Korean J Med Educ. 2023 Sep;35(3):303-307. doi: 10.3946/kjme.2023.269. Epub 2023 Aug 31.

NO ABSTRACT

PMID:37670527 | DOI:10.3946/kjme.2023.269

JAAPA. 2023 Sep 1;36(9):1-6. doi: 10.1097/01.JAA.0000947084.60262.4e.

ABSTRACT

Cytochrome P450 enzyme metabolism is altered by environmental and genetic factors, which can affect the efficacy and safety of opioids. This article describes CYP polymorphisms and how pharmacogenetic testing could be used to help clinicians make safer decisions about opioid use in patients.

PMID:37668489 | DOI:10.1097/01.JAA.0000947084.60262.4e

Redox Biol. 2023 Aug 25;66:102861. doi: 10.1016/j.redox.2023.102861. Online ahead of print.

ABSTRACT

Uterine fibroids, the most common benign tumors of the myometrium in women, are characterized by abnormal extracellular matrix deposition and uterine smooth muscle cell neoplasia, with high recurrence rates. Here, we investigated the potential of the marine natural product manzamine A (Manz A), which has potent anti-cancer effects, as a treatment for uterine fibroids. Manz A inhibited leiomyoma cell proliferation in vitro and in vivo by arresting cell cycle progression and inducing caspase-mediated apoptosis. We performed target prediction analysis and identified sterol o-acyltransferases (SOATs) as potential targets of Manz A. Cholesterol esterification and lipid droplet formation were reduced by Manz A, in line with reduced SOAT expression. As a downstream target of SOAT, Manz A also prevented extracellular matrix deposition by inhibiting the β-catenin/fibronectin/metalloproteinases axis and enhanced autophagy turnover. Excessive free fatty acid accumulation by SOAT inhibition led to reactive oxygen species to impair mitochondrial oxidative phosphorylation and trigger endoplasmic reticulum stress via PERK/eIF2α/CHOP signaling. The inhibitory effect of ManzA on cell proliferation was partially restored by PERK knockdown and eliminated by tauroursodeoxycholic acid, suggesting oxidative stress plays a critical role in the mechanism of action of Manz A. These findings suggest that targeting SOATs by Manz A may be a promising therapeutic approach for uterine fibroids.

PMID:37666118 | DOI:10.1016/j.redox.2023.102861

Ann Hematol. 2023 Sep 4. doi: 10.1007/s00277-023-05431-y. Online ahead of print.

ABSTRACT

Cytarabine (Ara-C) plays an irreplaceable role in the treatment of acute myeloid leukemia (AML). However, there are significant differences in efficacy among patients. Our previous studies found that E2F1 rs3213150 polymorphism was associated with remission rate of Ara-C chemotherapy, but the specific mechanism is not clear. This study aimed to further confirm the correlation between E2F1 rs3213150 polymorphism and Ara-C resistance and prognosis in AML patients, and to provide valuable information for elucidating the molecular mechanisms involved.

METHODS: Rs3213150 genotyping was performed in 922 AML patients by Sanger sequencing, and the effects of different genotypes on chemosensitivity and prognosis were analyzed by Logistic regression and Cox regression. Meanwhile, a prediction model of Ara-C chemotherapy resistance was established. The impact of rs3213150 polymorphism on E2F1 expression level was determined by luciferase reporter gene assay, and differentially expressed genes between patients with different genotypes were identified by RNA sequencing.

RESULTS: Compared with rs3213150 G allele carriers, patients with AA genotype had more obvious Ara-C resistance (41.94% vs. 27.94%, P = 0.002), shorter overall survival (529 d vs. 644 d, P = 0.008) and disease-free survival (519 d vs. 556 d, P = 0.023). Rs3213150G > A mutation resulted in decreased E2F1 expression.

CONCLUSION: E2F1 rs3213150 polymorphism influences the chemosensitivity and prognosis of Ara-C in Chinese AML patients.

PMID:37665348 | DOI:10.1007/s00277-023-05431-y

iScience. 2023 Aug 17;26(9):107627. doi: 10.1016/j.isci.2023.107627. eCollection 2023 Sep 15.

