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BMJ Open May 2024DNA-informed prescribing (termed pharmacogenomics, PGx) is the epitome of personalised medicine. Despite international guidelines existing, its implementation in...
Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children (MARVEL- PIC): protocol for a national randomised controlled trial of pharmacogenomics implementation.
INTRODUCTION
DNA-informed prescribing (termed pharmacogenomics, PGx) is the epitome of personalised medicine. Despite international guidelines existing, its implementation in paediatric oncology remains sparse.
METHODS AND ANALYSIS
Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children is a national prospective, multicentre, randomised controlled trial assessing the impact of pre-emptive PGx testing for actionable PGx variants on adverse drug reaction (ADR) incidence in patients with a new cancer diagnosis or proceeding to haematopoetic stem cell transplant. All ADRs will be prospectively collected by surveys completed by parents/patients using the National Cancer Institute Pediatric Patient Reported [Ped-PRO]-Common Terminology Criteria for Adverse Events (CTCAE) (weeks 1, 6 and 12). Pharmacist will assess for causality and severity in semistructured interviews using the CTCAE and Liverpool Causality Assessment Tool. The primary outcome is a reduction in ADRs among patients with actionable PGx variants, where an ADR will be considered as any CTCAE grade 2 and above for non-haematological toxicities and any CTCAE grade 3 and above for haematological toxicities Cost-effectiveness of pre-emptive PGx (secondary outcome) will be compared with standard of care using hospital inpatient and outpatient data along with the validated Childhood Health Utility 9D Instrument. Power and statistics considerations: A sample size of 440 patients (220 per arm) will provide 80% power to detect a 24% relative risk reduction in the primary endpoint of ADRs (two-sided α=5%, 80% vs 61%), allowing for 10% drop-out.
ETHICS AND DISSEMINATION
The ethics approval of the trial has been obtained from the Royal Children's Hospital Ethics Committee (HREC/89083/RCHM-2022). The ethics committee of each participating centres nationally has undertaken an assessment of the protocol and governance submission.
TRIAL REGISTRATION NUMBER
NCT05667766.
Topics: Humans; Child; Drug-Related Side Effects and Adverse Reactions; Pharmacogenetics; Prospective Studies; Randomized Controlled Trials as Topic; Neoplasms; Multicenter Studies as Topic; Precision Medicine; Hematopoietic Stem Cell Transplantation
PubMed: 38760050
DOI: 10.1136/bmjopen-2024-085115 -
Parasite (Paris, France) 2024In the last few years, the number of studies on feline hepatozoonosis has increased, but our knowledge on the actual species of Hepatozoon and/or different genotypes...
In the last few years, the number of studies on feline hepatozoonosis has increased, but our knowledge on the actual species of Hepatozoon and/or different genotypes affecting felines is still incipient. At least three species, namely Hepatozoon felis, H. canis, and H. silvestris, have been isolated from domestic cats in various countries. Additionally, there are indications that other species and genotypes may affect felines in given geographic areas. This study was carried out to investigate the occurrence of Hepatozoon spp. in cats from Niterói, a municipality within the metropolitan area of Rio de Janeiro, Brazil. Individual blood samples were collected from 28 cats enrolled in a spaying/castration program. DNA was extracted from all samples and subjected to sequencing specific for Hepatozoon spp. DNA of H. felis was found in 21/28 cats (75%), and four genetic polymorphisms never described thus far were detected. This is the first report of H. felis in cats living in the State of Rio de Janeiro, and the present data confirm that H. felis is a species complex encompassing different genotypes circulating within cat populations. Further studies are warranted to investigate whether different genotypes have different biology or pathogenicity for felids.
Topics: Animals; Cats; Brazil; Cat Diseases; Coccidiosis; Eucoccidiida; Male; DNA, Protozoan; Female; Genotype; Polymorphism, Genetic; Phylogeny
PubMed: 38759154
DOI: 10.1051/parasite/2024026 -
Medicine May 2024To explore the therapeutic effectiveness of tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) on the treatment for chronic hepatitis B (CHB).... (Observational Study)
Observational Study
To explore the therapeutic effectiveness of tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) on the treatment for chronic hepatitis B (CHB). Retrospectively analyzing 241 cases of chronic hepatitis B patients admitted to our hospital from January 2020 to December 2021, they were divided into a TAF group of 180 cases and a TDF group of 61 cases. The liver function, serum virus markers, clinical efficacy, adverse reactions and cost-effectiveness ratio (CER) analysis of 2 groups were compared. Two groups of patients had no statistically significant difference in the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) before treatment. After treatment, the levels of ALT, AST and TBIL were lower than before treatment in both groups (P < .05), but the inter-group difference was not statistically significant (P > .05). After treatment, Hepatitis B surface antigen (HBsAg) conversion rate and Hepatitis B virus DNA (HBV-DNA) conversion rate in the 2 groups had no statistically significant difference. After treatment, the difference in total clinical cure rate between the 2 groups has no statistical significance (P > .05), adverse reactions rate of TAF group was lower than that of TDF group (P < .05). The drug cost median of TAF group was higher than that of TDF (P < .05), but Cost-effectiveness analysis showed the CER of TAF group was similar of TDF group. TAF or TDF therapy can both improve liver function and promote recovery in patients with CHB, achieving the goal of treatment. TAF have more cost but have similar CER to TDF. Moreover, TAF therapy has a higher safety profile.
