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Science Translational Medicine Oct 2023Traditional vaccines are difficult to deploy against the diverse antimicrobial-resistant, nosocomial pathogens that cause health care-associated infections. We developed...
Traditional vaccines are difficult to deploy against the diverse antimicrobial-resistant, nosocomial pathogens that cause health care-associated infections. We developed a protein-free vaccine composed of aluminum hydroxide, monophosphoryl lipid A, and fungal mannan that improved survival and reduced bacterial burden of mice with invasive blood or lung infections caused by methicillin-resistant , vancomycin-resistant , extended-spectrum beta-lactamase-expressing , and carbapenem-resistant strains of , , and The vaccine also conferred protection against the fungi and . Efficacy was apparent by 24 hours and lasted for up to 28 days after a single vaccine dose, with a second dose restoring efficacy. The vaccine acted through stimulation of the innate, rather than the adaptive, immune system, as demonstrated by efficacy in the absence of lymphocytes that were abrogated by macrophage depletion. A role for macrophages was further supported by the finding that vaccination induced macrophage epigenetic alterations that modulated phagocytosis and the inflammatory response to infection. Together, these data show that this protein-free vaccine is a promising strategy to prevent deadly antimicrobial-resistant health care-associated infections.
Topics: Animals; Mice; Anti-Bacterial Agents; Methicillin-Resistant Staphylococcus aureus; Cross Infection; Anti-Infective Agents; Vaccines; Immunity, Innate; Microbial Sensitivity Tests; Drug Resistance, Bacterial
PubMed: 37792959
DOI: 10.1126/scitranslmed.adf9556 -
International Endodontic Journal Sep 2023The results of vital pulp treatments in permanent teeth have been encouraging. Currently, pulpotomy treatment for permanent teeth primarily utilizes mineral trioxide... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The results of vital pulp treatments in permanent teeth have been encouraging. Currently, pulpotomy treatment for permanent teeth primarily utilizes mineral trioxide aggregate (MTA) as the dressing material, followed by calcium hydroxide. While other calcium-silicate-based cements have been suggested for pulpotomy, there is a limited number of studies evaluating their long-term effectiveness.
OBJECTIVES
The objective of this systematic review and meta-analysis was to evaluate the success rate of pulpotomies performed on permanent teeth, comparing the use of ProRoot MTA with that of calcium hydroxide and other bioceramic materials.
METHODS
A comprehensive search was conducted in several electronic databases, including PubMed, Cochrane Library, Scopus, Web of Science, Embase and Science Direct until December 2022. The search was guided by PICOS criteria, including only randomized clinical trials (RCTs) that evaluated the success rate of pulpotomy treatments in permanent teeth using ProRoot MTA in comparison to calcium hydroxide and other bioceramic materials. The quality of the included studies was assessed using the RoB-2 tool to evaluate the risk of bias, and relevant data were extracted and analysed in RevMan software 5.3 using fixed-effect models. The GRADE tool was used to determine the overall quality of evidence.
RESULTS
The initial search retrieved 1072 studies and, after eliminating duplicates, 677 studies were screened and 28 studies were considered for eligibility. In the final selection process, 16 studies were included in the systematic review, with 10 being determined as having a high risk of bias. Pulpotomy showed an overall mean success rate of 92% after 1 year. The meta-analysis indicated a significantly higher success rate for pulpotomies utilizing MTA in comparison with calcium hydroxide, while no significant difference was seen between MTA and calcium-enriched mixture (CEM) or Biodentine. The GRADE assessment revealed an overall low level of evidence for the included studies.
DISCUSSION
Most randomized controlled trials exhibited a significant absence of control over confounding factors.
CONCLUSIONS
This systematic review and meta-analysis demonstrate that pulpotomy is a highly effective treatment for managing permanent teeth. The results indicate that the success rate of pulpotomy using ProRoot MTA is significantly higher than when using calcium hydroxide. However, the certainty of evidence supporting these findings is low, and there is a need for well-designed RCTs to assess the long-term outcomes of pulpotomy using newer bioceramic materials.
REGISTRATION
This systematic review was registered in the PROSPERO database (registration number CRD42023393970).
Topics: Humans; Calcium Hydroxide; Pulpotomy; Calcium; Aluminum Compounds; Drug Combinations; Oxides; Randomized Controlled Trials as Topic; Calcium Compounds; Treatment Outcome; Silicates
PubMed: 37254176
DOI: 10.1111/iej.13939 -
Pharmaceutics Jul 2023Aluminum-based adjuvants will continue to be a key component of currently approved and next generation vaccines, including important combination vaccines. The widespread... (Review)
Review
Aluminum-based adjuvants will continue to be a key component of currently approved and next generation vaccines, including important combination vaccines. The widespread use of aluminum adjuvants is due to their excellent safety profile, which has been established through the use of hundreds of millions of doses in humans over many years. In addition, they are inexpensive, readily available, and are well known and generally accepted by regulatory agencies. Moreover, they offer a very flexible platform, to which many vaccine components can be adsorbed, enabling the preparation of liquid formulations, which typically have a long shelf life under refrigerated conditions. Nevertheless, despite their extensive use, they are perceived as relatively 'weak' vaccine adjuvants. Hence, there have been many attempts to improve their performance, which typically involves co-delivery of immune potentiators, including Toll-like receptor (TLR) agonists. This approach has allowed for the development of improved aluminum adjuvants for inclusion in licensed vaccines against HPV, HBV, and COVID-19, with others likely to follow. This review summarizes the various aluminum salts that are used in vaccines and highlights how they are prepared. We focus on the analytical challenges that remain to allowing the creation of well-characterized formulations, particularly those involving multiple antigens. In addition, we highlight how aluminum is being used to create the next generation of improved adjuvants through the adsorption and delivery of various TLR agonists.
