Transl Psychiatry. 2024 Aug 6;14(1):322. doi: 10.1038/s41398-024-02998-6.

ABSTRACT

In the past two decades, significant progress has been made in the development of polygenic scores (PGSs). One specific application of PGSs is the development and potential use of pharmacogenomic- scores (PGx-scores) to identify patients who can benefit from a specific medication or are likely to experience side effects. This systematic review comprehensively evaluates published PGx-score studies in psychiatry and provides insights into their potential clinical use and avenues for future development. A systematic literature search was conducted across PubMed, EMBASE, and Web of Science databases until 22 August 2023. This review included fifty-three primary studies, of which the majority (69.8%) were conducted using samples of European ancestry. We found that over 90% of PGx-scores in psychiatry have been developed based on psychiatric and medical diagnoses or trait variants, rather than pharmacogenomic variants. Among these PGx-scores, the polygenic score for schizophrenia (PGSSCZ) has been most extensively studied in relation to its impact on treatment outcomes (32 publications). Twenty (62.5%) of these studies suggest that individuals with higher PGSSCZ have negative outcomes from psychotropic treatment - poorer treatment response, higher rates of treatment resistance, more antipsychotic-induced side effects, or more psychiatric hospitalizations, while the remaining studies did not find significant associations. Although PGx-scores alone accounted for at best 5.6% of the variance in treatment outcomes (in schizophrenia treatment resistance), together with clinical variables they explained up to 13.7% (in bipolar lithium response), suggesting that clinical translation might be achieved by including PGx-scores in multivariable models. In conclusion, our literature review found that there are still very few studies developing PGx-scores using pharmacogenomic variants. Research with larger and diverse populations is required to develop clinically relevant PGx-scores, using biology-informed and multi-phenotypic polygenic scoring approaches, as well as by integrating clinical variables with these scores to facilitate their translation to psychiatric practice.

PMID:39107294 | DOI:10.1038/s41398-024-02998-6

ERJ Open Res. 2024 Aug 5;10(4):00909-2023. doi: 10.1183/23120541.00909-2023. eCollection 2024 Jul.

ABSTRACT

INTRODUCTION: Type 2 (T2) asthma is often associated with chronic rhinosinusitis with nasal polyposis (CRSwNP). Additionally, nonsteroidal anti-inflammatory drug (NSAID) intolerance leads to NSAID-exacerbated respiratory disease (N-ERD). Previous transcriptomic data in non-CRSwNP T2 asthma patients showed differentially expressed genes. We focused on ALOX15, CLC, CYSLTR2, HRH4 and SMPD3 to investigate their role in T2 asthma.

METHODS: The study included 100 healthy controls and 103 T2 asthma patients, divided into patients with asthma (n=54), patients with asthma and CRSwNP (n=29) and patients with N-ERD (n=20). Quantitative PCR analysis was performed on blood-derived RNA samples first to validate the five differentially expressed genes. The data were further analysed to find potential associations and biomarkers.

RESULTS: Patients, regardless of stratification, exhibited significantly higher gene expression than healthy controls. The patterns of association revealed that ALOX15 was exclusively present in the non-comorbidity group, SMPD3 and CLC in the comorbidity groups, and HRH4 in all patient groups. ALOX15, CYSLTR2 and SMPD3 expression showed potential as biomarkers to confirm the diagnosis of T2 asthma using peripheral blood eosinophils as the initial criterion. Peripheral blood eosinophils combined with gene expression, especially SMPD3, may improve the diagnosis. CLC and CYSLTR2 expression play a specific role in discriminating N-ERD.

DISCUSSION: We validated the transcriptomic data of five differentially expressed genes in T2 asthma. Different patterns of association were identified in patient stratification, suggesting that different molecular mechanisms underlie the spectrum of T2 asthma. Potential biomarkers were also found and used to design an algorithm with practical diagnostic utility for T2 asthma, including risk stratification for N-ERD.

