J Yeungnam Med Sci. 2024 Dec 11. doi: 10.12701/jyms.2024.00794. Online ahead of print.

ABSTRACT

BACKGROUND: Large language models (LLMs), the most recent advancements in artificial intelligence (AI), have profoundly affected academic publishing and raised important ethical and practical concerns. This study examined the prevalence and content of AI guidelines in Korean medical journals to assess the current landscape and inform future policy implementation.

METHODS: The top 100 Korean medical journals determined by Hirsh index were surveyed. Author guidelines were collected and screened by a human researcher and AI chatbot to identify AI-related content. The key components of LLM policies were extracted and compared across journals. The journal characteristics associated with the adoption of AI guidelines were also analyzed.

RESULTS: Only 18% of the surveyed journals had LLM guidelines, which is much lower than previously reported in international journals. However, the adoption rates increased over time, reaching 57.1% in the first quarter of 2024. High-impact journals were more likely to have AI guidelines. All journals with LLM guidelines required authors to declare LLM tool use and 94.4% prohibited AI authorship. The key policy components included emphasizing human responsibility (72.2%), discouraging AI-generated content (44.4%), and exempting basic AI tools (38.9%).

CONCLUSION: While the adoption of LLM guidelines among Korean medical journals is lower than the global trend, there has been a clear increase in implementation over time. The key components of these guidelines align with international standards, but greater standardization and collaboration are needed to ensure the responsible and ethical use of LLMs in medical research and writing.

PMID:39659196 | DOI:10.12701/jyms.2024.00794

J Appl Lab Med. 2024 Dec 6:jfae128. doi: 10.1093/jalm/jfae128. Online ahead of print.

ABSTRACT

BACKGROUND: Pharmacogenomics has demonstrated benefits for clinical care, including a reduction in adverse events and cost savings. However, barriers in expanded implementation of pharmacogenomics testing include prolonged turnaround times and integration of results into the electronic health record with clinical decision support. A clinical workflow was developed and implemented to facilitate in-house result generation and incorporation into the electronic health record at a large academic medical center.

METHODS: An 11-gene actionable pharmacogenomics panel was developed and validated using a QuantStudio 12K Flex platform. Allelic results were exported to a custom driver and rules engine, and result messages, which included a diplotype and predicted metabolic phenotype, were sent to the electronic health record; an electronic consultation (eConsult) service was integrated into the workflow. Postimplementation monitoring was performed to evaluate the frequency of actionable results and turnaround times.

RESULTS: The actionable pharmacogenomics panel covered 39 alleles across 11 genes. Metabolic phenotypes were resulted alongside gene diplotypes, and clinician-facing phenotype summaries (Genomic Indicators) were presented in the electronic health record. Postimplementation, 8 clinical areas have utilized pharmacogenomics testing, with 56% of orders occurring in the outpatient setting; 22.1% of requests included at least one actionable pharmacogene, and 67% of orders were associated with a pre- or postresult electronic consultation. Mean turnaround time from sample collection to result was 4.6 days.

CONCLUSIONS: A pharmacogenomics pipeline was successfully operationalized at a quaternary academic medical center, with direct integration of results into the electronic health record, clinical decision support, and eConsult services.

PMID:39657156 | DOI:10.1093/jalm/jfae128

Oral Dis. 2024 Dec 10. doi: 10.1111/odi.15217. Online ahead of print.

ABSTRACT

BACKGROUND: The variability in patients' risk of oral mucositis (OM) has been, in part, attributed to differences in host genomics. The aim better define the role of genomics as an OM risk by investigating the association between genetic variants and the presence and severity of OM in pediatric patients with osteosarcoma (OS) undergoing chemotherapy (CT).

METHODS: A longitudinal observational retrospective study was conducted. Severity of OM was assessed daily using World Health Organization (WHO) criteria. Blood samples were collected, and DNA was extracted. 54 coding regions were analyzed for 17 candidate genes using next-generation sequencing.

RESULTS: A total of 164 CT cycles were evaluated in 14 pediatric patients being treated for OS with HDMTX (66.9%) and doxorubicin + cisplatin (34.1%). OM was diagnosed in 129 cycles (78.7%). Whereas the presence of OM was associated with ABCA3 (rs13332514) in HDMTX cycles, OM severity was associated with ABCC2 (rs2273697) in multivariate analysis. In doxorubicin + cisplatin, genetic variants of ABC family genes (ABCC2 and ABCC6) were associated with OM in multivariate analysis.

