Hematol Rep. 2025 Jun 12;17(3):30. doi: 10.3390/hematolrep17030030.

ABSTRACT

Background: Cephalosporins are considered safe antibiotics. However, serious hematological abnormalities may occur, although rarely, after their therapeutic use. Case Presentation: We present a case of pancytopenia in a 72-year-old female patient treated with ceftriaxone for a urinary tract infection. After five days of therapy, pancytopenia was observed. Other causes were excluded through extensive diagnostic evaluation, including immunological tests, viral serologies, bone marrow aspiration, and peripheral blood smear. The patient's clinical condition significantly improved following the discontinuation of ceftriaxone and the administration of granulocyte colony-stimulating factor (G-CSF). Bone marrow findings revealed hypocellularity without malignant infiltration, and peripheral smear showed no dysplasia, blasts, or hemolysis. Conclusions: This case demonstrates that ceftriaxone, although widely regarded as a safe antibiotic, can induce rare but serious hematologic complications such as pancytopenia. A high index of suspicion is required when patients on antibiotic therapy develop unexplained cytopenias. Detailed medication history, exclusion of other causes, and prompt discontinuation of the suspected drug are essential. The patient's favorable outcome supports the likelihood of an idiosyncratic, immune-mediated mechanism. Future research should explore pharmacogenomic screening in patients at increased risk, particularly involving HLA variants.

PMID:40558808 | DOI:10.3390/hematolrep17030030

Cells. 2025 Jun 6;14(12):854. doi: 10.3390/cells14120854.

ABSTRACT

STRAP (serine-threonine kinase receptor-associated protein), a WD domain-containing 38.5 kDa protein, was first identified in TGF-ß signaling and participates in scaffold formation in numerous cellular multiprotein complexes. It is involved in the regulation of several oncogenic biological processes, including cell proliferation, apoptosis, migration/invasion, tumor initiation and progression, and metastasis. STRAP upregulation in epithelial tumors regulates several signaling pathways, such as TGF-ß, MEK/ERK, Wnt/β-Catenin, Notch, PI3K, NF-κB, and ASK-1 in human cancers, including colon, breast, lung, osteosarcoma, and neuroblastoma. The upregulation of STRAP expression is correlated with worse survival in colorectal cancer following post-adjuvant therapy. Strap knockout sensitizes colon tumors to chemotherapy, delays APC-induced tumor progression, and reduces cancer cell stemness. The loss of Strap disrupts lineage differentiation, delays neural tube closure, and alters exon skipping, resulting in early embryonic lethality in mice. Collectively, the purpose of this review is to update and describe the diversity of targets functionally interacting with STRAP and to rationalize the involvement of STRAP in a variety of signaling pathways and biological processes. Therefore, these in vitro and in vivo studies provide a proof of concept that lowering STRAP expression in solid tumors decreases tumorigenicity and metastasis, and targeting STRAP provides strong translational potential to develop pre-therapeutic leads.

PMID:40558481 | DOI:10.3390/cells14120854

Am J Health Syst Pharm. 2025 Jun 25:zxaf150. doi: 10.1093/ajhp/zxaf150. Online ahead of print.

ABSTRACT

PURPOSE: Results of the 2024 ASHP National Survey of Pharmacy Practice in Hospital Settings are presented.

METHODS: Pharmacy directors at 1,497 general and children's medical-surgical hospitals in the United States were surveyed using a mixed-mode method of contact by email and mail. Survey completion was online using Qualtrics. IQVIA supplied data on hospital characteristics; the survey sample was drawn from IQVIA's hospital database.

RESULTS: The response rate was 16.7%. Pharmacists routinely provide clinical pharmacy services to a majority of inpatients in over 75% of hospitals and are most commonly assigned to general medical-surgical (73.3%), critical care (68.5%), oncology (56.9%), cardiology (48.5%), infectious disease/antimicrobial stewardship (48.1%) units and the emergency department (46.5%). Pharmacists independently prescribe in 18.5% of hospitals. Progress towards the ASHP Practice Advancement Initiative (PAI) 2030 goals has been mixed; except for technicians performing more advanced roles, measures have remained relatively stable over the past 5 years. Over 80% of pharmacy directors reported perceived shortages of experienced technicians, and about 60% reported perceived shortages of clinical specialists and clinical coordinators.

CONCLUSION: Hospital pharmacy departments are facing many challenges, including worsening shortages of pharmacists and pharmacy technicians, drug shortages, reimbursement and formulary concerns, and regulatory compliance. Despite these challenges, inpatient and ambulatory care clinical pharmacy services continue to expand across the country, with most hospitals routinely providing care to a majority of patients in over three-quarters of hospitals. While progress toward other PAI 2030 focused initiatives has been mixed over the past 5 years, responsibilities of pharmacy technicians are trending toward advanced roles.

PMID:40557732 | DOI:10.1093/ajhp/zxaf150

Front Pain Res (Lausanne). 2025 Jun 10;6:1621147. doi: 10.3389/fpain.2025.1621147. eCollection 2025.

NO ABSTRACT

PMID:40557279 | PMC:PMC12186450 | DOI:10.3389/fpain.2025.1621147

Front Cell Dev Biol. 2025 Jun 10;13:1626242. doi: 10.3389/fcell.2025.1626242. eCollection 2025.