PMID:39104947 | PMC:PMC11299009 | DOI:10.1183/23120541.00909-2023

J Clin Oncol. 2024 Aug 5:JCO2400500. doi: 10.1200/JCO.24.00500. Online ahead of print.

ABSTRACT

PURPOSE: Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear.

METHODS: Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs. Twenty-three ALL molecular subtypes were identified using RNA sequencing. We systematically characterized the associations between drug response and ALL genomics in children, adolescents and young adults, and elderly adults. We evaluated the effect of age-related gene expression signature on ALL treatment outcomes.

RESULTS: Seven ALL drugs (asparaginase, prednisolone, mercaptopurine, dasatinib, nelarabine, daunorubicin, and inotuzumab ozogamicin) showed differential activity between children and adults, of which six were explained by age-related differences in leukemia molecular subtypes. Adolescents and young adults showed similar patterns of drug resistance as older adults, relative to young children. Mercaptopurine exhibited subtype-independent greater sensitivity in children. Transcriptomic profiling uncovered subclusters within CRLF2-, DUX4-, and KMT2A-rearranged ALL that were linked to age and cytotoxic drug resistance. In particular, a subset of children had adult-like ALL on the basis of leukemia gene expression patterns across subtypes, despite their chronological age. Resistant to cytotoxic drugs, children with adult-like ALL exhibited poor prognosis in pediatric ALL trials, even after adjusting for age and minimal residual diseases.

CONCLUSION: Our results provide pharmacogenomic insights into age-related disparities in ALL cure rates and identify leukemia prognostic features for treatment individualization across age groups.

PMID:39102629 | DOI:10.1200/JCO.24.00500

Pharmacogenet Genomics. 2024 Sep 1;34(7):226-235. doi: 10.1097/FPC.0000000000000539. Epub 2024 May 20.

ABSTRACT

OBJECTIVE: It is unclear whether renal transplant recipients treated with mycophenolic acid (MPA) who carry the reduced-function allele at polymorphism SLCO1B1 c.521T>C differ from their wild-type peers regarding renal outcomes and tolerability. We aimed to estimate the effect of this polymorphism on the graft function (estimated glomerular filtration rate, eGFR) over the first 12 post-transplant months in patients on MPA-based maintenance immunosuppression.

METHODS: In a 12-month observational cohort study, consecutive adult patients were repeatedly assessed for eGFR. The SLCO1B1 c.521C>T variant allele carriers (exposed) and wild-type subjects (controls) were balanced on a range of demographic, medical, and genetic variables at baseline, and eGFR trajectory was estimated with further adjustment for time-varying covariates. A subset of patients were assessed for exposure to MPA 5-7 days after the transplantation.

RESULTS: The adjusted eGFR slopes from day 1 to day 28 (daily), and from day 28 to day 365 (monthly) were practically identical in exposed (n = 86) and control (n = 168) patients [geometric means ratios (GMR) = 0.99, 95% confidence interval (CI) = 0.92-1.06 and GMR = 0.98, 0.94-1.01, respectively]. The rates of adverse renal outcomes and possible MPA-related adverse effects were low, and similar in exposed and controls [rate ratios (RR) = 0.94, 0.49-1.84 and RR = 1.08, 0.74-1.58, respectively]. The pharmacokinetic analysis did not signal meaningful differences regarding exposure to MPA, overall (exposed n = 23, control n = 45), if cotreated with cyclosporine (n = 17 vs. n = 26) or with tacrolimus (n = 8 vs. n = 17).

CONCLUSIONS: In patients treated with MPA, variant allele SLCO1B1 c.521T>C appears of no practical relevance regarding the 12-month renal graft function, MPA safety and exposure to MPA at early steady-state.

PMID:39101384 | DOI:10.1097/FPC.0000000000000539

Clin Pharmacol Ther. 2024 Aug 5. doi: 10.1002/cpt.3403. Online ahead of print.

NO ABSTRACT

PMID:39101255 | DOI:10.1002/cpt.3403

Transl Androl Urol. 2024 Jul 31;13(7):1206-1218. doi: 10.21037/tau-24-26. Epub 2024 Jul 15.