CONCLUSION: Oral mucositis risk and severity in a pediatric population being treated for OS with HDMTX, doxorubicin, and cisplatin were associated with genes in the ABC family (ABCA3, ABCC2, and ABCC6 genes).

PMID:39655685 | DOI:10.1111/odi.15217

Ther Adv Urol. 2024 Dec 8;16:17562872241297554. doi: 10.1177/17562872241297554. eCollection 2024 Jan-Dec.

ABSTRACT

The advancements of technological devices and software are putting mixed reality in the frontline of teaching medical personnel. The Microsoft® HoloLens 2® offers a unique 3D visualization of a hologram in a physical, real environment and allows the urologists to interact with it. This review provides a state-of-the-art analysis of the applications of the HoloLens® in a medical and healthcare context of teaching through simulation designed for medical students, nurses, residents especially in urology. Our objective has been to perform a comprehensively analysis of the studies in PubMed/Medline database from January 2016 to April 2023. The identified articles that researched Microsoft HoloLens, having description of feasibility and teaching outcomes in medicine with an emphasize in urological healthcare, have been included. The qualitative analysis performed identifies an increasing use of HoloLens in a teaching setting that covers a great area of expertise in medical sciences (anatomy, anatomic pathology, biochemistry, pharmacogenomics, clinical skills, emergency medicine and nurse education, imaging), and above these urology applications (urological procedures and technique, skill improvement, perception of complex renal tumors, accuracy of calyx puncture guidance in percutaneous nephrolithotomy and targeted biopsy of the prostate) can mostly benefit from it. The future potential of HoloLens technology in teaching is immense. So far, studies have focused on feasibility, applicability, perception, comparisons with traditional methods, and limitations. Moving forward, research should also prioritize the development of applications specifically for urology. This will require validation of needs and the creation of adequate protocols to standardize future research efforts.

PMID:39654822 | PMC:PMC11626676 | DOI:10.1177/17562872241297554

Front Pharmacol. 2024 Nov 25;15:1500235. doi: 10.3389/fphar.2024.1500235. eCollection 2024.

ABSTRACT

INTRODUCTION: Increasingly, pharmacogenetic testing helps providers with medication selection based upon patient-specific DNA results. While several government-funded organizations work towards consensus and standardization for testing and interpretation, compliance to these best practices remains inconsistent. Pharmacogenetic testing companies often develop proprietary practices for interpreting and reporting, which can lead to incongruency of reported results among companies and potential discrepancies in interpretation.

METHODS: To identify the differences of commercial pharmacogenetic testing vendors' interpretation of genotype-to-phenotype translations and medication recommendations from the Clinical Pharmacogenetic Implementation Consortium (CPIC) guidelines, a retrospective manual chart review was completed in a large rural healthcare system that utilizes two institution-approved pharmacogenetic vendors. One hundred patients were evaluated: 50 who completed testing through Company A and 50 who completed testing through Company B. Genes of interest for genotype-to-phenotype translation included CYP2B6, CYP2C19, and CYP2D6. Comparison of medication recommendations for drug-gene pairs sertraline (CYP2B6 and/or CYP2C19), escitalopram (CYP2C19), and paroxetine (CYP2D6) were compared with recommendations from CPIC, with consideration of the CPIC Serotonin Reuptake Inhibitor Antidepressants (SSRI) guideline 2023 update. This was accomplished via a novel binning process to enable comparison of company-provided binned medication recommendations with CPIC guideline recommendations. Briefly, the binning system included three categorizations based upon the relevant CPIC guideline recommendations-no action needed (green), recommend monitoring (yellow) and therapeutic intervention or alternative recommended (red).

RESULTS: There were 32/250 (12.8%) genotype-to-phenotype translation discrepancies from CPIC guidelines, all from Company A. Of 266 evaluated binned medication recommendations, there were 114 (42.9%) discrepancies between the pharmacogenetic testing companies (Company A: 93 discrepancies, Company B: 21 discrepancies) and CPIC's guideline based upon comparison with the novel binning system.

DISCUSSION: Significant differences were observed between testing companies' interpretations and recommendations, which is concerning as these discrepancies could lead to providers making medication decisions that are not supported by CPIC's clinical practice guidelines. This may result in suboptimal outcomes for patients, leading to patient and provider dissatisfaction and erosion of trust with pharmacogenetic testing. A proposed resolution for the discrepancies in company-to-company interpretation is adherence to the CPIC guidelines and transparency in interpretation practices.

PMID:39654624 | PMC:PMC11626124 | DOI:10.3389/fphar.2024.1500235

Nat Med. 2024 Dec 9. doi: 10.1038/s41591-024-03284-0. Online ahead of print.