ABSTRACT

Robust and accurate survival prediction of clinical trials using high-throughput genomics data is a fundamental challenge in pharmacogenomics. Current machine learning tools often provide limited predictive performance and model interpretation in these settings. In the present study, we extend the application of REFINED-CNN from regression tasks to making survival predictions, by mapping high-dimensional RNA sequencing data into REFINED images which are conducive to CNN modeling. We show that the REFINED-CNN survival model can be easily adapted to new tasks of a similar nature (e.g., predicting on new cancer types) using transfer learning with a low number of patients. Furthermore, the model can also be interpreted both locally and globally through risk score back propagation that quantifies each feature (e.g., gene) importance in survival prediction task for the patient or cancer type of interest.

PMID:37664631 | PMC:PMC10474067 | DOI:10.1016/j.isci.2023.107627

Infect Drug Resist. 2023 Aug 28;16:5665-5680. doi: 10.2147/IDR.S418176. eCollection 2023.

ABSTRACT

PURPOSE: Sepsis is an organ dysfunction with high mortality. Early identification, diagnosis, and effective treatment of sepsis are beneficial to the survival of patients. This study aimed to find potential diagnosis and immune-related genes, and drug targets, which could provide novel diagnostic and therapeutic markers for sepsis.

PATIENTS AND METHODS: The GSE69063, GSE154918 and GSE28750 datasets were integrated to evaluate immune infiltration and identify differentially expressed genes (DEGs) and immune-related genes. Weighted gene co-expression network analysis (WGCNA) was applied to find the hub module related to immune score and sepsis. Immune-related key genes were screened out by taking interaction of DEGs, immune-related genes, and genes in hub module. Protein-protein interaction (PPI) analysis was used to further screen immune-related hub genes, followed by construction of a diagnostic model based on immune-related hub genes. Functional analysis and drug prediction of immune-related hub genes were, respectively, performed by David software and DGIdb database, followed by expression validation by reverse transcriptase polymerase chain reaction (RT-PCR).

RESULTS: Totally, 93 immune-related key genes were identified between 561 DEGs, 1793 immune-related genes and 12,459 genes in the hub module of WGCNA. Through PPI analysis, a total of 5 diagnose and immune-related hub genes were further obtained, including IL7R, IL10, CD40LG, CD28 and LCN2. Relationship pairs between these 5 genes and immune cell were identified, including LCN2/IL7R/CD28-activated dendritic cell and IL10-immature B cell. Based on pharmacogenomics, 17 candidate drugs might interact with IL 10, including CYCLOSPORINE. Six candidate drugs might interact with CD28 and 11 with CD40LG, CD40LG and CD28 were drug targets of ALDESLEUKIN. Four significantly enriched signaling pathways were identified, such as T cell receptor signaling pathway, NF-kappa B signaling pathway and JAK-STAT signaling pathway.

CONCLUSION: The 5-gene diagnostic model could be used to diagnose and guide clinical immunotherapy for sepsis.

PMID:37662976 | PMC:PMC10473429 | DOI:10.2147/IDR.S418176

Front Immunol. 2023 Aug 16;14:1211612. doi: 10.3389/fimmu.2023.1211612. eCollection 2023.

ABSTRACT

BACKGROUND: COVID-19 could develop severe respiratory symptoms in certain infected patients, especially in the patients with immune disorders. Gut microbiome and plasma metabolome act important immunological modulators in the human body and could contribute to the immune responses impacting the progression of COVID-19. However, the causal relationship between specific intestinal bacteria, metabolites and severe COVID-19 remains not clear.

METHODS: Based on two-sample Mendelian randomization (MR) framework, the causal effects of 131 intestinal taxa and 452 plasma metabolites on severe COVID-19 were evaluated. Single nucleotide polymorphisms (SNPs) strongly associated with the abundance of intestinal taxa and the concentration of plasma metabolites had been utilized as the instrument variables to infer whether they were causal factors of severe COVID-19. In addition, mediation analysis was conducted to find the potential association between the taxon and metabolite, and further colocalization analysis had been performed to validate the causal relationships.