ABSTRACT

BACKGROUND: Having a spicy diet and smoking habit may be important factors causing erectile dysfunction (ED). The aim of this study is to investigate the impact of spicy diet and smoking habits on the risk of ED in men, with a focus on the interaction between these lifestyle factors.

METHODS: Our investigation was conducted as a retrospective analysis spanning from June 2017 to June 2023. Participants underwent interviews utilizing the Structured Interview on Erectile Dysfunction (SIEDY) to evaluate the degree of pathological factors. The International Index of Erectile Function-5 (IIEF-5) was employed as a metric for assessing ED. Additionally, the subjects were comprehensively questioned about their smoking history and dietary preferences, which included an inquiry into how often they consumed spicy meals.

RESULTS: Our research involved 373 participants, with 67.6% being individuals with ED. Among the participants, 50.7% were non-smokers and 49.3% were smokers, totaling 188 and 185, respectively. There was no significant difference in the spicy food frequency consumption among smokers with ED. However, non-smokers who consumed spicy food more frequently experienced more severe ED (P=0.02). ED patients showed significant differences in body mass index (BMI), blood glucose and testosterone, which were linked to vascular damage (P=0.03, P=0.02, P=0.04, respectively). Additionally, non-smokers who consumed more spicy food had higher scores on the SIEDY 2 scale, indicating marital factors (P=0.004). In non-smoking participant, a high spicy ratio indicated an even higher risk of ED [odds ratio 2.58, 95% confidence interval: 1.27-5.26; P=0.008], while there was no significant impact on ED in smoking participants (data not shown).

CONCLUSIONS: This retrospective study suggests that a considerable consumption of spicy foods is independently correlated with an elevated risk of ED, particularly among non-smoking men.

PMID:39100824 | PMC:PMC11291414 | DOI:10.21037/tau-24-26

Eur J Clin Invest. 2024 Aug 5:e14297. doi: 10.1111/eci.14297. Online ahead of print.

ABSTRACT

BACKGROUND: An individual's genetic fingerprint is emerging as a pivotal predictor of numerous disease- and treatment-related factors. Single nucleotide polymorphisms (SNPs) in drug-metabolizing enzymes play key roles in an individual's exposure to a malignancy-associated risk, such as Aflatoxin B1 (AFB1)-induced hepatocellular carcinoma (HCC).

AIM: This study aimed at reviewing literature on the polymorphisms that exist in CYP enzymes and their possible link with susceptibility to AFB1-induced HCC.

MATERIALS & METHODS: A set of keywords associated with the study subject of interest was used to search the Google Scholar and the PubMed database. The last ten years' worth of research projects were included in the results filter. The research involved HCC patients and any connection between polymorphic forms of CYP enzymes and their susceptibility to AFB1-induced HCC, including older but significant data.

RESULTS: Variations in CYP1A2 and CYP3A4 were reported to impact the rate and magnitude of AFB1 bio-activation, thus influencing an individual's vulnerability to develop HCC. In HCC patients, the activity of CYP isoforms varies, where increased activity has been reported with CYP2C9, CYP2D6, and CYP2E1, while CYP1A2, CYP2C8, and CYP2C19 exhibit decreased activity. CYP2D6*10 frequency has been discovered to differ considerably in HCC patients. Rs2740574 (an upstream polymorphism in CYP3A4 as detected in CYP3A4*1B) and rs776746 (which affects CYP3A5 RNA splicing), both of which influence CYP3A expression, thus impacting the variability of AFB1-epoxide adducts in HCC patients.

DISCUSSION: CYP1A2 is the primary enzyme accountable for the formation of harmful AFBO globally. CYP3A4, CYP3A5, CYP3A7, CYP2B7, and CYP3A3 are also implicated in the bio-activation of AFB1 to mutagenic metabolites. It is thought that CYP3A4 is the protein that interacts with AFB1 metabolism the most.