ABSTRACT

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by an excess of lipids, mainly triglycerides, in the liver and components of the metabolic syndrome, which can lead to cirrhosis and liver cancer. While there is solid epidemiological evidence that MASLD clusters with cardiometabolic disease, several leading genetic risk factors for MASLD do not increase the risk of cardiovascular disease, suggesting no causal relationship between MASLD and cardiometabolic derangement. In this work, we leveraged measurements of visceral adiposity identifying 27 previously unknown genetic loci associated with MASLD (n = 36,394), six replicated in four independent cohorts (n = 3,903). Next, we generated two partitioned polygenic risk scores based on the presence of lipoprotein retention in the liver. The two polygenic risk scores suggest the presence of at least two distinct types of MASLD, one confined to the liver resulting in a more aggressive liver disease and one that is systemic and results in a higher risk of cardiometabolic disease. These findings shed light on the heterogeneity of MASLD and have the potential to improve the prediction of clinical trajectories and inform precision medicine approaches.

PMID:39653778 | DOI:10.1038/s41591-024-03284-0

Cancer Chemother Pharmacol. 2024 Dec 9;95(1):2. doi: 10.1007/s00280-024-04722-z.

ABSTRACT

DPYD polymorphisms have been widely found to be related to 5-FU-induced toxicities. The aim of this study was to establish significant associations between five single-nucleotide polymorphisms of DPYD and 5-FU hematological toxicities in Thai colorectal cancer patients. The toxicities were analyzed at the first and second cycles of 5-FU administration in 75 patients. Genotyping was performed using TaqMan real-time PCR. The genotype frequencies of DPYD*2A,1905 + 1 G > A and DPYD 1774 C > T were all wild type. The frequencies of genetic testing for DPYD*5, 1627 A > G, DPYD 1896T > C, and DPYD*9A, 85 A > G were 37.30% (AG; 34.60%, GG; 2.70%), 32.00% (TC; 25.30%, CC; 6.70%), and 13.40% (AG; 10.70%, GG; 2.70%), respectively. The results reveal significant findings with neutropenia occurring in 100% (2/2) of the patients with homozygous variant DPYD*9A (GG) from the first cycle of treatment for both Grade 1-4 and Grade 3-4 toxicities (P = 0.003 and P < 0.001 respectively). DPYD *9A was related to Grade 1-4 leukopenia (P = 0.001) and both Grade 1-4 and severe thrombocytopenia (P < 0.001 and P < 0.001) in the first cycle. In the second cycle, DPYD*5 was shown to be closely associated with no Grade 1-4 toxicity (P = 0.02). However, we found that 100% (2/2) of patients carrying the homozygous variant (GG) DPYD*5, presented no significant toxicity, so, DPYD*5 may be a predictive marker of neutropenia in patients treated with 5-FU. These outcomes suggest that there may be an increased risk of developing 5-FU-induced neutropenia in patients carrying the DPYD*9A, which should be considered as part of the standard procedure.

PMID:39652193 | DOI:10.1007/s00280-024-04722-z

CPT Pharmacometrics Syst Pharmacol. 2024 Dec 9. doi: 10.1002/psp4.13291. Online ahead of print.

ABSTRACT

Trained pharmacometricians remain scarce in Africa due to limited training opportunities, lack of a pharmaceutical product development ecosystem, and emigration to high-income countries. The Applied Pharmacometrics Training (APT) fellowship program was established to address these gaps and specifically foster job creation for talent retention. We review the APT program's progress over 3 years and encourage collaboration to enhance local clinical data analysis in Africa. Initiated in 2021 by Pharmacometrics Africa, a non-profit educational entity, with support from partners including the Bill & Melinda Gates Foundation and Certara, the APT program targets African doctoral-level scientists and clinicians. This 6-month program is jointly managed by partners, with Pharmacometrics Africa handling logistics and sponsor liaison. Job creation initiatives include inviting fellows to join consulting teams or local research centers. Over the 3 year reporting period, 177 applications were received, with 27 individuals (41% female, median age 35 years) from nine African countries selected into and completing the full program. The fellows worked on 13 data analysis projects, with six so far being presented at international conferences and/or submitted for publication in peer-reviewed journals. Nine fellows have joined consulting teams or research centers working from offices in Africa. Currently, in the 3rd year, the APT program has demonstrated success in skills development, job creation, and fostering a critical mass of African pharmacometricians. Collaboration is essential for the sustainable advancement of model-informed drug development in Africa.

