical University of South Carolina; and Carlos Barrero and Magda Florez, Department of Pharmaceutical Sciences, School of Pharmacy, Temple University.

The research was supported in part by grants from the National Institutes of Health and the W.W. Smith Charitable Trust.

Source:

Temple University Health System

Journal reference:

Liu, H., et al. (2023) Strategic Self-Limiting Production of Infectious HIV Particles by CRISPR in Permissive Cells. Molecular Therapy — Nucleic Acids. doi.org/10.1016/j.omtn.2023.04.027.

Microbiology

Mouse study offers clues to developing an effective vaccine for Klebsiella bacteria

19 May, 2023 Admin Leave a comment

Reviewed by Danielle Ellis, B.Sc.May 18 2023

A mouse study at Washington University School of Medicine in St. Louis points to data that could be key to developing an effective vaccine for the bacterium Klebsiella pneumoniae. The bug is often resistant to antibiotics, making it difficult to treat in some.

In the U.S., the bacterium Klebsiella pneumoniae is a common cause of urinary tract infection, bloodstream infection and pneumonia. While infections with the bacterium can be easily treated in some, Klebsiella has a dangerous flip side: It also is frequently resistant to antibiotics, making it extraordinarily difficult to treat in others. About half of people infected with a hypervirulent, drug-resistant strain of the bacterium die.

Scientists are working on vaccines for Klebsiella, but the optimal vaccine design is still unknown. However, a new study in mice by scientists at Washington University School of Medicine in St. Louis and Omniose, a St. Louis startup company specializing in vaccine production, provides critical data that could be key to developing an effective vaccine for Klebsiella. The findings, published in PLoS Pathogens, are a step toward taming the superbug.

When you think about the bugs that can be resistant to almost all antibiotics — the scary superbugs in the news — a lot of them are strains of Klebsiella. For a long time, the bacterium wasn’t even a pressing issue. But now it is, due to an explosion in antibiotic-resistant Klebsiella. Our goal is to diminish Klebsiella’s superbug status by developing a vaccine before hypervirulent or resistant strains sicken and kill even more people.”

David A. Rosen, MD, PhD, study’s senior author, assistant professor of pediatrics and of molecular microbiology at Washington University

Hypervirulent Klebsiella strains have spread globally, often causing community-acquired infections.

In the U.S., Klebsiella infections primarily occur in health-care facilities where medically vulnerable patients are immunocompromised, require long courses of antibiotics to treat other conditions, have chronic diseases, or are elderly people or newborns. “But now we’re seeing the emergence of hypervirulent strains dangerous enough to cause serious disease or death among healthy people in the community,” Rosen said.

Most concerning among scientists are the strains of Klebsiella impervious to carbapenems, a class of broad-spectrum antibiotics used to treat the most severe bacterial infections. For this reason, the World Health Organization and the U.S. Centers for Disease Control and Prevention have identified carbapenem-resistant Klebsiella as an urgent threat to public health.

The rod-shaped bacterium is immobile and, like chocolate-covered candies, encapsulated in sugar coatings. In the new study, researchers created two experimental vaccines based on two different sugars, or polysaccharides, on Klebsiella’s surface: the terminal sugars on lipopolysaccharide, called O-antigen, and a capsular polysaccharide, or K-antigen. Since sugars by themselves tend to produce weak immune responses, the researchers linked each of the sugars to a protein to boost the immune response, creating so-called conjugate vaccines. Sugar-protein conjugate vaccines have proven successful in combating several bacteria including Streptococcus pneumoniae, the most common cause of pneumonia. Historically, this connection between the sugar and protein carrier has been achieved using synthetic chemistry in a test tube; however, the vaccines created for this study are called bioconjugate vaccines, because the researchers connected the sugar to the protein all within an engineered bacteria system.

Once the vaccines were created, the researchers tested the experimental bioconjugate vaccines’ ability to protect mice from disease caused by Klebsiella.

“It turned out that the capsule vaccine was far superior to the O-antigen vaccine,” said the study’s first author, Paeton Wantuch, PhD, a postdoctoral associate in Rosen’s lab. “Mice that received the capsule vaccine were significantly more likely to survive Klebsiella infection in their lungs or their bloodstream than mice that received the O-antigen vaccine.”

Both vaccines elicited high levels of antibodies against their respective targets. But the antibodies against the O-antigen just weren’t as effective as the ones against the capsule. In some strains of Klebsiella, the O-antigen may be obscured by other sugars, so the antibodies that target the O-antigen cannot make contact with their target.

“Our findings suggest that we may also need to include the capsule-based antigens in vaccine formulations developed against Klebsiella,” Rosen said. “This is why it’s so important for us to continue studying antibody-antigen interactions in the different strains, with the goal of identifying the ideal vaccine composition for clinical trials soon. The need has never been more imperative, especially as Klebsiella’s drug-resistant, hypervirulent strains become stronger, bolder and more dangerous to human health.”

