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JAMA Network Open Jun 2024Among patients with rheumatoid arthritis (RA) who had an inadequate response to methotrexate, a treatment sequence initiated with biosimilar disease-modifying... (Comparative Study)
Comparative Study
IMPORTANCE
Among patients with rheumatoid arthritis (RA) who had an inadequate response to methotrexate, a treatment sequence initiated with biosimilar disease-modifying antirheumatic drugs (DMARDs) provides better clinical efficacy compared with conventional synthetic DMARDs recommended by current treatment guidelines; but its cost-effectiveness evidence remains unclear.
OBJECTIVE
To evaluate the cost-effectiveness of the treatment sequence initiated with biosimilar DMARDs after failure with methotrexate vs leflunomide and inform formulary listing decisions.
DESIGN, SETTING, AND PARTICIPANTS
This economic evaluation's cost-effectiveness analysis was performed at a Hong Kong public institution using the Markov disease transition model to simulate the lifetime disease progression and cost for patients with RA, using monetary value in 2022. Scenario and sensitivity analyses were performed to test the internal validity of the modeling conclusion. Participants included patients diagnosed with RA from 2000 to 2021 who were retrieved retrospectively from local electronic medical records to generate model input parameters. Statistical analysis was performed from January 2023 to March 2024.
INTERVENTIONS
The model assesses 3 competing treatment sequences initiated with biosimilar infliximab (CT-P13), biosimilar adalimumab (ABP-501), and leflunomide; all used in combination with methotrexate.
MAIN OUTCOMES AND MEASURES
Lifetime health care cost and quality-adjusted life-years (QALYs) of the simulated cohort.
RESULTS
In total, 25 099 patients with RA were identified (mean [SD] age, 56 [17] years; 19 469 [72.7%] women). In the base-case analysis, the lifetime health care cost and QALYs for the treatment sequence initiated with leflunomide were US $154 632 and 14.82 QALYs, respectively; for biosimilar infliximab, they were US $152 326 and 15.35 QALYs, respectively; and for biosimilar adalimumab, they were US $145 419 and 15.55 QALYs, respectively. Both biosimilar sequences presented lower costs and greater QALYs than the leflunomide sequence. In the deterministic sensitivity analysis, the incremental cost-effectiveness ratio (US$/QALY) comparing biosimilar infliximab sequence vs leflunomide sequence and biosimilar adalimumab sequence vs leflunomide sequence ranged from -15 797 to -8615 and -9088 to 10 238, respectively, all below the predefined willingness-to-pay threshold (US $48 555/QALY gain). In the probabilistic sensitivity analysis, the probability of treatment sequence initiated with leflunomide, biosimilar infliximab, and biosmilar adalimumab being cost-effective out of 10 000 iterations was 0%, 9%, and 91%, respectively.
CONCLUSIONS AND RELEVANCE
In this economic evaluation study, the treatment sequences initiated with biosimilar DMARDs were cost-effective compared with the treatment sequence initiated with leflunomide in managing patients with RA who experienced failure with the initial methotrexate treatment. These results suggest the need to update clinical treatment guidelines for initiating biosimilars immediately after the failure of methotrexate for patients with RA.
Topics: Humans; Arthritis, Rheumatoid; Leflunomide; Biosimilar Pharmaceuticals; Cost-Benefit Analysis; Antirheumatic Agents; Female; Male; Middle Aged; Infliximab; Adult; Hong Kong; Retrospective Studies; Quality-Adjusted Life Years; Adalimumab; Aged
PubMed: 38922614
DOI: 10.1001/jamanetworkopen.2024.18800 -
ImmunoHorizons Jun 2024The underlying contribution of immune complexes in modulating adaptive immunity in mucosal tissues remains poorly understood. In this report, we examined, in mice, the...