PMID:39648964 | DOI:10.1002/psp4.13291

Br J Psychiatry. 2024 Dec 9:1-5. doi: 10.1192/bjp.2024.236. Online ahead of print.

ABSTRACT

BACKGROUND: Clozapine therapy presents a risk of agranulocytosis, necessitating monitoring of white blood cell count. The detection of benign ethnic neutropenia (BEN), in which neutropenia can be present without an increased risk of infection, is particularly important in preventing unnecessary withdrawal of clozapine. BEN is strongly linked to the CC homozygote of the single nucleotide polymorphism rs2814778 in the atypical chemokine receptor-1 (ACKR1) gene.

AIMS: We introduced voluntary genetic testing for BEN in one of our clozapine clinics, with the aim of assessing the prevalence of undiagnosed BEN in patients on clozapine.

METHOD: We offered genetic testing for BEN to patients undergoing medium- and long-term clozapine treatment, and conducted a comparative analysis of neutrophil counts across three identified groups: those previously diagnosed with BEN, those with newly discovered BEN and those confirmed by genetic testing not to have BEN.

RESULTS: We conducted genetic testing for BEN on 108 patients. Of these, 16 were already registered as having BEN and had the CC homozygote. A further 26 patients (24% of the cohort) who were previously not diagnosed with BEN by standard haematological monitoring were found to have the CC homozygote on genetic testing. Unadjusted mean neutrophil counts were lowest for those with previously diagnosed BEN (2.5 × 109/L, 95% CI 2.2-2.8; P < 0.001 v. other groups), but those with newly discovered BEN had mean counts that were significantly lower (4.1 × 109/L, 95% CI 3.6-4.7) than those with TT and CT genotypes (5.1 × 109/L, 95% CI 4.7-5.4; P = 0.006).

CONCLUSIONS: Undiagnosed BEN was common in our naturalistic cohort. The integration of genetic testing into standard monitoring would enhance the management of clozapine therapy, potentially allowing for the safe reintroduction or continuation of clozapine in patients with hitherto unrecognised BEN. All current and prospective clozapine patients should be genetically tested for BEN.

PMID:39648666 | DOI:10.1192/bjp.2024.236

Adv Healthc Mater. 2024 Dec 8:e2404303. doi: 10.1002/adhm.202404303. Online ahead of print.

ABSTRACT

A self-propulsion Janus gallium (Ga)/magnesium (Mg) bimetallic micromotor is designed with favorable biocompatibility and antimicrobial properties as a therapeutic strategy for periodontitis. The Janus Ga/Mg micromotors are fabricated by microcontact printing technique to asymmetrically modify liquid metallic gallium onto magnesium microspheres. Hydrogen bubbles produced by the magnesium-water reaction can provide the driving performance of up to 31.03 µm s-1 (pH 6.8), prompting the micromotor to actively breakthrough the biological barrier of saliva and gingival crevice fluid (GCF) into the bottom of periodontal pockets. In addition, the Janus Ga/Mg micromotors are effectively converted by degradation into the built-in antimicrobial ion Ga(III) to eliminate deep-seated Porphyromonas gingivalis (P.gingivalis), with bactericidal efficiencies of over 99.8%. The developed Janus Ga/Mg micromotors have demonstrated potent antimicrobial and anti-inflammatory activity both in vitro and in vivo studies. Crucially, it reduces alveolar bone resorption, demonstrating the superior efficacy of liquid metal gallium in treating periodontitis. Therefore, Ga/Mg bimetallic micromotors hold great promise to be an innovative and translational drug delivery system to treat periodontitis or other inflammation-related diseases in the near future.

PMID:39648545 | DOI:10.1002/adhm.202404303

Arch Pathol Lab Med. 2024 Dec 9. doi: 10.5858/arpa.2024-0081-OA. Online ahead of print.

ABSTRACT

CONTEXT.—: A correlation between the morphology of ovarian high-grade serous carcinomas (HGSOCs) and BRCA mutations has been previously reported.

OBJECTIVE.—: To investigate, beyond BRCA, the association between the morphology of HGSOC and the presence of homologous recombination deficiency (HRD).

DESIGN.—: We reviewed 522 of 806 cases of HGSOC from the PAOLA-1 clinical trial, including 163 cases with tumor BRCA mutation, 345 cases without tumor BRCA mutation, and 14 cases with inconclusive BRCA tests. Regarding HRD status (myChoice HRD Plus assay), 269 cases (52%) were positive (HRD+), 198 (38%) negative (HRD-), and 55 (10%) inconclusive. Morphologic analysis included tumor architecture (with more than 25% of solid, pseudoendometrioid, and transitional patterns defining a SET architecture), tumor-infiltrating intraepithelial lymphocytes (ieTILs), and tumor stromal lymphocytes (sTILs).