Source:

Washington University School of Medicine

Journal reference:

Wantuch, P. L., et al. (2023) Area-deprivation, social care spending and the rates of children in care proceedings in local authorities in Engl Capsular polysaccharide inhibits vaccine-induced O-antigen antibody binding and function across both classical and hypervirulent K2:O1 strains of Klebsiella pneumoniae. PLOS Pathogens. doi.org/10.1371/journal.ppat.1011367.

Microbiology

Novel computational platform can expand the pool of cancer immunotherapy targets

17 May, 2023 Admin Leave a comment

Reviewed by Megan Craig, M.Sc.May 17 2023

Researchers at Children’s Hospital of Philadelphia (CHOP) and the University of California, Los Angeles (UCLA) have developed a computational platform capable of discovering tumor antigens derived from alternative RNA splicing, expanding the pool of cancer immunotherapy targets. The tool, called “Isoform peptides from RNA splicing for Immunotherapy target Screening” (IRIS), was described in a paper published today in the Proceedings of the National Academy of Sciences.

Immunotherapy has revolutionized cancer treatment, but for many cancers including pediatric cancers, the repertoire of antigens is incomplete, underscoring a need to expand the inventory of actionable immunotherapy targets. We know that aberrant alternative RNA splicing is widespread in cancer and generates a range of potential immunotherapy targets. In our study, we were able to show that our computational platform was able to identify immunotherapy targets that arise from alternative splicing, introducing a broadly applicable framework for discovering novel cancer immunotherapy targets that arise from this process.”

Yi Xing, PhD, co-senior author, director of the Center for Computational and Genomic Medicine at CHOP

Cancer immunotherapy has ushered in a sea change in the treatment of many hematologic cancers, harnessing the power of a patient’s own immune system to fight the disease. Chimeric antigen receptor T-cell (CAR-T) and T cell receptor-engineered T cell (TCR-T) therapies modify a patient’s own T cells to attack known antigens on the surface of cancer cells and have often led to durable responses for cancers that were once considered incurable. However, the field has encountered challenges in the solid tumor space, in large part due to a lack of known and suitable targets for these cancers, highlighting the need for novel approaches to expand the pool of immunotherapy targets.

Alternative splicing is an essential process that allows for one gene to code for many gene products, based on where the RNA is cut and joined, or spliced, before being translated into proteins. However, the splicing process is dysregulated in cancer cells, which often take advantage of this process to produce proteins that promote growth and survival, allowing them to replicate uncontrollably and metastasize. This happens in many adult and pediatric cancers. Scientists have suggested splicing dysregulation could be a source of novel tumor antigens for immunotherapy, but identifying such antigens has been a challenge.

To address this difficulty, the researchers created IRIS to leverage large-scale tumor and normal RNA sequencing data and incorporate multiple screening approaches to discover tumor antigens that arise due to alternative splicing. Integrating RNA sequencing-based transcriptomics data and mass spectrometry-based proteomics data, the researchers showed that hundreds of IRIS-predicted TCR targets are presented by human leukocyte antigen (HLA) molecules, the part of the human immune system that presents antigens to T cells.

The researchers then applied IRIS to RNA sequencing data from neuroendocrine prostate cancer (NEPC), a metastatic and highly lethal disease known to involve shifts in RNA splicing, as discovered in a prior study by CHOP and UCLA researchers. From 2,939 alternative splicing events enriched in NEPC, IRIS predicted 1,651 peptides as potential TCR targets. The researchers then applied a more stringent screening test, which prioritized 48 potential targets. Interestingly, the researchers found that these targets were highly enriched for peptides encoded by short sequences of less than 30 nucleotides in length – also known as “microexons” – which may arise from a unique program of splicing dysregulation in this type of cancer.

To validate the immunogenicity of these targets, the researchers isolated T cells reactive to IRIS-predicted targets, and then used single-cell sequencing to identify the TCR sequences. The researchers modified human peripheral blood mononuclear cells with seven TCRs and found they were highly reactive against targets predicted by IRIS to be good immunotherapy candidates. One TCR was particularly efficient at killing tumor cells expressing the target peptide of interest.

“Immunotherapy is a powerful tool that has had a significant impact on the treatment of some cancers, but the benefits have not been fully realized in many lethal cancers that could benefit from this approach,” said Owen N. Witte, MD, University Professor of Microbiology, Immunology, and Molecular Genetics and member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “The discovery of new antigenic targets that may be shared among different patients – and even different tumor types – could be instrumental in expanding the value of cell-based therapies. Analyzing massive amounts of data on tumor and normal tissues, which requires sophisticated computational tools like those developed by the Xing Lab, provides actionable insights on targets that one day could be tested in the clinic.”

“This proof-of-concept study demonstrates that alternatively spliced RNA transcripts are viable targets for cancer immunotherapy and provides a big data and multiomics-powered computational platform for finding these targets,” Dr. Xing added. “We are applying IRIS for target discovery across a wide range of pediatric and adult cancers. We are also developing a next-generation IRIS platform that harnesses newer transcriptomics technologies, such as long read and single cell analysis.”