CONCLUSION: Polymorphic variants of CYP enzymes have a functional impact on the susceptibility to AFB1-induced HCC. Outlining such variation and their implications may provide deeper insights into approaching HCC in a more personalized manner for guiding future risk-assessment, diagnosis, and treatment.

PMID:39099542 | DOI:10.1111/eci.14297

Neurotherapeutics. 2024 Aug 3:e00428. doi: 10.1016/j.neurot.2024.e00428. Online ahead of print.

ABSTRACT

Intracranial aneurysm (IA) is the most prevalent type of cerebral vascular disease causing life-threatening subarachnoid hemorrhages (SAH). A long-term vascular structure remodeling is considered as the main pathophysiological feature of IAs. However, the causal factors triggering the pathophysiological process are not clear. Recently, the abnormalities of peripheral circulating proteins and metabolites have been found in IAs patients and associated with the ruptures. We comprehensively investigated the potential causal relationship between blood metabolites and proteins and IAs using the mendelian randomization (MR) analysis. We applied two-sample MR to explore the potential causal association between peripheral circulating metabolites (191 blood metabolites) and proteins (1398 proteins) and IAs using data from the FinnGen study and the GWAS datasets published by Bakker et al. We identified palmitoylcarnitine, stearoylcarnitine and 2-tetradecenoylcarnitine as causal contributors of IAs and ruptures. Further two-step mediation MR analysis suggested that hypertension as one of the contributors of IAs and ruptures mediated the causal relationship between palmitoylcarnitine, stearoylcarnitine and 2-tetradecenoylcarnitine and IAs. Together, our study demonstrates that blood metabolic palmitoylcarnitine, stearoylcarnitine and 2-tetradecenoylcarnitine are causally linked to the formation and rupture of IAs. Hypertension partially mediates the causal effects.

PMID:39098392 | DOI:10.1016/j.neurot.2024.e00428

Sci Rep. 2024 Aug 3;14(1):18005. doi: 10.1038/s41598-024-68665-4.

ABSTRACT

Cardiovascular disease (CVD) is one of the main causes of death in the world. The increased level of blood cholesterol is significantly correlated to CVD incidents. Statins are a group of drugs that decrease the synthesis of cholesterol in the liver by inhibiting the final enzyme of the pathway named HMG-CoA reductase. Several investigations showed that different patients give different responses to the administration of statin drugs according to their genetic background. In this research study, using Genome-Wide Association Studies (GWAS) data analysis methods, such as the SimpleM statistical approach and genomic connection matrix, we tried to discover the novel candidate SNPs that were involved in response to statin drugs. The investigation was carried out using 3,221 cardiovascular patients' data about genotypes and phenotypes of two important parameters including total cholesterol, and LDL level, in response to statin administration. Functional annotation of nearest genes to candidate SNPs was also carried out by using comprehensive databases and tools such as BioMart-Ensembl, UCSC, NCBI, and WebGestalt software. Our results represented eight novel SNPs (rs10820084, rs4803750, rs10989887, rs1966503, rs17502794, rs10785232, rs484071, rs4785621) significantly associated with statin response in different individual cardiovascular patients for the first time. In addition, the groups of genes that are close to the SNPs were also represented and evaluated in detail. Our results illustrated that some of the genes such as BAAT, BCL3, and CMTM6 have a direct functional impact on cholesterol level or LDL biosynthesis which confirmed the effects of neighbor SNPs on the response to statin drugs. Today, finding the loci, genes, and molecular mechanisms involved in the response to drugs is of great importance in pharmacogenomics and personalized medicine.

PMID:39097628 | DOI:10.1038/s41598-024-68665-4

Farm Hosp. 2024 Jul;48 Suppl 1:TS5-TS12. doi: 10.1016/j.farma.2024.02.009.

ABSTRACT

OBJECTIVE: The aim of this article was to perform a narrative review of how pharmacogenetics and pharmacogenomics is being applied in the clinics, especially in Spain.