RESULTS: MR analysis identified 13 taxa and 53 metabolites, which were significantly associated with severe COVID-19 as causal factors. Mediation analysis revealed 11 mediated relationships. Myo-inositol, 2-stearoylglycerophosphocholine, and alpha-glutamyltyrosine, potentially contributed to the association of Howardella and Ruminiclostridium 6 with severe COVID-19, respectively. Butyrivibrio and Ruminococcus gnavus could mediate the association of myo-inositol and N-acetylalanine, respectively. In addition, Ruminococcus torques abundance was colocalized with severe COVID-19 (PP.H4 = 0.77) and the colon expression of permeability related protein RASIP1 (PP.H4 = 0.95).

CONCLUSIONS: Our study highlights the potential causal relationships between gut microbiome, plasma metabolome and severe COVID-19, which potentially serve as clinical biomarkers for risk stratification and prognostication and benefit the mechanism mechanistic investigation of severe COVID-19.

PMID:37662924 | PMC:PMC10468967 | DOI:10.3389/fimmu.2023.1211612

Inform Health Soc Care. 2023 Sep 4:1-17. doi: 10.1080/17538157.2023.2250435. Online ahead of print.

ABSTRACT

Childhood asthma is a common and serious chronic lung disease. Mobile health (mHealth) technologies may assist clinical providers, caregivers, and children in managing pediatric asthma. This study evaluated the Nemours app, an mHealth application. We examined: a) frequency of data access by providers and feature use by caregivers (parents/legal guardians) of 5-11-year-old children diagnosed with asthma and b) whether utilization was related to benefits. Nine providers (allergists/pulmonologists) and 80 patient-families (caregiver/child dyads) participated. Two-years of retrospective data were obtained for asthma control, in-person urgent healthcare utilization, and app utilization. Six-months of prospective data included asthma control, in-person urgent healthcare utilization, app utilization, surveys, and health literacy screeners. Providers (56%) accessed app data and caregivers (61%) utilized the app. Caregiver use of messaging feature predicted gains in health literacy scores (b = .44, p = .041), suggesting app use may offer some educational benefits. Implementation of strategies that support app engagement and utilization may help to maximize intended benefits.

PMID:37661853 | DOI:10.1080/17538157.2023.2250435

Am J Hum Genet. 2023 Aug 24:S0002-9297(23)00286-0. doi: 10.1016/j.ajhg.2023.08.010. Online ahead of print.

ABSTRACT

Response to the anti-IL17 monoclonal antibody secukinumab is heterogeneous, and not all participants respond to treatment. Understanding whether this heterogeneity is driven by genetic variation is a key aim of pharmacogenetics and could influence precision medicine approaches in inflammatory diseases. Using changes in disease activity scores across 5,218 genotyped individuals from 19 clinical trials across four indications (psoriatic arthritis, psoriasis, ankylosing spondylitis, and rheumatoid arthritis), we tested whether genetics predicted response to secukinumab. We did not find any evidence of association between treatment response and common variants, imputed HLA alleles, polygenic risk scores of disease susceptibility, or cross-disease components of shared genetic risk. This suggests that anti-IL17 therapy is equally effective regardless of an individual's genetic background, a finding that has important implications for future genetic studies of biological therapy response in inflammatory diseases.

PMID:37659414 | DOI:10.1016/j.ajhg.2023.08.010

Cancer Med. 2023 Sep 1. doi: 10.1002/cam4.6480. Online ahead of print.

ABSTRACT

BACKGROUND: Acute myeloid leukemia (AML) is a highly aggressive form of cancer that is frequently diagnosed in adults and small molecule inhibitors have gained significant attention as a potential treatment option for AML.

METHODS: The up-regulated genes in AML were identified through bioinformatics analysis. Potential candidate agents were selected through pharmacogenomics analysis. Proteomic experiments were conducted to determine the molecular mechanism after inhibitor treatment. To evaluate drug synergy, both cellular functional experiments and an AML mouse model were used.