RESULTS.—: SET architecture (51% versus 40%, P = .02), high number of ieTILs (16% versus 8%, P = .007) and more than 10% of sTILs (27% versus 18%, P = .02) were associated with tumor BRCA mutation, mostly for tumors with a BRCA1 mutation. These criteria were also associated with HRD status: 54% versus 33% (P < .001) for SET architecture, 14% versus 6% (P = .008) for high number of ieTILs, and 27% versus 15% (P = .003) for more than 10% of sTILs. SET architecture was also significantly associated with HRD+ tumors without tumor BRCA mutation (P < .001) when compared with HRD- tumors. The combination of these 3 criteria showed high specificity (0.99; 95% CI, 0.97-0.99) but low sensitivity (0.07; 95% CI, 0.04-0.10).

CONCLUSIONS.—: The morphology of HGSOC correlates with HRD status and BRCA status but cannot substitute for molecular analysis in daily practice.

PMID:39648143 | DOI:10.5858/arpa.2024-0081-OA

Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2024 Dec 9;40:e20240035. doi: 10.62958/j.cjap.2024.035.

ABSTRACT

This study means to investigate the capability of pharmacogenetics which can customize drug treatment through altered treatment of male genetic profiles. We finished hereditary profiling utilizing cutting edge sequencing (NGS) to figure out the key hereditary varieties that impact the medications metabolic adequacy and security. Patients were checked for a very long time to evaluate clinical results including ADRs and general wellness. Hereditary assessment uncovered variations in enormous qualities, for example, CYP2C9 CYP2D6 ABCB1 VKORC1 and SLCO1B1 which assume significant parts in drug digestion and transport. These hereditary markers are related with clinical realities to evaluate their effect on drug reactions and unfriendly impacts. The outcomes recommend that customized treatment dependent exclusively upon hereditary profiles could prompt better treatment results. For instance, patients with VKORC1 changes answer better to anticoagulants and drain less while patients with SLCO1B1 transformations have statin-incited myopathy which is more expensive and requires portion changes. This mirrors the useful effect of altered treatment on wellness results. Pharmacogenomics gives a useful asset to customized medication to tailor drug medicines dependent exclusively upon a person's genetic profile.

PMID:39647853 | DOI:10.62958/j.cjap.2024.035

Lancet. 2024 Dec 7;404(10469):2341-2370. doi: 10.1016/S0140-6736(24)02246-3.

ABSTRACT

BACKGROUND: The capacity to anticipate future health issues is important for both policy makers and practitioners in the USA, as such insights can facilitate effective planning, investment, and implementation strategies. Forecasting trends in disease and injury burden is not only crucial for policy makers but also garners substantial interest from the general populace and leads to a better-informed public. Through the integration of new data sources, the refinement of methodologies, and the inclusion of additional causes, we have improved our previous forecasting efforts within the scope of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) to produce forecasts at the state and national levels for the USA under various possible scenarios.

METHODS: We developed a comprehensive framework for forecasting life expectancy, healthy life expectancy (HALE), cause-specific mortality, and disability-adjusted life-years (DALYs) due to 359 causes of disease and injury burden from 2022 to 2050 for the USA and all 50 states and Washington, DC. Using the GBD 2021 Future Health Scenarios modelling framework, we forecasted drivers of disease, demographic drivers, risk factors, temperature and particulate matter, mortality and years of life lost (YLL), population, and non-fatal burden. In addition to a reference scenario (representing the most probable future trajectory), we explored various future scenarios and their potential impacts over the next several decades on human health. These alternative scenarios comprised four risk elimination scenarios (including safer environment, improved behavioural and metabolic risks, improved childhood nutrition and vaccination, and a combined scenario) and three USA-specific scenarios based on risk exposure or attributable burden in the best-performing US states (improved high adult BMI and high fasting plasma glucose [FPG], improved smoking, and improved drug use [encompassing opioids, cocaine, amphetamine, and others]).