METHOD: Publications and websites of major interest have been reviewed.

RESULTS: Pharmacogenes and variants used in several hospitals, available methodologies, and the implementation process are discussed.

PMID:39097377 | DOI:10.1016/j.farma.2024.02.009

Farm Hosp. 2024 Jul;48 Suppl 1:S5-S12. doi: 10.1016/j.farma.2023.09.011.

ABSTRACT

OBJECTIVE: The aim of this article is to perform a narrative review of how pharmacogenetics and pharmacogenomics is being applied in the clinic, especially in Spain.

METHOD: Publications and websites of major interest have been reviewed.

RESULTS: Pharmacogenes and variants used in several hospitals, available methodologies, and the implementation process are discussed.

PMID:39097368 | DOI:10.1016/j.farma.2023.09.011

Sci Rep. 2024 Aug 2;14(1):17941. doi: 10.1038/s41598-024-68369-9.

ABSTRACT

Polychlorinated biphenyls (PCBs) and dioxin are persistent endocrine disrupting chemicals (EDCs) and have been associated with an increased risk of metabolic syndrome (MetS). The aim of this systematic review and meta-analysis was to assess the associations of PCBs and dioxin with MetS and its risk factors, including obesity, hypertriglyceridaemia (HTG), hypertension (HTN) and diabetes mellitus (DM). We searched three electronic databases for epidemiological studies concerning PCBs and dioxin with MetS published up to the end of 2023. Meta-analysis was performed for MetS itself and each of the MetS risks based on a random-effects meta-analysis model, and odds ratios (ORs) with 95% confidence intervals (CIs) were obtained. Publication bias was assessed based on Egger's test. Eleven studies were included from three databases up to 2023. There were 40,528 participants aged 18-89, where 18-100% of them were males, included in our meta-analysis. The meta-analysis results showed a strong association between PCB exposure and DM (OR = 3.593, 95% CI 2.566, 5.031), while most of the risk factors for MetS, including obesity (OR = 1.875, 95% CI 0.883, 3.979), HTN (OR = 1.335, 95% CI 0.902, 1.976) and HTG (OR = 1.611, 95% CI 0.981, 2.643), were weakly associated with PCB. Furthermore, both PCBs (OR = 1.162, 95% CI 0.994, 1.357) and dioxin (OR = 2.742, 95% CI 1.936, 3.883) were found to be weakly and strongly associated with MetS, respectively. Meta-regression analysis showed that DM in the Asian population is associated with PCB exposure, while HTG in the Northern American population is associated with PCB exposure. Our meta-analysis has demonstrated a strong relationship between DM and PCBs, while the relationship between PCBs with MetS and other risk factors is less pronounced. Additionally, MetS is weakly associated with dioxin exposure. To improve primary care outcomes, healthcare providers should consider incorporating the assessment of patients' risk of exposure to PCBs and dioxins into their evaluation procedures for more targeted medical interventions.

PMID:39095444 | DOI:10.1038/s41598-024-68369-9

Blood Adv. 2024 Aug 2:bloodadvances.2023011540. doi: 10.1182/bloodadvances.2023011540. Online ahead of print.

ABSTRACT

For several decades, induction therapy with nucleoside analogs, in particular cytarabine (Ara-C) and, to a lesser extent, fludarabine, has been the standard of care for patients diagnosed with acute myeloid leukemia (AML). Still, the anti-tumor efficacy of nucleoside analogs is often limited by intrinsic and acquired drug resistance, thereby leading to poor therapeutic response and suboptimal clinical outcomes. Here, we used genome-wide CRISPR-based pharmacogenomic screening to map the genetic factors that modulate the response to nucleoside analogs in AML and identified the E3 ubiquitin ligase Herc1 as a key modulator of Ara-C response in the MLL/AF9 (MA) and the HOXA9/MEIS1 (HM) murine AML models both in vitro and in vivo. Loss of HERC1 enhanced nucleoside analog-induced cell death in both murine and human AML cell lines by compromising cell cycle progression. In-depth proteomic analysis and subsequent validation identified deoxycytidine kinase Dck as a novel target of Herc1 in MA and HM murine cells. We observed that HERC1 is overexpressed in AML compared to other cancer types and higher HERC1 expression is associated with shorter overall survival of patients with AML in the TCGA and BEAT-AML cohorts. Collectively, this study highlights the importance of HERC1 in the response of AML cells to nucleoside analogs, thereby establishing this E3 ubiquitin ligase as a novel predictive biomarker and potential therapeutic target for the treatment of AML.