This research was supported in part by the Immuno-Oncology Translational Network (IOTN) of the National Cancer Institute’s Cancer Moonshot Initiative, other National Institutes of Health funding, the Parker Institute for Cancer Immunotherapy, the Cancer Research Institute, and the Ressler Family Fund.

Source:

Children’s Hospital of Philadelphia

Journal reference:

Pan, Y., et al. (2023) IRIS: Discovery of cancer immunotherapy targets arising from pre-mRNA alternative splicing. PNAS. doi.org/10.1073/pnas.2221116120.

Microbiology

Study identifies key genetic mechanism of drug resistance in the deadliest malaria parasites

13 May, 2023 Admin Leave a comment

Reviewed by Emily Henderson, B.Sc.May 11 2023

An important genetic mechanism of drug resistance in one of the deadliest human malaria parasites has been identified in a new study published in Nature Microbiology.

A second key gene, pfaat1, responsible for encoding a protein that transports amino acids in the membrane of Plasmodium falciparum, is involved in its resistance to the major anti-malaria drug, chloroquine.

The findings may have implications for the ongoing battle against malaria, which infects an estimated 247 million people worldwide and kills more than 619,000 each year, most of which are young children.

Chloroquine is a major antimalaria drug, however in recent years, resistance has emerged in malaria parasites, first spreading through Southeast Asia and then through Africa in the 1970s and 1980s. Although alternative antimalarial drugs have been developed, resistance to chloroquine remains a big challenge.

Since its discovery in 2000, only one gene has been believed to have been responsible for resistance to chloroquine – the resistance transporter pfcrt which helps the malaria parasite transport the drug out of a key region in their cells, subsequently rendering it ineffective.

In this study, researchers from the Medical Research Council (MRC) Unit The Gambia at the London School of Hygiene & Tropical Medicine (LSHTM) analysed more than 600 genomes of P. falciparum that were collected in The Gambia over a period of 30 years. The team found that mutant variants of a second gene, pfaat1, which encodes an amino acid transporter, increased in frequency from undetectable to very high levels between 1984 and 2014. Importantly, their genome-wide population analyses also indicated long term co-selection on this gene alongside the previously-known resistance gene pfcrt.

In the laboratory, a further team of researchers including from Texas Biomed, University of Notre Dame and Seattle Children’s Research Institute found that replacing these mutations in parasite genomes using CRISPR gene-editing technology impacted drug resistance. A team from Nottingham University also found that these mutations could impact the function of pfaat1 in yeast, resulting in drug resistance.

Complementary analysis of malaria genome datasets additionally suggested that parasites from Africa and Asia may carry different mutations in pfaat1 which could help explain differences in the evolution of drug resistance across these continents.

Alfred Amambua-Ngwa, Professor of Genetic Epidemiology at MRC Unit The Gambia at LSHTM said: “This is a very clear example of natural selection in action – these mutations were preferred and passed on with extremely high frequency in a very short amount of time, suggesting they provide a significant survival advantage.

“The mutations in pfaat1 very closely mirror the increase of pfcrt mutations. This, and other genetic analyses in the paper demonstrate that the transporter AAT1 has a major role in chloroquine resistance.”

Grappling with drug resistance, for malaria and other pathogens, requires taking a holistic approach to both drug development and pathogen surveillance. We must be aware that different genes and molecules will be working together to survive treatments. That is why looking at whole genomes and whole populations is so critical.”

David Conway, Professor of Biology, LSHTM

Source:

London School of Hygiene & Tropical Medicine (LSHTM)

Journal reference:

Amambua-Ngwa, A., et al. (2023). Chloroquine resistance evolution in Plasmodium falciparum is mediated by the putative amino acid transporter AAT1. Nature Microbiology. doi.org/10.1038/s41564-023-01377-z.

Microbiology

Anticoronavirals: the development of COVID-19 therapies and the challenges that remain

8 May, 2023 Admin Leave a comment

By Neha MathurMay 8 2023Reviewed by Danielle Ellis, B.Sc.

In a recent article published in Nature Microbiology, researchers highlighted the pace of development of coronavirus disease 2019 (COVID-19) therapies during the pandemic and the challenges that hinder the widespread availability of anticoronavirals.

*Study: Therapeutics for COVID-19. Image Credit: Viacheslav Lopatin/Shutterstock.com*

Background

COVID-19 is the third coronavirus disease in the past 20 years after severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). While the two predecessors caused severe mortality, they did not cause a pandemic. On the contrary, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered a pandemic, and by 21 February 2023, it had caused more than 757 million confirmed cases, including >6.8 million deaths worldwide.

Vaccines and monoclonal antibody (mAb) treatments for COVID-19 became available within a year of the pandemic. Yet, there is a substantial need for more effective therapeutics to treat unvaccinated and immunocompromised patients and those whose vaccine immunity waned over time.

About the study

In this study, the authors highlighted four stages of SARS-CoV-2 infection that require different therapeutic interventions as critical for identifying COVID-19 therapeutic targets. At stage 1, when viral replication begins inside the host, oral or intravenous administration of monoclonal antibodies and antiviral therapies are effective. However, an ideal time for prophylactic administration of vaccines is Stage 0 preceding the infection.