FINDINGS: Life expectancy in the USA is projected to increase from 78·3 years (95% uncertainty interval 78·1-78·5) in 2022 to 79·9 years (79·5-80·2) in 2035, and to 80·4 years (79·8-81·0) in 2050 for all sexes combined. This increase is forecasted to be modest compared with that in other countries around the world, resulting in the USA declining in global rank over the 2022-50 forecasted period among the 204 countries and territories in GBD, from 49th to 66th. There is projected to be a decline in female life expectancy in West Virginia between 1990 and 2050, and little change in Arkansas and Oklahoma. Additionally, after 2023, we projected almost no change in female life expectancy in many states, notably in Oklahoma, South Dakota, Utah, Iowa, Maine, and Wisconsin. Female HALE is projected to decline between 1990 and 2050 in 20 states and to remain unchanged in three others. Drug use disorders and low back pain are projected to be the leading Level 3 causes of age-standardised DALYs in 2050. The age-standardised DALY rate due to drug use disorders is projected to increase considerably between 2022 and 2050 (19·5% [6·9-34·1]). Our combined risk elimination scenario shows that the USA could gain 3·8 additional years (3·6-4·0) of life expectancy and 4·1 additional years (3·9-4·3) of HALE in 2050 versus the reference scenario. Using our USA-specific scenarios, we forecasted that the USA could gain 0·4 additional years (0·3-0·6) of life expectancy and 0·6 additional years (0·5-0·8) of HALE in 2050 under the improved drug use scenario relative to the reference scenario. Life expectancy and HALE are likewise projected to be 0·4-0·5 years higher in 2050 under the improved adult BMI and FPG and improved smoking scenarios compared with the reference scenario. However, the increases in these scenarios would not substantially improve the USA's global ranking in 2050 (from 66th of 204 in life expectancy in the reference scenario to 63rd-64th in each of the three USA-specific scenarios), indicating that the USA's best-performing states are still lagging behind other countries in their rank throughout the forecasted period. Regardless, an estimated 12·4 million (11·3-13·5) deaths could be averted between 2022 and 2050 if the USA were to follow the combined scenario trajectory rather than the reference scenario. There would also be 1·4 million (0·7-2·2) fewer deaths over the 28-year forecasted period with improved adult BMI and FPG, 2·1 million (1·3-2·9) fewer deaths with improved exposure to smoking, and 1·2 million (0·9-1·5) fewer deaths with lower rates of drug use deaths.

INTERPRETATION: Our findings highlight the alarming trajectory of health challenges in the USA, which, if left unaddressed, could lead to a reversal of the health progress made over the past three decades for some US states and a decline in global health standing for all states. The evidence from our alternative scenarios along with other published studies suggests that through collaborative, evidence-based strategies, there are opportunities to change the trajectory of health outcomes in the USA, such as by investing in scientific innovation, health-care access, preventive health care, risk exposure reduction, and education. Our forecasts clearly show that the time to act is now, as the future of the country's health and wellbeing-as well as its prosperity and leadership position in science and innovation-are at stake.

FUNDING: Bill & Melinda Gates Foundation.

PMID:39645377 | DOI:10.1016/S0140-6736(24)02246-3

Biomacromolecules. 2024 Dec 7. doi: 10.1021/acs.biomac.4c01076. Online ahead of print.

ABSTRACT

The YES-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are two important transcriptional coactivators that are often aberrantly activated in cancer cells. Their dysregulation promotes cancer development and can confer resistance to anticancer therapies. Therefore, the pharmacological inhibition of YAP/TAZ presents a promising approach for treating tumors with heightened YAP/TAZ activity. However, the clinical use of a known YAP/TAZ inhibitor, niflumic acid (NA), is limited by its poor in vivo half-life. To improve its bioavailability, we developed a series of NA-based prodrug polymers and investigated the impact of NA monomer units on the physicochemical properties of their self-assembled nanoparticles. The optimal pNA polymer was selected as a prodrug micellar nanocarrier to load hydrophobic receptor tyrosine kinase inhibitors (RTKIs) for combination therapy. The nanocarrier selectively accumulated in the tumor and synergistically inhibited tumor growth with the cargo RTKIs, particularly Dasatinib, introducing a nanocombination therapy enhanced breast cancer treatment.

PMID:39644231 | DOI:10.1021/acs.biomac.4c01076

Clin Immunol. 2024 Dec 4:110414. doi: 10.1016/j.clim.2024.110414. Online ahead of print.