RESULTS: Through bioinformatics analysis, we conducted a screening for genes that are highly expressed in AML, which led to the identification of nine small-molecule inhibitors. Among these inhibitors, the PI3K/mTOR inhibitor VS-5584 demonstrated significant effectiveness in inhibiting AML cell proliferation at low concentrations. Further testing revealed that VS-5584 induced apoptosis and cycle arrest of AML cells in a dose- and time-dependent manner. Proteomics analysis showed significant changes in protein expression profiles of AML cells after VS-5584 treatment, with 287 proteins being down-regulated and 71 proteins being up-regulated. The proteins that exhibited differential expression were primarily involved in regulating the cell cycle and apoptosis, as determined by GO analysis. Additionally, KEGG analysis indicated that the administration of VS-5584 predominantly affected the P53 and SIRT2 signaling pathways. The use of SIRT2 inhibitor SirReal2 alongside VS-5584 caused a significant reduction in the half-maximal inhibitory concentration (IC50 ) of VS-5584 on AML cells. In vivo, experiments suggested that VS-5584 combined with SirReal2 suppressed tumor growth in the subcutaneous model and extended the survival rate of mice injected with tumor cells via tail vein.

CONCLUSIONS: Taken together, the PI3K/mTOR inhibitor VS-5584 was effective in suppressing AML cell proliferation. PI3K/mTOR inhibitor combined with SIRT2 inhibitor exhibited a synergistic inhibitory effect on AML cells. Our findings offer promising therapeutic strategies and drug candidates for the treatment of AML.

PMID:37658623 | DOI:10.1002/cam4.6480

BMC Genomics. 2023 Sep 1;24(1):513. doi: 10.1186/s12864-023-09625-6.

ABSTRACT

BACKGROUND: Atabecestat, a potent brain penetrable BACE1 inhibitor that reduces CSF amyloid beta (Aβ), was developed as an oral treatment for Alzheimer's disease (AD). Elevated liver enzyme adverse events were reported in three studies although only one case met Hy's law criteria to predict serious hepatotoxicity.

METHOD: We performed a case-control genome-wide association study (GWAS) to identify genetic risk variants associated with liver enzyme elevation using 42 cases with alanine transaminase (ALT) above three times the upper limit of normal (ULN) and 141 controls below ULN. Additionally, we performed a GWAS using continuous maximal ALT/ULN (expressed as times the ULN) upon exposure to atabecestat as the outcome measure (n = 285).

RESULTS: No variant passed the genome-wide significance threshold (p = 5 × 10- 8) in the case-control GWAS. We identified suggestive association signals in genes (NLRP1, SCIMP, and C1QBP) implicated in the inflammatory processes. Among the genes implicated by position mapping using variants suggestively associated (p < 1 × 10- 5) with ALT elevation case-control status, gene sets involved in innate immune response (adjusted p-value = 0.05) and regulation of cytokine production (adjusted p-value = 0.04) were enriched. One genomic region in the intronic region of GABRG3 passed the genome-wide significance threshold in the continuous max(ALT/ULN) GWAS, and this variant was nominally associated with ALT elevation case status (p = 0.009).

CONCLUSION: The suggestive GWAS signals in the case-control GWAS analysis suggest the potential role of inflammation in atabecestat-induced liver enzyme elevation.

PMID:37658353 | DOI:10.1186/s12864-023-09625-6

BMC Med Genomics. 2023 Sep 1;16(1):207. doi: 10.1186/s12920-023-01642-4.

ABSTRACT

BACKGROUND: Statin-induced myopathy is reported to be associated with the solute carrier organic anion transporter family member 1B1 gene single nucleotide polymorphism, c.521 T > C. There is no epidemiologic data on this gene polymorphism in several countries. Therefore, this study aimed at assessing the genotype and allele frequencies of the gene variant in three countries.

METHODS: This study involved healthy individuals from Colombia, Mozambique, and Portugal. Genomic DNA was isolated from blood samples using the Qiamp DNA Extraction Kit (Qiagen). The isolated DNA was genotyped using novel Polymerase Chain Reaction-Restriction Fragment Length Polymorphism. Microstat and GraphPad QuickCal software were used for the Chi-square test and the evaluation of Hardy-Weinberg equilibrium respectively.

RESULTS: A total of 181 individuals' blood samples were analyzed. Overall, the TT (74.0%) genotype was the highest and the CC (7.8%) was the lowest. Country wise genotypic frequencies were Colombia 47(70.2%) TT, 12(17.9%) TC and 8(11.9%) CC; Mozambique 47(88.7%) TT, 5(9.4%) TC, and 1(1.9%) CC; and Portugal 40(65.6%) TT, 16(26.2%) TC, and 5(8.2%) CC. The reference (T) allele was highest among Mozambicans (93.4%) compared to Colombians (79.1%) and Portuguese (78.7%). Mozambicans showed statistically significant genotypic and allelic frequency differences compared to Colombians (p < 0.01) and Portuguese (p < 0.01).