The underlying contribution of immune complexes in modulating adaptive immunity in mucosal tissues remains poorly understood. In this report, we examined, in mice, the proinflammatory response elicited by intranasal delivery of the biothreat agent ricin toxin (RT) in association with two toxin-neutralizing mAbs, SylH3 and PB10. We previously demonstrated that ricin-immune complexes (RICs) induce the rapid onset of high-titer toxin-neutralizing Abs that persist for months. We now demonstrate that such responses are dependent on CD4+ T cell help, because treatment of mice with an anti-CD4 mAb abrogated the onset of RT-specific Abs following intranasal RICs exposure. To define the inflammatory environment associated with RIC exposure, we collected bronchoalveolar lavage fluid (BALF) and sera from mice 6, 12, and 18 h after they had received RT or RICs by the intranasal route. A 32-plex cytometric bead array revealed an inflammatory profile elicited by RT that was dominated by IL-6 (>1500-fold increase in BALF) and secondarily by KC (CXCL1), G-CSF, GM-CSF, and MCP-1. RICs induced inflammatory profiles in both BALF and serum response that were similar to RT, albeit at markedly reduced levels. These results demonstrate that RICs retain the capacity to induce local and systemic inflammatory cytokines/chemokines that, in turn, may influence Ag sampling and presentation in the lung mucosa and draining lymph nodes. A better understanding of the fate of immune complexes following intranasal delivery has implications for the development of mucosal vaccines for biothreats and emerging infectious diseases.
Topics: Animals; Administration, Intranasal; Ricin; Mice; Bronchoalveolar Lavage Fluid; Female; Antigen-Antibody Complex; Antibodies, Neutralizing; Immunization; Inflammation; Antibodies, Monoclonal; Cytokines; CD4-Positive T-Lymphocytes; Mice, Inbred BALB C; Mice, Inbred C57BL
PubMed: 38922287
DOI: 10.4049/immunohorizons.2400007 -
Toxins Jun 2024Despite their evolutionary novelty, lizard venoms are much less studied in comparison to the intense research on snake venoms. While the venoms of helodermatid lizards...
Despite their evolutionary novelty, lizard venoms are much less studied in comparison to the intense research on snake venoms. While the venoms of helodermatid lizards have long been assumed to be for defensive purposes, there is increasing evidence of toxic activities more useful for predation than defence (such as paralytic neurotoxicity). This study aimed to ascertain the effects of , , and lizard venoms on the coagulation and cardiovascular systems. Anticoagulant toxicity was demonstrated for the species studied, with the venoms prolonging clotting times in human and bird plasma due to the destructive cleavage of fibrinogen. In contrast, thromboelastographic analyses on human and bird plasmas in this study demonstrated a procoagulant bioactivity for venoms. A previous study on venom using factor-depleted plasmas as a proxy model suggested a procoagulant factor was present that activated either Factor XI or Factor XII, but could not ascertain the precise target. Our activation studies using purified zymogens confirmed FXII activation. Comparisons of neonate and adult , revealed the neonates to be more potent in the ability to activate FXII, being more similar to the venom of the smaller species than the adult This suggests potent FXII activation a basal trait in the genus, present in the small bodied last common ancestor. This also indicates an ontogenetic difference in prey preferences in the larger species paralleing the change in venom biochemistry. In addition, as birds lack Factor XII, the ability to clot avian plasma suggested an additional procoagulant site of action, which was revealed to be the activation of Factor VII, with being the most potent. This study also examined the effects upon the cardiovascular system, including the liberation of kinins from kininogen, which contributes to hypotension induction. This form of toxicity was previously described for venoms, and was revealed in this study was to also be a pathophysiological effect of and venoms. This suggests that this toxic activity was present in the venom of the last common ancestor of the anguimorph lizards, which is consistent with kallikrein enzymes being a shared toxin trait. This study therefore uncovered novel actions of anguimorph lizard venoms, not only contributing to the evolutionary biology body of knowledge but also revealing novel activities to mine for drug design lead compounds.
Topics: Animals; Lizards; Blood Coagulation; Humans; Anticoagulants; Birds; Venoms; Cardiotoxins; Thrombelastography; Cardiotoxicity
PubMed: 38922177
DOI: 10.3390/toxins16060283 -
Exploring the Efficacy of Using , , , Clay Minerals, and Walnut Nutshells for Mycotoxin Remediation.Toxins Jun 2024The aim of this study was to evaluate the effectiveness of nine different biological compounds to reduce mycotoxins concentrations. The hypothesis of this study was that...