Clinical trials have established that mAbs and antivirals effectively combat COVID-19 when administered up to 10 days after symptom onset and within three to five days following the onset of symptoms, respectively. COVID-19 patients in stage 2 develop viral pneumonia, cough and fever, lung inflammation causing shortness of breath, and lung aberrations, such as ground glass opacities.

The most serious is stage 3 characterized by a hyperinflammatory state or acute respiratory distress syndrome (ARDS). Some patients might also develop coagulation disorders or shock or systemic inflammatory response syndrome (SIRS). Thus, at stage 3, a patient needs antiviral drugs and immunomodulatory therapy.

Stage 4 represents post-COVID-19 conditions when patients experience hyperinflammatory illnesses, e.g., multi-system inflammatory syndrome in children (MISC), following acute SARS-CoV-2 infection. Unfortunately, possible preventative measures and treatment for post-acute sequelae of SARS-CoV-2 (PASC) are not fully understood. It is a growing area of unmet medical need; thus, extensive research efforts are ongoing to classify PASC, which might be a conglomeration of several syndromes, and determine its cause(s).

The National Institutes of Health (NIH) Treatment Guidelines Panel makes recommendations for the treatment and prevention of COVID-19. Early in the pandemic, clinicians used azithromycin and hydroxychloroquine as a possible COVID-19 treatment for hospitalized patients based on in vitro evidence of their synergistic effect on SARS-CoV-2 infection. Later, clinical trials found this combination ineffective. Similarly, the NIH panel did not specify recommendations for empirical antimicrobials.

The NIH rejected giving vitamin/mineral supplements, e.g., zinc, for hospitalized COVID-19 patients. On the contrary, they recommended prompt use of supplemental oxygenation and high-flow nasal cannula in patients with ARDS. In the absence of effective treatments, clinical recommendations by NIH continue to change and evolve.

Early drug repurposing efforts targeted nucleotide prodrugs, e.g., remdesivir (or GS-5734), AT-527, favipiravir, and molnupiravir (or MK-4482). However, only three antivirals received full Emergency Use Authorization (EUA) approval from the United States Food and Drug Administration (US-FDA), remdesivir, molnupiravir, and nirmatrelvir.

Pre-clinical characterization of remdesivir for other coronaviruses, pharmacokinetic and safety evaluation in humans in a failed clinical trial for Ebola virus, all acquired before the beginning of the COVID-19 pandemic, enabled rapid progression of remdesivir.

A phase 3 study conducted among patients in outpatient facilities and nursing facilities showed that remdesevir administration within seven days of symptom onset decreased hospitalization risk by 87%. Thus, its approval extended to high-risk non-hospitalized patients as well. Currently, phase 1b/2a study for inhaled remdesivir, and pre-clinical evaluation of an oral prodrug based on remdesivir is ongoing.

Another randomized phase III trial evaluated ivermectin, metformin, and fluvoxamine, all repurposed drug candidates, for early COVID-19 treatment of overweight or obese adults. Earlier pivotal efficacy and clinical studies found that molnupiravir provided no clinical benefit in hospitalized COVID-19 patients.

Conversely, the MOVe-OUT outpatient study demonstrated that treatment initiated within five days of symptom onset reduced the hospitalization risk or death. Accordingly, molnupiravir attained an EUA in the US on in late 2021 for treatment of mild-to-moderately ill COVID-19 patients at high risk of progression to severe disease. However, an outpatient study suggested that molnupiravir might augment SARS-CoV-2 evolution in immunocompromised individuals.

In the USA, multiple initiatives have been undertaken to identify candidate agents that may be repurposed as COVID-19 drugs. For instance, the Bill and Melinda Gates Foundation launched the Therapeutics Accelerator in March 2020, wherein they adopted a three-way approach to test approved drugs, screen drug repositories, and evaluate novel small molecules, including mAbs against SARS-CoV-2.

Encouragingly, apilimod, a PIKfyve kinase inhibitor developed for treating autoimmune diseases, is being tested for COVID-19 in clinical studies. Likewise, multiple clinical trials are ongoing for camostat mesilate, an inhibitor of transmembrane protease serine 2 (TMPRSS2), an approved chronic pancreatitis treatment in Japan.

Among anti-inflammatory and immunomodulating drugs, dexamethasone, a corticosteroid, baricitinib, a Janus kinase (JAK) inhibitor, and tocilizumab have received FDA approval. Among mAb therapies, casirivimab with imdevimab and bamlanivimab with etesevimab, Sotrovimab, Bebtelovimab, Tixagevimab–cilgavimab have received FDA approval. However, as SARS-CoV-2 continues to evolve, changes in the spike protein led to EUAs being withdrawn for all mAb therapies due to loss of efficacy.