CONCLUSIONS: Overall and country-wise, CC genotype was less frequent and it is relatively high for Colombians and Portuguese populations. This finding may imply statins risk-benefit variability associated with CC genotype among these populations that needs further understanding.

PMID:37658350 | DOI:10.1186/s12920-023-01642-4

BMJ Mil Health. 2023 Sep 1:e002447. doi: 10.1136/military-2023-002447. Online ahead of print.

ABSTRACT

Pharmacological interventions for treating posttraumatic stress disorder in Canadian Armed Forces (CAF) members and Veterans often achieve modest results. The field of pharmacogenetics, or the study of how genes influence an individual's response to different medications, offers insight into how prior knowledge of gene-drug interactions may potentially improve the trial-and-error process of drug selection in pharmacotherapy, thereby improving treatment effects and remission rates. Given the relative recency of pharmacogenetics testing and sparse research in military samples, we used pharmacogenetics testing in a small pilot group (n=23) of CAF members and Veterans who were already engaged in pharmacotherapy for a service-related mental health condition to better understand the associated opportunities and challenges of pharmacogenetics testing in this population. Our preliminary evaluation involved: (1) reporting the prevalence of pharmacogenetics testing 'bin' status according to participants' reports ('green', 'yellow' or 'red'; intending to signal 'go', 'caution' or 'stop', regarding the potential for gene-drug interactions); (2) calculating the percentage of currently prescribed psychotropic medications that were assessed and included in the reports; (3) evaluating whether prescribers used pharmacogenetics testing information according to clinical notes and (4) collecting informal feedback from participating psychiatrists. While pharmacogenetics testing appeared to provide valuable information for a number of clients, a major limitation was the number of commonly prescribed medications not included in the reports.

PMID:37657847 | DOI:10.1136/military-2023-002447

Stem Cell Reports. 2023 Aug 19:S2213-6711(23)00303-X. doi: 10.1016/j.stemcr.2023.08.005. Online ahead of print.

ABSTRACT

The chemotherapeutic doxorubicin (DOX) detrimentally impacts the heart during cancer treatment. This necessitates development of non-cardiotoxic delivery systems that retain DOX anticancer efficacy. We used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), endothelial cells (hiPSC-ECs), cardiac fibroblasts (hiPSC-CFs), multi-lineage cardiac spheroids (hiPSC-CSs), patient-specific hiPSCs, and multiple human cancer cell lines to compare the anticancer efficacy and reduced cardiotoxicity of single protein encapsulated DOX (SPEDOX-6), to standard unformulated (UF) DOX. Cell viability assays and immunostaining in human cancer cells, hiPSC-ECs, and hiPSC-CFs revealed robust uptake of SPEDOX-6 and efficacy in killing these proliferative cell types. In contrast, hiPSC-CMs and hiPSC-CSs exhibited substantially lower cytotoxicity during SPEDOX-6 treatment compared with UF DOX. SPEDOX-6-treated hiPSC-CMs and hiPSC-CSs maintained their functionality, as indicated by sarcomere contractility assessment, calcium imaging, multielectrode arrays, and RNA sequencing. This study demonstrates the potential of SPEDOX-6 to alleviate cardiotoxic side effects associated with UF DOX, while maintaining its anticancer potency.

PMID:37657447 | DOI:10.1016/j.stemcr.2023.08.005

JCO Precis Oncol. 2023 Sep;7:e2300418. doi: 10.1200/PO.23.00418.

NO ABSTRACT

PMID:37656954 | DOI:10.1200/PO.23.00418

Drug Metab Pers Ther. 2023 Sep 4. doi: 10.1515/dmpt-2023-0050. Online ahead of print.