The aim of this study was to evaluate the effectiveness of nine different biological compounds to reduce mycotoxins concentrations. The hypothesis of this study was that a static in vitro gastrointestinal tract model, as an initial screening tool, can be used to simulate the efficacy of , , yeast cell walls and their polysaccharides, red and white clay minerals, and walnuts nutshells claiming to detoxify AFB1, ZEA, DON, and T-2 toxin mycotoxins. Mycotoxin concentrations were analyzed using high-performance liquid chromatography (HPLC) with fluorescent (FLD) and ultraviolet detectors (UV). The greatest effects on reducing mycotoxin concentrations were determined as follows: for AFB1, inserted cell wall polysaccharides and walnut nutshells; for ZEA, inserted and cell walls and red clay minerals; for DON, cell wall polysaccharides and red clay minerals; and for T-2 toxin, cell walls, and cell wall polysaccharides and walnut nutshells. The present study indicated that selected mycotoxin-detoxifying biological compounds can be used to decrease mycotoxin concentrations.
Topics: Juglans; Rhodotorula; Mycotoxins; Clay; Geotrichum; Nuts; Aluminum Silicates; Minerals
PubMed: 38922175
DOI: 10.3390/toxins16060281 -
Toxins Jun 2024Mycotoxins are toxic secondary metabolites produced by various fungi that can contaminate food crops, which, in turn, may lead to human exposure. Chronic exposure to...
Mycotoxins are toxic secondary metabolites produced by various fungi that can contaminate food crops, which, in turn, may lead to human exposure. Chronic exposure to mycotoxins can cause adverse health effects including reproductive and developmental toxicity. Pregnant women and their foetuses present a vulnerable group for exposure to mycotoxins that can cross the placenta. Human biomonitoring of mycotoxins provides a real-life approach to estimate internal exposure. In this pilot study, 24-h urine samples from 36 pregnant Dutch women were analysed for aflatoxin M1 (AFM1), total deoxynivalenol (DON), de-epoxy-deoxynivalenol (DOM-1), total zearalenone (ZEN), total α-zearalenol (α-ZEL), total β-zearalenol (β-ZEL) and total zearalanone (ZAN), where 'total' refers to mycotoxins and their conjugated forms. Serum samples from these women were analysed for fumonisin B1 (FB1) and ochratoxin A (OTA). All samples were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The most prevalent mycotoxins were total DON, total ZEN and OTA, with a detection frequency of 100%. DOM-1, total α-ZEL and total β-ZEL were detected but to a lesser extent, while AFM1, total ZAN and FB1 were undetected. Median concentrations were 4.75 μg total DON/L, 0.0350 μg DOM-1/L, 0.0413 μg total ZEN/L, 0.0379 μg total α-ZEL/L, 0.0189 μg total β-ZEL/L, and 0.121 μg OTA/L. The calculated median concentration for total ZEN and its metabolites was 0.105 μg/L. Based on two separate risk assessment approaches, total DON exposure in this group was considered to be of low concern. Similarly, exposure to total ZEN and its metabolites in this group was of low concern. For OTA, the risk of non-neoplastic effects was of low concern based on exposure in this group, and the risk of neoplastic effects was of low concern in the majority of participants in this group. The findings of this pilot study confirm the presence of mycotoxins in the urine and serum of pregnant Dutch women, with total DON, total ZEN, and OTA most frequently detected. Exposure to all measured mycotoxins was considered to be of low concern in this group, except for exposure to OTA, which was of low concern for the majority of participants. The study's findings offer valuable insights but should be confirmed using a larger and more diverse sample of the Dutch general population.
Topics: Humans; Female; Mycotoxins; Biological Monitoring; Pregnancy; Adult; Netherlands; Pilot Projects; Risk Assessment; Young Adult; Tandem Mass Spectrometry; Maternal Exposure
PubMed: 38922172
DOI: 10.3390/toxins16060278 -
Toxins Jun 2024Viticulture has been an important economic sector for centuries. In recent decades, global wine production has fluctuated between 250 and almost 300 million hectoliters,... (Review)
Review
Viticulture has been an important economic sector for centuries. In recent decades, global wine production has fluctuated between 250 and almost 300 million hectoliters, and in 2022, the value of wine exports reached EUR 37.6 billion. Climate change and the associated higher temperatures could favor the occurrence of ochratoxin A (OTA) in wine. OTA is a mycotoxin produced by some species of the genera and and has nephrotoxic, immunotoxic, teratogenic, hepatotoxic, and carcinogenic effects on animals and humans. The presence of this toxin in wine is related to the type of wine-red wines are more frequently contaminated with OTA-and the geographical location of the vineyard. In Europe, the lower the latitude, the greater the risk of OTA contamination in wine. However, climate change could increase the risk of OTA contamination in wine in other regions. Due to their toxic effects, the development of effective and environmentally friendly methods to prevent, decontaminate, and degrade OTA is essential. This review summarises the available research on biological aspects of OTA prevention, removal, and degradation.