Conclusions

There is a vast knowledge gap regarding COVID-19 pathogenesis. Despite the absence of a viral reservoir, severe disease persists for weeks or even months after COVID-19 recovery. Another intriguing area of investigation is why autoantibodies increase over time during COVID-19. In February 2022, the government of the United States of America (USA) started a flagship program, RECOVER, to understand, prevent and treat COVID-19-related long-term health effects.

Amid decreasing vaccine uptake and waning efficacy of mAbs as SARS-CoV-2 mutates, there is a need for new, safe, and effective COVID-19 therapies for population-level deployment and the potential to reduce resistance development. Researchers need to accelerate research targeting small molecule candidates that would mechanistically target the conserved region of SARS-CoV-2 and not become ineffective across mutant strains.

To be prepared for another pandemic, a large repository of small molecules that have already progressed through early pre-clinical and clinical evaluation is needed to develop drugs, like remdesivir, developed in a short span of two years.

More importantly, research efforts should continue to advance the development of antivirals for other pathogens, including coronaviruses, in preparation for the next pandemic.

Journal reference:

Toussi, S. et al. (2023) “Therapeutics for COVID-19”, Nature Microbiology, 8(5), pp. 771-786. doi: 10.1038/s41564-023-01356-4. https://www.nature.com/articles/s41564-023-01356-4

Microbiology

What are the trends in severe outcomes among patients hospitalized with COVID-19 during the first 2 years of the COVID-19 pandemic?

24 April, 2023 Admin Leave a comment

By Neha MathurApr 24 2023Reviewed by Lily Ramsey, LLM

In a recent study published in the JAMA Network Open, researchers performed a cohort study for prospective surveillance across a network of 155 acute care hospitals in Canada between March 15, 2020, and May 28, 2022, i.e., during the first two years of the coronavirus disease 2019 (COVID-19) pandemic.

Study: Trends in Severe Outcomes Among Adult and Pediatric Patients Hospitalized With COVID-19 in the Canadian Nosocomial Infection Surveillance Program, March 2020 to May 2022. Image Credit: angellodeco/Shutterstock.com

Introduction

The study summarized trends in severe outcomes among adult and pediatric patients, aged ≥18 years and zero to 17 years, respectively, hospitalized with reverse transcription-polymerase chain reaction (RT-PCR)-confirmed COVID-19 at any of the Canadian Nosocomial Infection Surveillance Program (CNISP)–participating hospitals.

Background

Any changes to the clinical manifestations of COVID-19, especially its severe or critical cases, have significant implications for the healthcare system.

However, data summarizing the trend of severe illness outcomes for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients is limited in Canada. Data from a network of Canadian hospitals, such as CNISP, could help inform public health measures in the future.

CNISP, an alliance between Canada’s Public Health Agency, sentinel hospitals, and the Association of Medical Microbiology and Infectious Disease, began collating weekly data on COVID-19 patients, stratified by age, source, and vaccination status, from March 2020 onwards.

About the study

In the present study, trained infection control professionals reviewed patient medical records from 155 acute care hospitals in 10 Canadian provinces and one territory.

They identified patients with the first COVID-19-positive RT-PCR test result within 14 days before they sought hospital admission or while in the hospital. The study population comprised adults and pediatric patients.

For study analysis, they considered several severe outcomes in patients testing positive for COVID-19, as follows:

i) hospitalization;

ii) those admitted to an intensive care unit (ICU);

iii) those receiving mechanical ventilation;

iv) those receiving mechanical ventilation (MV);

v) those receiving extracorporeal membrane oxygenation (ECMO); and

vi) all-cause in-hospital mortality

The team identified healthcare–related COVID-19 cases based on three prespecified criteria, the onset of symptoms or a positive RT-PCR test at least seven days after hospital admission, rehospitalization with a positive RT-PCR test within seven days after discharge, or a case with an epidemiological link to another COVID-19 case among staff members.

Further, the team identified six waves (periods) for the study with different SARS-CoV-2 variant predominance based on the weeks they detected increased COVID-19-related hospitalizations in the CNISP network.

For instance, the wild-type variant was dominant during waves one and two, while Alpha, Beta, and Gamma variants were predominant during wave three. During wave four, only Alpha was predominant, while the Omicron variant remained dominant during waves five and six.

The week-on-week proportion of severe disease outcomes indicated COVID-19–positivity per 1,000 hospital admissions. For this assessment, the researchers estimated weekly patient admissions by dividing quarterly hospital admissions during 2020-2021 by weeks in a quarter.

The main comparison parameter was severe outcome trends during waves five and six compared to earlier waves. For all severe outcomes, the team pooled patient data from waves one to four and waves five to six. Conversely, they pooled all wave (1-6) data for adult patients for all-cause in-hospital mortalities.

The team computed odd ratios (OR) and 95% confidence intervals (CIs) (unadjusted) to compare the severe outcomes between pooled data of all pandemic waves. They compared proportional variations using the χ2 test, where two-tailed P≤ 0.05 held statistical significance.

Finally, the team computed cumulative incidence rates (IRs) by COVID-19 vaccination status and age-stratified incidence rate ratios (IRRs) to compare these rates between these groups.