Topics: Humans; Tenofovir; Hepatitis B, Chronic; Male; Female; Retrospective Studies; Antiviral Agents; Adult; Middle Aged; Treatment Outcome; Cost-Benefit Analysis; Alanine; DNA, Viral; Alanine Transaminase; Hepatitis B Surface Antigens
PubMed: 38758884
DOI: 10.1097/MD.0000000000037953 -
Medicine May 2024Identifying prognostic factors in elderly patients with severe coronavirus disease 2019 (COVID-19) is crucial for clinical management. Recent evidence suggests... (Observational Study)
Observational Study
Identifying prognostic factors in elderly patients with severe coronavirus disease 2019 (COVID-19) is crucial for clinical management. Recent evidence suggests malnutrition and renal dysfunction are associated with poor outcome. This study aimed to develop a prognostic model incorporating prognostic nutritional index (PNI), estimated glomerular filtration rate (eGFR), and other parameters to predict mortality risk. This retrospective analysis included 155 elderly patients with severe COVID-19. Clinical data and outcomes were collected. Logistic regression analyzed independent mortality predictors. A joint predictor "L" incorporating PNI, eGFR, D-dimer, and lactate dehydrogenase (LDH) was developed and internally validated using bootstrapping. Decreased PNI (OR = 1.103, 95% CI: 0.78-1.169), decreased eGFR (OR = 0.964, 95% CI: 0.937-0.992), elevated D-dimer (OR = 1.001, 95% CI: 1.000-1.004), and LDH (OR = 1.005, 95% CI: 1.001-1.008) were independent mortality risk factors (all P < .05). The joint predictor "L" showed good discrimination (area under the curve [AUC] = 0.863) and calibration. The bootstrapped area under the curve was 0.858, confirming model stability. A combination of PNI, eGFR, D-dimer, and LDH provides useful prognostic information to identify elderly patients with severe COVID-19 at highest mortality risk for early intervention. Further external validation is warranted.
Topics: Humans; COVID-19; Aged; Male; Female; Retrospective Studies; Glomerular Filtration Rate; Prognosis; Nutrition Assessment; SARS-CoV-2; Aged, 80 and over; Fibrin Fibrinogen Degradation Products; Risk Factors; L-Lactate Dehydrogenase; Severity of Illness Index; Malnutrition
PubMed: 38758852
DOI: 10.1097/MD.0000000000038213 -
Microbiology Spectrum May 2024Monkeypox virus (MPXV) poses a global health threat. Droplet digital PCR (ddPCR) holds potential as an accurate diagnostic tool for clinical microbiology. However, there...
UNLABELLED
Monkeypox virus (MPXV) poses a global health threat. Droplet digital PCR (ddPCR) holds potential as an accurate diagnostic tool for clinical microbiology. However, there is limited literature on the applicability of ddPCR in clinical settings. In this study, the clinical features of patients with MPXV during the initial outbreak in China in June 2023 were reviewed, and an optimized ddPCR method with dilution and/or inhibitor removal was developed to enhance MPXV detection efficiency. Eighty-two MPXV samples were tested from nine different clinical specimen types, including feces, urine, pharyngeal swabs, anal swabs, saliva, herpes fluid, crust, and semen, and the viral load of each specimen was quantified. A comparative analysis was performed with qPCR to assess sensitivity and specificity and to investigate the characteristics of MPXV infection by analyzing viral loads in different clinical specimens. Consequently, common pharyngeal and gastrointestinal symptoms were observed in patients with MPXV. The optimized ddPCR method demonstrated relatively high sensitivity for MPXV quantification in the clinical materials, with a limit of detection of 0.1 copies/μL. This was particularly evident in low-concentration samples like whole blood, semen, and urine. The optimized ddPCR demonstrated greater detection accuracy compared with normal ddPCR and qPCR, with an area under the curve (AUC) of 0.939. Except for crust samples, viral loads in the specimens gradually decreased as the disease progressed. Virus levels in feces and anal swabs kept a high detection rate at each stage of post-symptom onset, and feces and anal swabs samples may be suitable for clinical diagnosis and continuous monitoring of MPXV.