PMID:39093953 | DOI:10.1182/bloodadvances.2023011540

Rev Med Chil. 2023 Oct;151(10):1375-1384. doi: 10.4067/s0034-98872023001001375.

ABSTRACT

Siponimod is a selective immunosuppressive medication, developed as the first oral therapy for active secondary progressive multiple sclerosis. This medication acts by modulating the sphingosine 1 phosphate (S1P) receptor, as an antagonist of S1P1 and S1P5, thus preventing the egress of lymphocytes from lymph nodes and preventing inflammatory processes in the Central Nervous System that trigger demyelination. There is extensive scientific knowledge regarding the administration of the medication to patients, which will depend on their pharmacogenetic characteristics. Therefore, the FDA strongly recommends conducting a genotyping study of the enzyme that metabolizes siponimod, CYP2C9, whose genetic variants *2 and *3 classify patients as poor, extensive, or rapid metabolizers. Siponimod is completely contraindicated for patients who are homozygous for CYP2C9*3. Additionally, before prescribing it, an electrocardiogram, assessments of antibody status, ophthalmic evaluation, varicella vaccination status, and peripheral lymphocyte count should be conducted, as the medication's effect is dose-dependent. Therefore, a titration process is carried out starting from 0.25mg up to 2 mg. The pharmacotherapeutic protocol of siponimod is a reliable reflection of the utility of pharmacogenetics in personalized medicine.

PMID:39093141 | DOI:10.4067/s0034-98872023001001375

Pharmacogenomics. 2024 Aug 2:1-9. doi: 10.1080/14622416.2024.2380240. Online ahead of print.

ABSTRACT

Aim: This study evaluated associations between CYP3A4*22 and variants in other pharmacogenes (CYP3A5, SULT2A1, ABCB1, ABCG2, ERCC1) and the risk for palbociclib-associated toxicities. Materials & methods: Two hundred cancer patients who received standard-of-care palbociclib were genotyped and associations with toxicity were evaluated retrospectively. Results: No significant associations were found for CYP3A4*22, CYP3A5*3, ABCB1_rs1045642, ABCG2_rs2231142, ERCC1_rs3212986 and ERCC1_rs11615. Homozygous variant carriers of SULT2A1_rs182420 had higher incidence of dose modifications due to palbociclib toxicity (odds ratio [OR]: 4.334, 95% CI: 1.057-17.767, p = 0.042). ABCG2_rs2231137 variant carriers had borderline higher incidence of grade 3-4 neutropenia (OR: 4.14, 95% CI: 0.99-17.37, p = 0.052). Conclusion: Once validated, SULT2A1 and ABCG2 variants may be useful to individualize palbociclib dosing to minimize toxicities and improve treatment outcomes.

PMID:39092502 | DOI:10.1080/14622416.2024.2380240

F1000Res. 2024 May 7;13:452. doi: 10.12688/f1000research.147794.1. eCollection 2024.

ABSTRACT

INTRODUCTION: Carriers of variant alleles of genes that encode liver CYP450 and UGT enzymes may experience abnormal plasma levels of antipsychotics and, consequently, worse efficacy or tolerability. Although pharmacogenomics is a rapidly developing field, current guidelines often rely on limited, underpowered evidence. We have previously demonstrated that meta-analysis is a viable strategy for overcoming this problem. Here, we propose a project that will expand our previous work and create a living systematic review and meta-analysis of drug plasma level differences between carriers and non-carriers of variant genotype-predicted phenotypes for every pharmacokinetic drug-gene interaction relevant to commonly used antipsychotic drugs.