Results

Between March 15, 2020, and May 28, 2022, there were 1,513,065 admissions in 155 CNISP hospitals, where 51,679 and 4,035 were adult and pediatric patients, respectively. Of these, 8,683 adults and 498 children sought ICU admission.

Compared to Omicron-dominant waves five and six, for waves one through four combined, the proportion of COVID-19 hospitalizations among adult and pediatric patients per 1,000 hospital admissions were much lower. (24.7 vs. 77.3).

During wave five, hospitalized cases peaked for adult and pediatric patients at 146.8 and 96.3, respectively, and outpaced all previous and following waves.

During the January 16, 2022 week (wave five), the highest proportion of adult and pediatric ICU COVID-19 admissions were 18.3 and 15.6 per 1,000 hospital admissions, respectively.

Among 51,496 adult patients hospitalized during the study, 7,012 acquired COVID-19 while in the hospital. This number was higher for waves five and six combined than for waves two through two (16.9% vs. 10.8%).

Likewise, the proportion of adult patients who needed ICU admission during waves five and six was lower than in waves two through four (8.7% vs. 21.8%).

The proportion of adult patients in the ICU who received MV during waves five and six was markedly lower than for waves two through four (47.6% vs. 67.2%).

Likewise, those who received extracorporeal membrane oxygenation (ECMO) were markedly lesser during waves five and six (1.3 vs. 4.6%). The cases of all-cause in-hospital mortality also declined from waves one and two to waves five and six (16% vs. 7%).

Among pediatric patients, the proportion of hospitalized patients needing an ICU was significantly lesser in waves five and six (9.4% vs. 18.1%) than in waves one through four. However, those who received MV during waves five and six were comparable to observed numbers for waves one through four [25.8% vs. 26.8%].

Only one pediatric patient received ECMO, 31 died, and even all-cause in-hospital deaths in a total of 1,359 pediatric cases were comparable across all pandemic waves, 0.9% for waves one through four and 0.7% for waves five & six combined, though this finding was statistically insignificant (p=0.60).

Strikingly, the age-standardized IR for ICU admission in unvaccinated vs. fully vaccinated patients during waves five and six was much higher. However, the same for all-cause in-hospital mortality was lower in unvaccinated vs. fully vaccinated patients (3.9 vs. 15.1).

Conclusions

Although COVID-19-related hospitalizations peaked in wave five, a markedly reduced proportion of adult and pediatric patients sought ICU admission. Even lesser adult COVID-19 patients received MV or ECMO during later than earlier waves, though numbers were significantly higher among unvaccinated patients.

However, during waves five and six, although Canadian hospitals experienced a surge in COVID-19-related hospitalizations and nosocomial transmission, severe disease outcomes declined substantially.

Yet, the COVID-19 burden on the Canadian healthcare system remained substantial even during waves five & six. Multiple factors likely resulted in the observed reductions, such as greater COVID-19 vaccine uptake & coverage by the time Omicron became predominant, which was inherently less virulent.

During later pandemic waves, people also developed natural immunity, and even COVID-19 management at hospitals improved over time.

Together, the study data highlighted the significance of COVID-19 vaccination in reducing the burden of COVID-19 and its severe outcomes on the Canadian healthcare system.

Journal reference:

Mitchell, R. et al. (2023) “Trends in Severe Outcomes Among Adult and Pediatric Patients Hospitalized With COVID-19 in the Canadian Nosocomial Infection Surveillance Program, March 2020 to May 2022”, JAMA Network Open, 6(4), p. e239050. doi: 10.1001/jamanetworkopen.2023.9050. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2803959

Microbiology

Most kids recover from Lyme disease within six months of completing antibiotic treatment

24 April, 2023 Admin Leave a comment

Reviewed by Emily Henderson, B.Sc.Apr 21 2023

A majority of parents of children diagnosed with Lyme disease reported that their kids recovered within six months of completing antibiotic treatment, according to a new joint study from Children’s National Research Institute and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, published in Pediatric Research. The findings, based on Lyme disease treatment outcome data from 102 children in the United States, also revealed that a notably small percentage of children took longer than six months to recover and experienced a significant impact on their daily functioning.

Lyme disease is the most common vector-borne disease in the United States, with most cases caused by the bacterium Borrelia burgdorferi transmitted through the bites of infected blacklegged or deer ticks. Children between the ages 5 and 9 years account for a large proportion of the approximately 476,000 Lyme disease cases diagnosed and treated annually in the United States. Common symptoms of Lyme disease include: fever; headache; fatigue; and a distinct skin rash called erythema migrans. Without treatment, the infection can spread to joints, the heart and the nervous system. Antibiotic treatment resulting in full recovery is successful in most Lyme cases. For some, however, symptoms of pain, fatigue, or difficulty thinking persist or return after antibiotic treatment. Symptoms that substantially reduce levels of activity and impact quality of life for more than six months after treatment are classified as post-treatment Lyme disease (PTLD) syndrome.