ABSTRACT

OBJECTIVES: Tamsulosin is a first-line drug for the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Despite its high ratings for efficacy and safety, these parameters may vary due to genetic polymorphisms of CYP2D6 enzyme, which is involved in the metabolism of the drug. This variability may have great impact on the therapy of LUTS associated with BPH and may require an individualized approach to drug selection. The aim of the study was to assess the impact of genetic polymorphisms in CYP2D6 on the efficacy and safety of tamsulosin therapy in patients with LUTS associated with BPH.

METHODS: The study included 106 patients with LUTS/BPH (N40 according to ICD-10). All patients received monotherapy with tamsulosin 0.4 mg/day for at least 8 weeks. Depending on the severity of symptoms, all patients were divided into 2 groups based on the IPSS score: the first group of patients had moderate symptoms (n=57), and the second group of patients had severe symptoms (n=49). The results of treatment were assessed using the IPSS questionnaire with determination of quality of life (QoL), transrectal ultrasound of the prostate with determination of prostate volume and postvoid residual urine volume, and uroflowmetry. The carriage of allelic variants of CYP2D6 (*3, *4, *9, *10, and *41) were determined by polymerase chain reaction in all patients.

RESULTS: In patients with moderate symptoms who was classified as «intermediate» metabolizers by CYP2D6, a statistically significant greater reduction in symptoms according to the overall IPSS scale at 8 weeks (p=0.046) and the obstructive symptom subscale starting from 4 weeks of treatment (p<0.05) was shown. Allelic variants of the CYP2D6 gene did not affect the frequency of adverse reactions to tamsulosin.

CONCLUSIONS: The results of the study show that in patients with moderate LUTS associated with BPH who are «intermediate» metabolizers by CYP2D6, there is a better therapeutic effect of tamsulosin.

PMID:37656138 | DOI:10.1515/dmpt-2023-0050

Curr Opin Pulm Med. 2023 Sep 4. doi: 10.1097/MCP.0000000000001014. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: This review highlights the problem of neuropsychiatric adverse effects (AEs) associated with elexacaftor/tezacaftor/ivacaftor (ETI), current suboptimal mitigation approaches, a novel testable mechanistic hypothesis, and potential solutions requiring further research.

RECENT FINDINGS: Studies show that a minority of persons with cystic fibrosis (PwCF) initiating cystic fibrosis transmembrane conductance regulator (CFTR) modulators experience neuropsychiatric AEs including worsening mood, cognition, anxiety, sleep, and suicidality. The GABA-A receptor is a ligand-gated chloride channel, and magnetic resonance spectroscopy neuroimaging studies have shown that reduced GABA expression in rostral anterior cingulate cortex is associated with anxiety and depression. Recent research details the impact of peripheral inflammation and the gut-brain axis on central neuroinflammation. Plasma ETI concentrations and sweat chloride have been evaluated in small studies of neuropsychiatric AEs but not validated to guide dose titration or correlated with pharmacogenomic variants or safety/efficacy.

SUMMARY: Although ETI is well tolerated by most PwCF, some experience debilitating neuropsychiatric AEs. In some cases, these AEs may be driven by modulation of CFTR and chloride transport within the brain. Understanding biological mechanisms is a critical next step in identifying which PwCF are likely to experience AEs, and in developing evidence-based strategies to mitigate them, while retaining modulator efficacy.

PMID:37655981 | DOI:10.1097/MCP.0000000000001014

Sci Rep. 2023 Aug 30;13(1):14198. doi: 10.1038/s41598-023-39401-1.

ABSTRACT

Circadian rhythms (CRs) are fundamental biological processes that significantly impact human well-being. Disruption of these rhythms can trigger insufficient neurocognitive development, insomnia, mental disorders, cardiovascular diseases, metabolic dysfunctions, and cancer. The field of chronobiology has increased our understanding of how rhythm disturbances contribute to cancer pathogenesis, and how circadian timing influences the efficacy of cancer treatments. As the circadian clock steadily gains recognition as an emerging factor in tumorigenesis, a thorough and comprehensive multi-omics analysis of CR genes/proteins has never been performed. To shed light on this, we performed, for the first time, an integrated data analysis encompassing genomic/transcriptomic alterations across 32 cancer types (n = 10,918 tumors) taken from the PanCancer Atlas, unfavorable prognostic protein analysis, protein-protein interactomics, and shortest distance score pathways to cancer hallmark phenotypes. This data mining strategy allowed us to unravel 31 essential CR-related proteins involved in the signaling crossroad between circadian rhythms and cancer. In the context of drugging the clock, we identified pharmacogenomic clinical annotations and drugs currently in late phase clinical trials that could be considered as potential cancer therapeutic strategies. These findings highlight the diverse roles of CR-related genes/proteins in the realm of cancer research and therapy.