ABSTRACT

The aim of this research was to prospectively evaluate the impact of NOX2 gene expression profile (including NCF1, NCF2 and NCF4 genes) in peripheral blood mononuclear cells (PBMCs) on immune signatures, clinical characteristics and responsiveness to anti-TNFα treatment in RA patients. Blood specimens were collected from 31 rheumatoid arthritis (RA) patients and 25 healthy controls, and 16 RA patients were followed at two timepoints during anti-TNF treatment. mRNA expression levels of selected genes and immunoregulatory cytokines concentrations were determined. We observed the significant upregulation of NCF4 and CD14 expression in RA group. The mRNA levels of NCF1 and CD14 positively correlated both in groups of RA patients and healthy controls. NOX2 gene expression profile was not associated with anti-TNFα responsiveness, nor with RA clinical features. TNFα inhibition has not influenced NOX2 expression either. Notably, this study indicate the novel links between expression levels of NCF1 and monocyte differentiation antigen CD14.

PMID:39643026 | DOI:10.1016/j.clim.2024.110414

JAMA Netw Open. 2024 Dec 2;7(12):e2449453. doi: 10.1001/jamanetworkopen.2024.49453.

NO ABSTRACT

PMID:39641933 | DOI:10.1001/jamanetworkopen.2024.49453

JAMA Netw Open. 2024 Dec 2;7(12):e2449441. doi: 10.1001/jamanetworkopen.2024.49441.

ABSTRACT

IMPORTANCE: To date, the clinical benefit and utility of implementing a DPYD/UGT1A1 pharmacogenetic-informed therapy with fluoropyrimidines and/or irinotecan have not been prospectively investigated.

OBJECTIVE: To examine clinically relevant toxic effects, hospitalizations, and related costs while preserving treatment intensity and efficacy outcomes in patients with gastrointestinal cancer.

DESIGN, SETTING, AND PARTICIPANTS: This nonprespecified secondary analysis stems from Pre-Emptive Pharmacogenomic Testing for Preventing Adverse Drug Reactions (PREPARE), a multicenter, controlled, open, block-randomized, crossover implementation trial conducted from March 7, 2017, to June 30, 2020, and includes data from Italy according to a sequential study design. The study population included 563 patients (intervention, 252; control [standard of care], 311) with gastrointestinal cancer (age ≥18 years) who were eligible for fluoropyrimidine and/or irinotecan treatment. Data analysis for the present study was performed from May 27 to October 10, 2024.

INTERVENTIONS: Participants with actionable variants (DPYD*2A, DPYD*13, .DPYD c.2846A>T, and DPYD c.1236G>A for fluoropyrimidines, and UGT1A1*28, UGT1A1*6, and UGT1A1*27 for irinotecan) received drug or dose adjustments based on Dutch Pharmacogenetics Working Group recommendations.

MAIN OUTCOMES AND MEASURES: The primary outcome was clinically relevant toxic effects (National Cancer Institute Common Terminology Criteria for Adverse Events grade ≥4 hematologic, grade ≥3 nonhematologic, or causing hospitalization, fluoropyrimidines and/or irinotecan causally related). Secondary outcomes included hospitalization rates, toxic effect management costs, intensity of treatment, quality-adjusted life-years, and 3-year overall survival.

RESULTS: Overall, 1232 patients were enrolled in Italy, with 563 included in this analysis (317 [56.3%] men; median age, 68.0 [IQR, 60.0-75.0] years). In the intervention arm, carriers of any actionable genotype exhibited a 90% lower risk of clinically relevant toxic effects compared with the control arm (odds ratio, 0.1; 95% CI, 0.0-0.8; P = .04). They also presented higher toxic effect management costs per patient ($4159; 95% CI, $1510-$6810) compared with patients in the intervention arm ($26; 95% CI, 0-$312) (P = .004) and a higher rate of hospitalization (34.8% vs 11.8%; P = .12). The differences were not significant among all patients. Three-year overall survival did not differ significantly between arms, while quality-adjusted life-years significantly improved in the intervention arm. The pharmacogenetics-informed approach did not manifest a detrimental effect on treatment intensity in actionable genotype carriers.

CONCLUSIONS AND RELEVANCE: In this secondary analysis of PREPARE, pretreatment application of DPYD- and UGT1A1-guided treatment appeared to increase safety and reduce hospitalizations and related costs in patients with gastrointestinal cancer. Clinical benefit did not appear to be affected.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03093818.

PMID:39641926 | DOI:10.1001/jamanetworkopen.2024.49441

J Pharm Policy Pract. 2024 Dec 4;17(1):2432460. doi: 10.1080/20523211.2024.2432460. eCollection 2024.

ABSTRACT

INTRODUCTION: Pharmacogenomics (PG), the study of how genetic variations impact individual responses to drugs, has seen significant advancements globally in recent years. Hospital pharmacists play a crucial role in multi-disciplinary teams and understanding their preparedness to deliver PG services is essential for successful integration into the healthcare systems. This study evaluates their knowledge, training and seeks their views on PG testing implementation.