This research studied the long-term outcomes of children with Lyme disease through a cross-sectional evaluation using validated surveys. The study collected survey responses from the parents of 102 children ages 5 to 18 years who had been diagnosed with Lyme disease between six months and 10 years before enrollment. Adolescents ages 10 to 18 years old were also invited to complete adolescent-specific questionnaires. According to these parent survey responses, 75% of children fully recovered within six months of completing treatment: 31% of all children recovered within one month; 30% recovered in one-to-three months; and 14% recovered in four-to-six months. Approximately 22% of children in the study experienced at least one symptom that persisted six or more months after completing treatment; of those, 9% had symptoms classified as PTLD syndrome. Six percent of the children were not fully recovered at the time of the survey, with 1% experiencing symptoms significant enough to impair daily functioning, the authors noted.

According to the authors, this study supports previous data showing an excellent overall prognosis for children with Lyme disease, which should help alleviate understandable parental stress associated with lingering non-specific symptoms among infected children. They note that the findings of this study can help clinicians manage families’ expectations about the varying post-treatment recovery times of pediatric Lyme disease patients. The researchers suggest this new data could help reduce the potential for families seeking dangerous alternative therapies for children who experience prolonged recovery times. PTLD syndrome remains poorly understood in children and adults, and more research is needed to better understand these prolonged symptoms and identify treatment targets, according to the authors.

This study was supported through a partnership between NIAID and the Children’s National Research Institute (CNRI). Researchers at the Center for Translational Research at CNRI and the NIAID Laboratory of Clinical Immunology and Microbiology conducted the study.

Source:

NIH/National Institute of Allergy and Infectious Diseases

Journal reference:

Monaghan, M., et al. (2023). Pediatric Lyme disease: systematic assessment of post-treatment symptoms and quality of life. Pediatric Research. doi.org/10.1038/s41390-023-02577-3.

Microbiology

GW one of 18 clinical trial sites across the United States testing monkeypox vaccine in adolescents

19 April, 2023 Admin Leave a comment

Reviewed by Emily Henderson, B.Sc.Apr 19 2023

The National Institutes of Health trial to evaluate the mpox (previously known as monkeypox) vaccine JYNNEOS has now entered the next stage and is studying the immune responses to and the safety of the vaccine in adolescents. The George Washington University is one of 18 clinical trial sites across the United States that have launched this stage testing the JYNNEOS vaccine.

The JYNNEOS vaccine was approved by the U.S. Food and Drug Administration for use in adults in 2019 and, in 2022, was authorized for use in people under 18 years of age on an emergency use basis. The latest stage of the trial, which is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, will look to see if the vaccine is safe and triggers an immune response in adolescents ages 12 to 17 that is comparable to adults ages 18 to 50 years. GW’s participation is funded through a contract with Frederick National Laboratory for Cancer Research, operated by Leidos Biomedical Research in Frederick, Maryland, which provides scientific support to NIH.

We are excited to have launched the next stage of this clinical trial, which can help determine if this vaccine can be used to protect adolescents should there be another large outbreak in the United States or some other part of the world.”

David Diemert, clinical director, George Washington University Vaccine Research Unit and professor of medicine, GW School of Medicine and Health Sciences

The GW Vaccine Research Unit is a collaboration between the Departments of Medicine and Microbiology, Immunology and Tropical Medicine located at the George Washington University School of Medicine and Health Sciences, and the GW Medical Faculty Associates. The GW Vaccine Research Unit conducts clinical trials of experimental products that are being developed for the prevention of infectious diseases.

The clinical investigators at GW and the other sites plan to test 135 adults ages 18 to 50 who will serve as a comparison group in this stage of the study. The researchers will also recruit about 315 adolescents ages 12 to 17 years. All of the recruits will get the standard dose of the vaccine delivered subcutaneously, Diemert said.

The trial will last for 13 months and investigators will check for safety and to see if the antibody response in adolescents in the study are comparable to that of adults.

Mpox historically occurs in West and Central Africa, but in 2022, a large outbreak began in the United States and other countries around the world where mpox is uncommon. The virus spreads through close contact with an infected person or animal.

Although kids in the United States rarely get mpox, experts say children and teens can and do get this painful and sometimes deadly disease.

“Having a safe and effective vaccine at the ready would help prepare the United States and other countries for the next outbreak of this disease,” Diemert said.

Source:

George Washington University

Microbiology

Study finds sugary beverages increase dementia risk, while natural juices may help prevent it

18 April, 2023 Admin Leave a comment

By Dr. Liji Thomas, MDApr 17 2023Reviewed by Danielle Ellis, B.Sc.

In an article published in the journal Current Opinion in Microbiology, scientists have provided a detailed overview of the factors affecting maternal gut microbiota during pregnancy and its impact on maternal and infant health.

Study: Sugary beverages and genetic risk in relation to brain structure and incident dementia: a prospective cohort study. Image Credit: Africa Studio / Shutterstock

Background

Pregnancy is associated with a wide range of hormonal, immunological, and metabolic changes needed for fetal development. The most notable changes include increased cardiac output, higher levels of T regulatory cells, and alteration in gut microbiome composition.