PMID:37648722 | DOI:10.1038/s41598-023-39401-1

JAMA Netw Open. 2023 Aug 1;6(8):e2331398. doi: 10.1001/jamanetworkopen.2023.31398.

ABSTRACT

IMPORTANCE: The DRAMES (Décès en Relation avec l'Abus de Médicaments Et de Substances) register is a database of drug-related deaths with the aim of identifying the psychoactive substances associated with and estimating the trends in these deaths. Our novel approach is based on the collection of data on all deaths for which toxicology experts have performed analyses.

OBJECTIVE: To describe drug-related deaths in France and report trends over an 11-year period.

DESIGN, SETTING, AND PARTICIPANTS: This case series used a national register to assess 4460 drug-related deaths that occurred from 2011 to 2021 in France. Data analyses were performed from January 1, 2012, to December 31, 2022.

MAIN OUTCOMES AND MEASURES: Demographic characteristics; medical and substance abuse history; forensic autopsy findings; and toxicology reports.

RESULTS: Among the 4460 deceased individuals (mean [SD] age, 37.8 [10.5] years), the mortality rate was highest among men (sex ratio, 4.4:1). Of the deaths involving a single or predominant drug, the legal substitution product, methadone, was the leading cause of death during the entire study period, ahead of heroin-44.7% and 35.9% for methadone vs 15.8% and 21.8% for heroin in 2011 and 2021, respectively. Between 2011 and 2021, most of the drug-related deaths shifted from licit to illicit drugs, and statistically significant variations were found for buprenorphine, cocaine, heroin, methadone, and other licit opioids. Deaths related to polydrug use increased from 23.2% in 2011 to 30.6% in 2021. In this context, opioids remained associated with most deaths, with at least 1 opioid being involved in approximately 9 of 10 cases (85.9%) in 2021. However, the main trend was the dramatic increase in drug combinations with cocaine, from less than one-third of cases in 2011 (30.8%) to more than half in 2021 (57.8%).

CONCLUSIONS AND RELEVANCE: This case series assessment of 4460 drug-related deaths found that opioids used alone or in combination were the main contributor to drug-related deaths, despite having a lower prevalence than other drugs. This finding is similar to that of other countries; however, in France licit methadone was the leading cause of opioid-related deaths (ahead of heroin) during the study period. Deaths associated with use of cannabis, new psychoactive substances, and stimulants (including amphetamine-type stimulants and cocaine, especially in combination) have increased and should be closely monitored.

PMID:37647066 | DOI:10.1001/jamanetworkopen.2023.31398

Front Pharmacol. 2023 Aug 14;14:1179364. doi: 10.3389/fphar.2023.1179364. eCollection 2023.

ABSTRACT

Introduction: Pharmacogenetics (PGx) has the potential to improve health outcomes but cost of testing is a barrier for equitable access. Reimbursement by insurance providers may lessen the financial burden for patients, but the extent to which PGx claims are covered in clinical practice has not been well-characterized in the literature. Methods: A retrospective analysis of outpatient claims submitted to payers for PGx tests from 1/1/2019 through 12/31/2021 was performed. A reimbursement rate was calculated and compared across specific test types (e.g., single genes, panel), payers, indication, and the year the claim was submitted. Results: A total of 1,039 outpatient claims for PGx testing were analyzed. The overall reimbursement rate was 46% and ranged from 36%-48% across payers. PGx panels were reimbursed at a significantly higher rate than single gene tests (74% vs. 43%, p < 0.001). Discussion: Reimbursement of claims for PGx testing is variable based on the test type, indication, year the claim was submitted, number of diagnosis codes submitted, and number of unique diagnosis codes submitted. Due to the highly variable nature of reimbursement, cost and affordability should be discussed with each patient.

PMID:37645439 | PMC:PMC10461057 | DOI:10.3389/fphar.2023.1179364