IMPORTANCE
The ddPCR technique proved to be a sensitive and valuable tool for accurately quantifying MPXV viral loads in various clinical specimen types. The findings provided valuable insights into the necessary pre-treatment protocols for MPXV diagnosis in ddPCR detection and the potentially suitable sample types for collection. Therefore, such results can aid in comprehending the potential characteristics of MPXV infection and the usage of ddPCR in clinical settings.
PubMed: 38757960
DOI: 10.1128/spectrum.00018-24 -
The Kaohsiung Journal of Medical... May 2024Colorectal cancer (CRC) is notable for its high mortality and high metastatic characteristics. The shear force generated by bloodstream provides mechanical signals...
Colorectal cancer (CRC) is notable for its high mortality and high metastatic characteristics. The shear force generated by bloodstream provides mechanical signals regulating multiple responses of cells, including metastatic cancer cells, dispersing in blood vessels. We, therefore, studied the effect of shear flow on circulating CRC cells in the present study. The CRC cell line SW620 was subjected to shear flow of 12.5 dynes/cm for 1 and 2 h separately. Resulting elevated caspase-9 and -3 indicated that shear flow initiated the apoptosis of SW620. Enlarged cell size associated with a higher level of cyclin D1 was coincident with the flow cytometric results indicating that the cell cycle was arrested at the G phase. An elevated phosphor-eNOS increased the production of nitric oxide and led to reactive oxygen species-mediated oxidative stress. Shear flow also regulated epithelial-mesenchymal transition (EMT) by increasing E-cadherin and ZO-1 while decreasing Snail and Twist1. The migration and invasion of sheared SW620 were also substantially decreased. Further investigations showed that mitochondrial membrane potential was significantly decreased, whereas mitochondrial mass and ATP production were not changed. In addition to the shear flow of 12.5 dynes/cm, the expressions of EMT were compared at lower (6.25 dynes/cm) and at higher (25 dynes/cm) shear flow. The results showed that lower shear flow increased mesenchymal characteristics and higher shear flow increased epithelial characteristics. Shear flow reduces the malignancy of CRC in their metastatic dispersal that opens up new ways to improve cancer therapies by applying a mechanical shear flow device.
PubMed: 38757734
DOI: 10.1002/kjm2.12844 -
Frontiers in Nutrition 2024The French maritime pine bark extract Pycnogenol is a proprietary product from Aiton. It complies with the quality specifications in the monograph "Pine extract" in... (Review)
Review
The French maritime pine bark extract Pycnogenol is a proprietary product from Aiton. It complies with the quality specifications in the monograph "Pine extract" in the section of dietary supplements. Pycnogenol is standardized to contain 65-75% procyanidins which are a variety of biopolymers consisting of catechin and epicatechin monomeric units. The effects of Pycnogenol have been researched in a multitude of human studies. The basis for any activity is the bioavailability of constituents and metabolites of the extract. General principles of compound absorption, distribution, metabolism and elimination as well as specific data from studies with Pycnogenol are summarized and discussed in this review. Based on plasma concentration profiles it can be concluded that low molecular weight constituents of the extract, such as catechin, caffeic and ferulic acid, taxifolin are readily absorbed from the small intestine into systemic circulation. Procyanidin oligomers and polymers are subjected to gut microbial degradation in the large intestine yielding small bioavailable metabolites such as 5-(3',4'-dihydroxyphenyl)-γ-valerolactone. After intake of Pycnogenol, constituents and metabolites have been also detected in blood cells, synovial fluid and saliva indicating a substantial distribution in compartments other than serum. In studies simultaneously investigating concentrations in different specimen, a preferential distribution of individual compounds has been observed, e.g., of ferulic acid and 5-(3',4'-dihydroxyphenyl)-γ-valerolactone into synovial fluid compared to serum. The main route of elimination of constituents and metabolites of the French pine bark extract is the renal excretion. The broad knowledge accumulated regarding the pharmacokinetics of compounds and metabolites of Pycnogenol constitute a rational basis for effects characterized on a cellular level and observed in human clinical studies.
PubMed: 38757126
DOI: 10.3389/fnut.2024.1389422 -
Frontiers in Public Health 2024This research delves into the disparities in access to oncology care among cancer patients in Georgia, with a specific focus on the distinct challenges faced by African...