PubMed: 37514070
DOI: 10.3390/pharmaceutics15071884 -
Expert Opinion on Pharmacotherapy 2023Among the clinical and metabolic complications of progressive chronic kidney disease (CKD), CKD-mineral bone disorder (CKD-MBD) significantly contributes to morbidity... (Review)
Review
INTRODUCTION
Among the clinical and metabolic complications of progressive chronic kidney disease (CKD), CKD-mineral bone disorder (CKD-MBD) significantly contributes to morbidity and mortality. While overt and persistent hyperphosphatemia is typical of advanced CKD and requires treatment, other abnormalities of calcium/phosphate metabolism begin to occur since the early stages of the disease.
AREAS COVERED
We searched on the PubMed database, without restrictions for language or time range, for randomized clinical trials and meta-analyses investigating phosphate-lowering therapies. The various phosphate binders show different safety profiles and diverse effects on calcium/phosphate metabolism and vascular calcification. The in-depth knowledge of the characteristics of these drugs is crucial to ensure adequate treatment to CKD patients.
EXPERT OPINION
A proper control of serum phosphate can be achieved using phosphate binders. These medications may induce side effects. Moreover, data on their impact on clinical outcomes are partly controversial or scarce, especially for the new generation drugs. Hyperphosphatemia favors cardiovascular disease and increases the risk for CKD progression. These effects are partially mediated by fibroblast growth factor 23 (FGF23), a phosphaturic hormone that raises to maintain normal serum phosphate. Since there are no data supporting the use of phosphate-lowering agents when phosphataemia is normal, a key role is played by reducing dietary phosphate intake with the aim to control serum phosphate and the compensatory FGF23 and parathyroid hormone (PTH) increase.
Topics: Humans; Hyperphosphatemia; Calcium; Phosphates; Renal Insufficiency, Chronic; Parathyroid Hormone; Sevelamer; Chelating Agents
PubMed: 37527180
DOI: 10.1080/14656566.2023.2243817 -
BioMed Research International 2023The present study is aimed at investigating the long-term effects of the aluminum hydroxide administration in the small intestine, lung, liver, and kidney of male BALB/c...
The present study is aimed at investigating the long-term effects of the aluminum hydroxide administration in the small intestine, lung, liver, and kidney of male BALB/c mice. The mice received via orogastric gavage phosphate buffered or 10 mg/kg aluminum hydroxide 3 times a week for 6 months. Administration of aluminum hydroxide decreased hemoglobin, hematocrit, and erythrocyte. In the blood, kidney and liver function markers were evaluated, and long-term administration of aluminum hydroxide led to an increase in AST levels and a decrease in urea levels. The animals exposed to aluminum showed higher lipid and protein oxidation in all the organs analyzed. In relation to the enzymes involved in antioxidant defense, the lungs showed lower superoxide dismutase (SOD) and catalase activity and a lower reduced and oxidized glutathione (GSH/GSSG) ratio. In the liver, aluminum administration led to a decrease in catalase activity and the GSH/GSSG ratio. Lower catalase activity was observed in the small intestine, as well as in the lungs and liver. In addition to alterations in antioxidant defense, increased levels of the chemokine CCL-2 were observed in the lungs, lower levels of IL-10 in the liver and small intestine, and decreased levels of IL-6 in the intestine of the animals that received aluminum hydroxide for 6 months. Long-term exposure to aluminum promoted steatosis in the liver. In the kidneys, mice treated with aluminum presented a decreased glomerular density than in the naive control group. In the small intestine, exposure caused villi shortening. Our results indicate that long-term oral administration of aluminum hydroxide provokes systemic histological damage, inflammation, and redox imbalance.