PROTOCOL: First, a baseline systematic review and meta-analysis will be conducted by searching for observational pharmacogenomics-pharmacokinetic studies. Data on dose-adjusted drug plasma levels will be extracted, and participants will be grouped based on their genotype for each drug-gene pair separately. Differences in plasma drug levels between different phenotypes will be compared using a random-effect ratio-of-means meta-analysis. The risk of bias will be assessed using ROBINS-I, and the certainty of evidence will be assessed using GRADE. Following the establishment of baseline results, the literature search will be re-run at least once every six months, and the baseline data will be updated and re-evaluated as new evidence is published. A freely available website will be designated to present up-to-date results and conclusions.

DISCUSSION: This systematic review will provide evidence-based results that are continuously updated with evidence as it emerges in the rapidly developing field of pharmacogenomics. These results may help psychiatrists in their decision-making, as clinicians are becoming increasingly aware of the patients' genetic data as testing becomes more widespread and cheaper. In addition, the results may serve as a scientific basis for the development of evidence-based pharmacogenomics algorithms for personalized dosing of antipsychotics to mitigate potentially harmful drug-gene interactions.

PMID:39091645 | PMC:PMC11292185 | DOI:10.12688/f1000research.147794.1

United European Gastroenterol J. 2024 Aug 1. doi: 10.1002/ueg2.12605. Online ahead of print.

ABSTRACT

INTRODUCTION: Gastric cancer (GC) is one of the most lethal malignancies worldwide. Helicobacter pylori is the primary cause of GC; therefore, its eradication reduces the risk of developing this neoplasia. There is extensive evidence regarding quadruple therapy with relevance to the European population. However, in Latin America, data are scarce. Furthermore, there is limited information about the eradication rates achieved by antibiotic schemes in European and Latin American populations.

OBJECTIVE: To compare the effectiveness of standard triple therapy (STT), quadruple concomitant therapy (QCT), and bismuth quadruple therapy (QBT) in six centers in Europe and Latin America.

METHODS: A retrospective study was carried out based on the LEGACy registry from 2017 to 2022. Data from adult patients recruited in Portugal, Spain, Chile, Mexico, and Paraguay with confirmed H. pylori infection who received eradication therapy and confirmatory tests at least 1 month apart were included. Treatment success by each scheme was compared using a mixed multilevel Poisson regression, adjusting for patient sex and age, together with country-specific variables, including prevalence of H. pylori antibiotic resistance (clarithromycin, metronidazole, and amoxicillin), and CYP2C19 polymorphisms.

RESULTS: 772 patients were incorporated (64.64% females; mean age of 52.93 years). The total H. pylori eradication rates were 75.20% (255/339) with STT, 88.70% (159/178) with QCT, and 91.30% (191/209) with QBT. Both quadruple therapies (QCT-QBT) showed significantly higher eradication rates compared with STT, with an adjusted incidence risk ratio (IRR) of 1.25 (p: <0.05); and 1.24 (p: <0.05), respectively. The antibiotic-resistance prevalence by country, but not the prevalence of CYP2C19 polymorphism, showed a statistically significant impact on eradication success.

CONCLUSIONS: Both QCT and QBT are superior to STT for H. pylori eradication when adjusted for country-specific antibiotic resistance and CYP2C19 polymorphism in a sample of individuals residing in five countries within two continents.

PMID:39090833 | DOI:10.1002/ueg2.12605

Pharmacogenomics J. 2024 Aug 1;24(4):23. doi: 10.1038/s41397-024-00337-y.