Alteration in gut microbiota composition and diversity is associated with changes in women’s metabolic, immunological, and neurological processes, irrespective of pregnancy status. In addition, changes in gut microbiota composition are known to affect insulin sensitivity. In children with type 1 diabetes, functional and metabolic changes in gut microbiota have been documented.

Alteration in gut microbiota during pregnancy

Only limited evidence is available to thoroughly understand the changes in gut microbiota during pregnancy and its impact on maternal and fetal health. However, according to the available literature, low-grade inflammation at the intestinal mucosa as well as hormonal changes, might be responsible for gut microbiota alteration during pregnancy.

Regarding hormonal changes, pregnancy-related induction in progesterone levels is known to directly associate with increased Bifidobacterium levels in women. Bifidobacterium is a beneficial bacterium that naturally resides in the intestine. Therefore, the gut-to-gut transmission of this bacterium from the mother to the infant is crucial during the neonatal period. In infants, this bacterium helps degrade human milk oligosaccharides coming from maternal milk, in addition to developing infant gut microbiota and immune system.

Factors influencing maternal gut microbiota during pregnancy

Adult human gut microbiota can be influenced by many factors, including body mass index (BMI), medications, diseases, environment, and lifestyle (diet, physical activity, smoking, and drinking habits). Pre-pregnancy exposure to these factors can lead to structural and functional alteration in maternal gut microbiota during pregnancy.

Animal studies have shown that maternal diet influences maternal and infant gut microbiota composition before and during pregnancy. Both pre-pregnancy body weight and pregnancy-related weight gain have been found to alter the composition and diversity of maternal gut microbiota.

Infant gut microbiota are influenced by the way they are delivered. For example, infants delivered vaginally have been shown to gain beneficial changes in gut microbiota compared to those delivered by c-section.

Functional studies in animals have shown that smoking-related nicotine exposure during pregnancy affects maternal gut microbiota, which in turn alters fetal exposure levels to circulating short-chain fatty acids and leptin during in-utero development.

Certain diseases before pregnancy, such as inflammatory bowel disease, have been found to influence maternal microbiota during pregnancy. The microbiota of the pregnant mother’s gut has also been shown to be affected pre-pregnancy and during pregnancy by certain medications, including antibiotics, proton-pump inhibitors, metformin, laxatives, and probiotics.

Maternal health impact of altered gut microbiota

Studies have found maternal gut microbiota alteration during pregnancy is associated with pregnancy complications, including gestational diabetes and preeclampsia.

Gestational diabetes

A spontaneous induction in blood glucose levels during pregnancy is medically termed gestational diabetes. Studies have shown that a reduced abundance of beneficial bacteria and an increased abundance of pathogenic bacteria are responsible for the onset of gestational diabetes.

In the microbiome of gestational diabetes patients, an increased abundance of membrane transport, energy metabolism, lipopolysaccharides, and phosphotransferase system pathways has been observed. Recent evidence indicates that gut microbiota-derived dopamine deficiency in the blood, impaired production of short-chain fatty acids, and excessive metabolic inflammation are collectively responsible for the development of gestational diabetes.

Preeclampsia

Preeclampsia is characterized by new-onset hypertension, proteinuria, and organ dysfunction during pregnancy. Studies involving pregnant women with preeclampsia have found gut microbiota dysbiosis (imbalance in gut microbiota composition) and increased plasma levels of lipopolysaccharide and trimethylamine N-oxide.

Recent evidence indicates that preeclampsia onset is associated with reduced bacterial diversity in gut microbiota. Specifically, the changes in gut microbiota include a depletion in beneficial bacteria and an enrichment in opportunistic bacteria.

Some mechanistic studies have pointed out that gut microbiota dysbiosis induces immune imbalance and intestinal barrier disruption in pregnant women, leading to the translocation of bacteria to the intrauterine cavity, placental inflammation, and poor placentation. All these factors collectively contribute to the development of preeclampsia.

Infant health impact of altered gut microbiota

Alteration in maternal gut microbiota has been found to affect the fetus’s neurodevelopment via signaling microbially modulated metabolites to neurons in the developing brain. These changes can have long-term effects on an infant’s behaviors.

Maternal microbiota-derived metabolites such as short-chain fatty acids are known to shape the metabolic system of infants. Some evidence has also indicated that maternal gut microbiota influences an infant’s susceptibility to allergic diseases.

Journal reference:

Sinha T. 2023. The maternal gut microbiome during pregnancy and its role in maternal and infant health. Current Opinion in Microbiology. https://www.sciencedirect.com/science/article/pii/S1369527423000462

Background

About the study

Conclusions

Introduction

Background

About the study

Results

Conclusions

Background

Alteration in gut microbiota during pregnancy

Factors influencing maternal gut microbiota during pregnancy

Maternal health impact of altered gut microbiota

Infant health impact of altered gut microbiota

Microbiome: From Research and Innovation to Market