Topics: Ochratoxins; Wine; Food Contamination; Animals; Humans
PubMed: 38922171
DOI: 10.3390/toxins16060277 -
Toxins Jun 2024Snakebite envenoming is a neglected tropical disease that causes >100,000 deaths and >400,000 cases of morbidity annually. Despite the use of mouse models, severe local...
Snakebite envenoming is a neglected tropical disease that causes >100,000 deaths and >400,000 cases of morbidity annually. Despite the use of mouse models, severe local envenoming, defined by morbidity-causing local tissue necrosis, remains poorly understood, and human-tissue responses are ill-defined. Here, for the first time, an ex vivo, non-perfused human skin model was used to investigate temporal histopathological and immunological changes following subcutaneous injections of venoms from medically important African vipers ( and ) and cobras ( and ). Histological analysis of venom-injected ex vivo human skin biopsies revealed morphological changes in the epidermis (ballooning degeneration, erosion, and ulceration) comparable to clinical signs of local envenoming. Immunostaining of these biopsies confirmed cell apoptosis consistent with the onset of necrosis. RNA sequencing, multiplex bead arrays, and ELISAs demonstrated that venom-injected human skin biopsies exhibited higher rates of transcription and expression of chemokines (CXCL5, MIP1-ALPHA, RANTES, MCP-1, and MIG), cytokines (IL-1β, IL-1RA, G-CSF/CSF-3, and GM-CSF), and growth factors (VEGF-A, FGF, and HGF) in comparison to non-injected biopsies. To investigate the efficacy of antivenom, SAIMR Echis monovalent or SAIMR polyvalent antivenom was injected one hour following or venom treatment, respectively, and although antivenom did not prevent venom-induced dermal tissue damage, it did reduce all pro-inflammatory chemokines, cytokines, and growth factors to normal levels after 48 h. This ex vivo skin model could be useful for studies evaluating the progression of local envenoming and the efficacy of snakebite treatments.
Topics: Humans; Skin; Necrosis; Animals; Cytokines; Snake Bites; Elapid Venoms; Viper Venoms; Inflammation; Viperidae; Chemokines
PubMed: 38922170
DOI: 10.3390/toxins16060276 -
Comparative Analysis of Maize Physico-Chemical Parameters and Mycotoxin Levels in Dual Environments.Toxins Jun 2024Maize ( L.) stands as a vital staple food globally, holding significant nutritional and economic value. However, its susceptibility to mycotoxin contamination under... (Comparative Study)
Comparative Study
Maize ( L.) stands as a vital staple food globally, holding significant nutritional and economic value. However, its susceptibility to mycotoxin contamination under stressful environmental conditions poses a considerable concern. This study aimed to assess the quality and pasting characteristics of maize varieties across two distinct regions and examine the occurrence of mycotoxins influenced by climatic factors. Five maize varieties were cultivated in triplicate in the Golegã and Coruche regions. The nutritional composition (protein, fat, fiber, ash, starch, and lutein), pasting properties, and mycotoxin levels were evaluated. A statistical analysis revealed notable differences in the nutritional profiles of the maize varieties between the two regions, particularly in the protein and lutein content. The peak viscosity ranged from 6430 to 8599 cP and from 4548 to 8178 cP in the maize varieties from the Coruche and Golegã regions, respectively. Additionally, a significant correlation was observed between the climatic conditions and the grain nutritional quality components ( < 0.05). The M variety showed the highest ash content, protein content, final viscosity, and setback viscosity and the lowest peak viscosity. The Y variety revealed the lowest fat, fiber, and lutein content and the maximum peak viscosity. The incidence of mycotoxins was notably higher in the varieties from Coruche, which was potentially attributable to higher temperatures and lower precipitation levels leading to more frequent drought conditions. Fumonisin B1 was detected in 58% of the varieties from Coruche and 33% of the samples from Golegã, while deoxynivalenol was found in 87% and 80% of the varieties from Coruche and Golegã, respectively. The H variety, which was harvested in Coruche, exhibited the highest number of fumonisins and higher amounts of protein, lutein, and fat, while fumonisins were not detected in the Golegã region, which was potentially influenced by the precipitation levels. The K variety revealed higher protein and lutein contents, a lower amount of fat, excellent pasting properties (a higher peak viscosity and holding strength and a lower peak time), and no fumonisins B1 or B2. This variety may be considered well adapted to higher temperatures and drier conditions, as verified in the Coruche region. In conclusion, our study underscored the profound impact of environmental factors on the quality and occurrence of mycotoxins in maize varieties.