This research delves into the disparities in access to oncology care among cancer patients in Georgia, with a specific focus on the distinct challenges faced by African American (AA) individuals compared to non-African American (Non-AA) counterparts. Leveraging data from the 2020 Behavioral Risk Factor Surveillance System (BRFSS) survey and supplementary online resources, the study meticulously examines socioeconomic factors, including income, education, and insurance coverage, which significantly influence the quality of cancer care received. The analysis reveals substantial income gaps between AA and Non-AA patients, underscoring the critical implications for healthcare access. Moreover, AA patients exhibit lower rates of full insurance coverage for cancer-related treatments, posing additional barriers to comprehensive care. By investigating the intersections of race, income, and education, the research aims to pinpoint the root causes of these disparities and proposes evidence-based solutions to address the identified challenges. The ultimate objective is to contribute valuable insights that inform targeted policy recommendations and community-based interventions, fostering a more equitable landscape for oncology care in Georgia. This study seeks to amplify awareness and advocate for tangible measures, striving toward healthcare equity for all cancer patients, irrespective of their racial or socioeconomic backgrounds.
Topics: Humans; Neoplasms; Georgia; Healthcare Disparities; Male; Female; Health Services Accessibility; Black or African American; Socioeconomic Factors; Middle Aged; Adult; Behavioral Risk Factor Surveillance System; Medical Oncology; Insurance Coverage; Aged
PubMed: 38756877
DOI: 10.3389/fpubh.2024.1381075 -
Frontiers in Immunology 2024Intracerebral hemorrhage (ICH) often triggers oxidative stress through reactive oxygen species (ROS). Transforming growth factor-β-activated kinase 1 (TAK1) plays a...
INTRODUCTION
Intracerebral hemorrhage (ICH) often triggers oxidative stress through reactive oxygen species (ROS). Transforming growth factor-β-activated kinase 1 (TAK1) plays a pivotal role in regulating oxidative stress and inflammation across various diseases. 5Z-7-Oxozeaenol (OZ), a specific inhibitor of TAK1, has exhibited therapeutic effects in various conditions. However, the impact of OZ following ICH and its underlying molecular mechanisms remain elusive. This study aimed to explore the possible role of OZ in ICH and its underlying mechanisms by inhibiting oxidative stress-mediated pyroptosis.
METHODS
Adult male Sprague-Dawley rats were subjected to an ICH model, followed by treatment with OZ. Neurobehavioral function, blood-brain barrier integrity, neuronal pyroptosis, and oxidative stress markers were assessed using various techniques including behavioral tests, immunofluorescence staining, western blotting, transmission electron microscopy, and biochemical assays.
RESULTS
Our study revealed that OZ administration significantly inhibited phosphorylated TAK1 expression post-ICH. Furthermore, TAK1 blockade by OZ attenuated blood-brain barrier (BBB) disruption, neuroinflammation, and oxidative damage while enhancing neurobehavioral function. Mechanistically, OZ administration markedly reduced ROS production and oxidative stress by facilitating nuclear factor-erythroid 2-related factor 2 (NRF2) nuclear translocation. This was accompanied by a subsequent suppression of the NOD-like receptor protein 3 (NLRP3) activation-mediated inflammatory cascade and neuronal pyroptosis.
DISCUSSION
Our findings highlight that OZ alleviates brain injury and oxidative stress-mediated pyroptosis via the NRF2 pathway. Inhibition of TAK1 emerges as a promising approach for managing ICH.
Topics: Animals; Pyroptosis; NF-E2-Related Factor 2; Oxidative Stress; Cerebral Hemorrhage; Male; Rats; Signal Transduction; MAP Kinase Kinase Kinases; Rats, Sprague-Dawley; Neurons; Blood-Brain Barrier; Disease Models, Animal; Brain Injuries; Reactive Oxygen Species; Lactones; Resorcinols; Zearalenone
PubMed: 38756773
DOI: 10.3389/fimmu.2024.1386780 -
Frontiers in Immunology 2024Impaired metabolism is recognized as an important contributor to pathogenicity of T cells in (SLE). Over the last two decades, we have acquired significant knowledge... (Review)
Review
Impaired metabolism is recognized as an important contributor to pathogenicity of T cells in (SLE). Over the last two decades, we have acquired significant knowledge about the signaling and transcriptomic programs related to metabolic rewiring in healthy and SLE T cells. However, our understanding of metabolic network activity derives largely from studying metabolic pathways in isolation. Here, we argue that enzymatic activities are necessarily coupled through mass and energy balance constraints with in-built network-wide dependencies and compensation mechanisms. Therefore, metabolic rewiring of T cells in SLE must be understood in the context of the entire network, including changes in metabolic demands such as shifts in biomass composition and cytokine secretion rates as well as changes in uptake/excretion rates of multiple nutrients and waste products. As a way forward, we suggest cell physiology experiments and integration of orthogonal metabolic measurements through computational modeling towards a comprehensive understanding of T cell metabolism in lupus.
Topics: Lupus Erythematosus, Systemic; Humans; T-Lymphocytes; Metabolic Networks and Pathways; Energy Metabolism; Animals; Signal Transduction; Cytokines
PubMed: 38756769
DOI: 10.3389/fimmu.2024.1371708