ABSTRACT

The influence of genetic variants related to opioid use disorder (OUD) was evaluated using multiple logistic regression analysis in self-reported assigned African American/Afro-Caribbean and European biogeographical ancestry groups (BGAGs) and by sex. From a sample size of 1301 adult patients (>18 years of age) seen in emergency departments of three medical centers in Ohio, six variants were found to be associated with OUD. Two of the variants, rs2740574 (CYP3A4) and rs324029 (DRD3), were included in the analysis having met criteria of at least five subjects for each BGAG, variant carrier status, and OUD status combinations. Variant carriers in the African/Afro-Caribbean BGAG had slightly lower predicted probabilities of OUD. Variant carriers in the European BGAG had slightly higher predicted probabilities of OUD. Relative to sex, all the six variants met evaluation criteria (five subjects for all sex, variant, and OUD status combinations). No statistically significant interactions were found between a given variant, BGAGs and sex. Findings suggest variant testing relative to OUD risk can be applied across BGAGs and sex, however, studies in larger populations are needed.

PMID:39090078 | DOI:10.1038/s41397-024-00337-y

Front Mol Med. 2022 Jul 12;2:933188. doi: 10.3389/fmmed.2022.933188. eCollection 2022.

ABSTRACT

Background: Heat shock protein 60 (HSP60), a potentially homeostatic antigen, is involved in physiological and non-physiological conditions. Experimental data support the role of HSP60 in placental and mitochondrial steroidogenesis. Furthermore, HSP60 is translocated into the endothelial-cell plasma membrane and the extracellular space under stress conditions, promoting the atherosclerotic process. Therefore, we investigated the association between HSP60 and endothelial function in postmenopausal women, considering the possible atherogenic effect of androgenic hormones. Methods: This study included 123 healthy postmenopausal women. Exclusion criteria were treated hypertension or dyslipidaemia, menopause hormone therapy during the last 6 months, and previously diagnosed peripheral vascular disease or cardiovascular disease. Fasting venous blood samples were obtained for biochemical and hormonal assessment and evaluation of HSP60. Sonographic assessment of flow-mediated dilation (FMD) occurred immediately after that in one session. Results: Univariate analysis showed that women with FMD values below median 5.12% had lower logHSP60 values (low vs. high FMD, HSP60 values: 2.01 ± 1.16 ng/ml vs. 3.22 ± 1.17 ng/ml, p-value = 0.031). Multivariable analysis showed that logHSP60 was associated with FMD (b-coefficient = 0.171, p-value = 0.046), adjusting for traditional cardiovascular risk factors (TRFs) and insulin levels. Further adjustment for testosterone and DHEAS rendered the result non-significant. In the multivariable analysis, FMD was associated with insulin (b-coefficient = -0.166, p-value = 0.034), testosterone (b-coefficient = -0.165, p-value = 0.034), DHEAS (b-coefficient = -0.187, p-value = 0.017), adjusting for TRFs. Discussion: The results of this study indicate that the association between androgens and endothelial function is possibly mediated by HSP60 molecules, in women with low insulin resistance and androgenicity. Further prospective studies are needed to explore the significance of our findings.

PMID:39086968 | PMC:PMC11285708 | DOI:10.3389/fmmed.2022.933188

Front Psychiatry. 2024 Jul 11;15:1276410. doi: 10.3389/fpsyt.2024.1276410. eCollection 2024.

ABSTRACT

AIM: To determine the efficacy and safety of pharmacogenomics (PGx)-guided antidepressant prescribing in patients with depression through an umbrella review and updated meta-analysis.

METHODS: A comprehensive systematic search was conducted on PsycINFO, PubMed, Embase and the Cochrane databases. The pooled effect sizes of randomized controlled trials (RCTs) were expressed as mean differences for continuous data and risk ratios for noncontinuous data.

RESULTS: Patients who received PGx-guided medications were 41% to 78% more likely to achieve remission and 20% to 49% more likely to respond to antidepressants than patients receiving treatment-as-usual (TAU).

CONCLUSION: PGx-guided antidepressant prescribing improves the treatment of depression. However, the significance and magnitude of the benefit varies widely between studies and different PGx testing panels.

SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier CRD42022321324.

PMID:39086729 | PMC:PMC11289719 | DOI:10.3389/fpsyt.2024.1276410