Topics: Zea mays; Mycotoxins; Food Contamination; Nutritive Value; Viscosity
PubMed: 38922169
DOI: 10.3390/toxins16060275 -
Toxins Jun 2024Envenomation by marine animals poses a significant health concern globally, affecting both local residents and tourists in coastal regions. The primary objective of this... (Review)
Review
Envenomation by marine animals poses a significant health concern globally, affecting both local residents and tourists in coastal regions. The primary objective of this review is to critically evaluate the existing scientific literature to determine the most effective first-aid treatment for envenomations caused by marine animals, specifically whether hot-water immersion (HWI) or ice-pack treatment (IPT) provides the best immediate care. This comprehensive review covers a wide range of marine envenomations, from jellyfish stings to stingray injuries. While our focus is primarily on the efficacy of HWI and IPT, we also explore the role of cold-water treatment as a result of its relevance and similarity to ice-pack applications. In addition, we examine other treatments mentioned in the literature, such as medications or vinegar, and highlight their findings where applicable. To provide a clear and structured overview, we summarised the articles in separate tables. These tables categorise the type of research conducted, the marine species studied, the region of origin of the marine species, and the key findings of each study. Our analysis of the available evidence indicates a general consensus in the scientific community on the effectiveness of HWI or IPT for envenomation by marine animals. However, when treating those injuries, it is crucial to consider all factors since there is no universally superior treatment due to the diverse nature of marine habitats.
Topics: Animals; Humans; First Aid; Bites and Stings; Aquatic Organisms; Hot Temperature; Immersion; Cryotherapy; Water
PubMed: 38922167
DOI: 10.3390/toxins16060273 -
Toxins Jun 2024The rise in cyanobacterial blooms due to eutrophication and climate change has increased cyanotoxin presence in water. Most current water treatment plants do not...
The rise in cyanobacterial blooms due to eutrophication and climate change has increased cyanotoxin presence in water. Most current water treatment plants do not effectively remove these toxins, posing a potential risk to public health. This study introduces a water treatment approach using nanostructured beads containing magnetic nanoparticles (MNPs) for easy removal from liquid suspension, coated with different adsorbent materials to eliminate cyanotoxins. Thirteen particle types were produced using activated carbon, CMK-3 mesoporous carbon, graphene, chitosan, 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-oxidised cellulose nanofibers (TOCNF), esterified pectin, and calcined lignin as an adsorbent component. The particles' effectiveness for detoxification of microcystin-LR (MC-LR), cylindrospermopsin (CYN), and anatoxin-A (ATX-A) was assessed in an aqueous solution. Two particle compositions presented the best adsorption characteristics for the most common cyanotoxins. In the conditions tested, mesoporous carbon nanostructured particles, P1-CMK3, provide good removal of MC-LR and Merck-activated carbon nanostructured particles, P9-MAC, can remove ATX-A and CYN with high and fair efficacy, respectively. Additionally, in vitro toxicity of water treated with each particle type was evaluated in cultured cell lines, revealing no alteration of viability in human renal, neuronal, hepatic, and intestinal cells. Although further research is needed to fully characterise this new water treatment approach, it appears to be a safe, practical, and effective method for eliminating cyanotoxins from water.
Topics: Cyanobacteria Toxins; Humans; Microcystins; Marine Toxins; Water Purification; Adsorption; Bacterial Toxins; Alkaloids; Magnetite Nanoparticles; Tropanes; Nanostructures; Uracil; Cyanobacteria; Cell Survival; Water Pollutants, Chemical
PubMed: 38922163
DOI: 10.3390/toxins16060269