METHODS: A cross-sectional study was conducted on hospital pharmacists practising in Southwest London with the sample size determined as 137. The study was ethically approved. A structured, self-administered questionnaire was initially piloted, then distributed using emails with a link to Microsoft Form over a three-month period. It comprised 31 questions covering training levels, confidence, knowledge, perceptions, barriers to implementation and demographics.

RESULTS: A total of 46 responses were received achieving a response rate of 33.6%. The study revealed that 65% of participants had limited familiarity or understanding of PG. Over 50% indicated not receiving previous undergraduate or postgraduate training relevant to PG and accordingly their responses to the PG knowledge questions were lacking. Pharmacists with postgraduate training demonstrated better awareness and knowledge. An overwhelming number of participants envisaged carving a role for themselves favouring those that would complement their expertise in medicine management such as recommending appropriate treatment and dosages and suggestions based on PG testing results. Barriers identified were mostly concerning financial cost and shortage of trained staff to support PG services.

CONCLUSIONS: Most surveyed pharmacists were not prepared to deliver PG services and thus require tailored training; nonetheless, they exhibited a positive attitude towards PG suggesting a willingness to bridge learning gaps. This presents an opportunity for relevant organisations to provide necessary training and for universities to enhance the curriculum enabling pharmacists to be involved in PG implementation.

PMID:39640415 | PMC:PMC11619020 | DOI:10.1080/20523211.2024.2432460

BMC Genom Data. 2024 Dec 5;25(1):103. doi: 10.1186/s12863-024-01286-y.

ABSTRACT

BACKGROUND: Tuberculosis (TB) patients undergoing anti-tuberculosis treatment often face serious adverse drug reactions, such as hepatotoxicity. Genetic variants of the N-acetyltransferase 2 (NAT2) gene have been linked to an increased risk of these toxic events.

OBJECTIVE: This study aims to provide a comprehensive evaluation of the evidence linking NAT2 genetic variants to anti-tuberculosis drug-related hepatotoxicity (ATDH).

METHOD: A comprehensive review and meta-analysis was performed by accessing databases such as PubMed, Scopus, and Web of Science. A total of 24 articles were incorporated into the dataset. Meta-analyses were conducted to gather estimates of the association between the slow acetlylators (SA) genotype and ATDH. The studies were stratified by ethnicity, regimen, genotyping methods, criteria for liver toxicity, and dosage. Also, meta-analysis for the specific SA type that was most likely responsible for the ATDH was also conducted.

RESULTS: The included studies showed individuals with a slow NAT2 acetylator had a significantly greater risk of experiencing hepatotoxicity ATDH (odds ratio [OR] 2.52 (95% CI: 1.95-3.27; p value < 0.001) compared to individuals with other types of acetylator (i.e., rapid and immediate). Among individuals with slow acetylator NAT2*5/7, NAT2*5/6, and NAT2*6/6 genotypes, there is a greater likelihood of association compared to other variations.

CONCLUSION: Our meta-analysis confirms a significant association between slow NAT2 acetylator and increased hepatotoxicity risk. The findings from the present underscore the potential of pharmacogenomic testing to improve TB treatment outcomes. By identifying patients with the slow acetylator NAT2 genotype, healthcare providers can predict an increased risk of anti-tuberculosis drug-induced hepatotoxicity. This allows for personalized treatment strategies, such as adjusting drug dosages or selecting alternative therapies, to minimize adverse effects and optimize efficacy.

PMID:39639188 | DOI:10.1186/s12863-024-01286-y

Cell Genom. 2024 Nov 26:100722. doi: 10.1016/j.xgen.2024.100722. Online ahead of print.

ABSTRACT

Identifying factors that affect treatment response is a central objective of clinical research, yet the role of common genetic variation remains largely unknown. Here, we develop a framework to study the genetic architecture of response to commonly prescribed drugs in large biobanks. We quantify treatment response heritability for statins, metformin, warfarin, and methotrexate in the UK Biobank. We find that genetic variation modifies the primary effect of statins on LDL cholesterol (9% heritable) as well as their side effects on hemoglobin A1c and blood glucose (10% and 11% heritable, respectively). We identify dozens of genes that modify drug response, which we replicate in a retrospective pharmacogenomic study. Finally, we find that polygenic score (PGS) accuracy varies up to 2-fold depending on treatment status, showing that standard PGSs are likely to underperform in clinical contexts.

PMID:39637863 | DOI:10.1016/j.xgen.2024.100722