Topics: Mice; Male; Animals; Antioxidants; Glutathione Disulfide; Glutathione; Catalase; Aluminum Hydroxide; Mice, Inbred BALB C; Aluminum; Oxidation-Reduction; Superoxide Dismutase; Liver; Inflammation; Oxidative Stress
PubMed: 37854793
DOI: 10.1155/2023/4499407 -
Nature Communications Jul 2023A Gamma Variant RBD-based aluminum hydroxide adjuvanted vaccine called ARVAC CG was selected for a first in human clinical trial. Healthy male and female... (Clinical Trial)
Clinical Trial
A Gamma Variant RBD-based aluminum hydroxide adjuvanted vaccine called ARVAC CG was selected for a first in human clinical trial. Healthy male and female participants (18-55 years old) with a complete COVID-19-primary vaccine scheme were assigned to receive two intramuscular doses of either a low-dose or a high-dose of ARVAC CG. The primary endpoint was safety. The secondary objective was humoral immunogenicity. Cellular immune responses were studied as an exploratory objective. The trial was prospectively registered in PRIISA.BA (Registration Code 6564) and ANMAT and retrospectively registered in ClinicalTrials.gov (NCT05656508). Samples from participants of a surveillance strategy implemented by the Ministry of Health of the Province of Buenos Aires that were boosted with BNT162b2 were also analyzed to compare with the booster effect of ARVAC CG. ARVAC CG exhibits a satisfactory safety profile, a robust and broad booster response of neutralizing antibodies against the Ancestral strain of SARS-CoV-2 and the Gamma, Delta, Omicron BA.1 and Omicron BA.5 variants of concern and a booster effect on T cell immunity in individuals previously immunized with different COVID-19 vaccine platforms.
Topics: Adolescent; Adult; Female; Humans; Male; Middle Aged; Young Adult; Adjuvants, Immunologic; Antibodies, Neutralizing; Antibodies, Viral; BNT162 Vaccine; COVID-19; COVID-19 Vaccines; SARS-CoV-2; Vaccines
PubMed: 37507392
DOI: 10.1038/s41467-023-40272-3 -
Vaccine Sep 2023Norovirus (NoV) is the most common cause of diarrheal episodes globally. Issues with in vitro cultivation systems, genetic variation, and animal models have hindered...
BACKGROUND
Norovirus (NoV) is the most common cause of diarrheal episodes globally. Issues with in vitro cultivation systems, genetic variation, and animal models have hindered vaccine development. Plant-derived virus-like particles (VLPs) may address some of these concerns because they are highly immunogenic, can be administered by different routes, and can be rapidly produced to accommodate emerging viral strains.
METHODS
NoV VLPs (NoVLP) composed of the surface viral protein (VP) 1 of the GI and GII genogroups were produced in Nicotiana benthamiana using an Agrobacterium tumefaciens-based recombinant transient expression system. Leaves from infiltrated plants were harvested and NoVLPs were extracted and purified. The safety and immunogenicity of the GII.4 NoVLP, the genotype currently causing most human disease, were subsequently examined in rabbits and mice.
RESULTS
Fifteen GI and GII NoVLPs were successfully expressed in N. benthamiana and were structurally similar to NoV virions, as determined by cryogenic transmission electron microscopy. The NoVLP was well-tolerated, with no local or systemic signs of toxicity in rabbits. Three intramuscular doses of the GII.4 NoVLP adjuvanted with aluminum hydroxide induced robust IgG titers, IgG-secreting cells, histo-blood group antigen blocking titers, and IFNγ-secreting T cells in mice. In addition to circulating antibodies, oral administration of the NoVLP in mice induced significant IgA levels in feces, indicative of a mucosal response.
CONCLUSIONS
The plant-made NoVLP vaccine was safe and immunogenic in mice and rabbits. Multi-modal vaccination, combining oral and intramuscular administration could be considered for future clinical development to maximize systemic and mucosal immune responses.
Topics: Humans; Rabbits; Animals; Mice; Antibodies, Viral; Norovirus; Viral Vaccines; Immunoglobulin G; Vaccines, Virus-Like Particle; Caliciviridae Infections
PubMed: 37625992
DOI: 10.1016/j.vaccine.2023.08.036 -
Metabolites Aug 2023Vaccination programs in the first years of a child's life are effective and extremely important strategies for the successful eradication of diseases. However, as no...
Vaccination programs in the first years of a child's life are effective and extremely important strategies for the successful eradication of diseases. However, as no intervention is without risks, the metal-based components of some vaccines, such as thimerosal (TMS), a preservative composed of ethylmercury, and aluminum (Al), have begun to generate distrust on the part of the population. Therefore, this study evaluated the effects of exposure to thimerosal and aluminum hydroxide (alone or in mixture) on (zebrafish) specimens. The fish were exposed to thimerosal and/or aluminum hydroxide intraperitoneally. The liver, kidney, and brain were removed for a biochemical biomarker analysis, histopathological analysis, and metal quantification. As a result, we observed changes in the activity of the analyzed enzymes (SOD, GST, GPx) in the kidney and brain of the zebrafish, a reduction in GSH levels in all analyzed tissues, and a reduction in MT levels in the kidney and liver as well as in the brain. Changes in AChE enzyme activity were observed. The biochemical results corroborate the changes observed in the lesion index and histomorphology sections. We emphasize the importance of joint research on these compounds to increase the population's safety against their possible toxic effects.
PubMed: 37755255
DOI: 10.3390/metabo13090975