ABSTRACT

Phospholamban (PLN) is a key regulator of cardiac muscle contractility and has become a central focus in the study of cardiac disease. Variants in the PLN gene have been identified in patients with a wide range of phenotypes, including hypertrophic, dilated, and arrhythmogenic cardiomyopathies. The growing number of identified variants highlights the previously underappreciated role of PLN in cardiac pathophysiology. This review offers a comprehensive examination of the genetic landscape of PLN and evaluates the mechanistic effects of specific variants on cardiac function, aiming to uncover potential genotype-phenotype correlations. The rapidly expanding body of knowledge in this area is driving the development of advanced diagnostic and prognostic tools, as well as highly targeted therapeutic strategies. These advances underscore the importance of recognizing PLN's role in cardiac disease and the value of genetic testing for accurate diagnosis, prognosis, effective management, and early risk prediction for family members.

PMID:40556736 | PMC:PMC12185491 | DOI:10.3389/fcell.2025.1626242

Scand J Immunol. 2025 Jul;102(1):e70039. doi: 10.1111/sji.70039.

NO ABSTRACT

PMID:40556349 | DOI:10.1111/sji.70039

Cancer Rep (Hoboken). 2025 Jun;8(6):e70251. doi: 10.1002/cnr2.70251.

ABSTRACT

BACKGROUND: This study evaluated awareness, prevalence, and utilization of dihydropyrimidine dehydrogenase (DPD) testing and pharmacogenomics among oncologists, residents, and clinical pharmacists working in Palestinian hospitals.

AIM: This study aimed to assess the knowledge and opinions of HCPsspecializing in oncology in Palestine regarding screening for DPYD testing prior to prescribing FP.

METHODS: A cross-sectional survey was distributed to 106 HCPs across various hospitals in Palestine.

RESULTS: A notable deficiency in training and implementation of pharmacogenomics was observed, with over 70% of participants lacking formal training in the field. Although there is high awareness of DPD deficiency and its impact, fewer than 50% of participants screen for DPD deficiency prior to prescribing fluoropyrimidines (FP). Standardization and promotion of DPD testing are low, and guidelines for prescribing FP are lacking, leading to variations in clinical practice.

CONCLUSION: These findings highlight the need for enhanced training, standardized protocols, and increased awareness to improve patient safety and outcomes in cancer treatment in Palestine.

PMID:40556331 | DOI:10.1002/cnr2.70251

Expert Opin Drug Metab Toxicol. 2025 Jun 24. doi: 10.1080/17425255.2025.2521048. Online ahead of print.

ABSTRACT

INTRODUCTION: Inflammatory bowel disease (IBD) treatment remains challenging, with many patients experiencing suboptimal responses despite advances in therapies. This necessitates more precise and personalized approaches.

AREAS COVERED: A literature search was conducted using Embase, Scopus, and PubMed (January 2000-March 2024) with keywords such as 'inflammatory bowel disease,' 'pharmacogenomics,' 'multi-omics,' and 'multi-omics.' This review discusses (1) key pharmacogenomic markers influencing drug metabolism, efficacy, and toxicity; (2) the role of multi-omics (genomics, proteomics, metabolomics) in elucidating IBD pathogenesis and predicting therapeutic outcomes; and (3) emerging technologies such as AI-driven predictive models and organoids. Challenges in translating these tools into clinical practice - including cost, data standardization, and workflow integration - are critically examined.

EXPERT OPINION: Integrating pharmacogenomics with multi-omics holds transformative potential for IBD care. While TPMT genotyping exemplifies current clinical utility, future frameworks will require harmonized multi-omic data to guide therapy selection. Key barriers include high costs of omics profiling, interpretative complexity, and clinician training gaps. Collaborative efforts among researchers, clinicians, and policymakers are essential to validate biomarkers, standardize methodologies, and implement cost-effective assays. Prioritizing real-world studies and AI-powered decision-support tools will accelerate the shift from trial-and-error to personalized IBD management.

PMID:40556317 | DOI:10.1080/17425255.2025.2521048

Drug Metab Dispos. 2025 May 20;53(7):100100. doi: 10.1016/j.dmd.2025.100100. Online ahead of print.

ABSTRACT

Clozapine's (CLZ) pharmacokinetics involves multiple enzymes and transporters, which may be influenced by genetic variability. A variant in the nuclear factor I B (NFIB) gene (rs28379954 T>C) has been associated with reduced CLZ serum concentrations. This study explored CLZ metabolism in relation to NFIB genotype in patients with known smoking habits. NFIB's role in regulating gene expression of transporters relevant for intestinal absorption of CLZ was investigated using Caco-2/TC7 cells. Metabolite spectra of CLZ-treated patients (n = 285) were included from a therapeutic drug monitoring service. Formation of 30 CLZ metabolites was compared between patients carrying NFIB CT and TT diplotypes. To investigate NFIB's possible role in regulating the expression of drug transporters of relevance for CLZ efflux (ABCB1, ABCC1, and ABCG2) or uptake (SLC transporters), NFIB was overexpressed in Caco-2/TC7 cells. CLZ dose-adjusted concentration was 25% lower in NFIB CT versus TT carriers (P = .017). No significant differences in primary metabolites were found, but a secondary metabolite, N-desmethylclozapine cysteinyl, was increased by 1.89-fold in smoking CT versus TT carriers (P = .038). In Caco-2/TC7 cells, NFIB overexpression significantly suppressed the expression of ABCB1 and ABCG2 by 25%-30%. In summary, NFIB CT carriers require higher CLZ doses for optimal clinical effect, yet their metabolite profiles are similar to those of TT carriers, suggesting no differences in enzyme activity. Instead, Caco-2/TC7 experiments showed reduced ABCB1 and ABCG2 expression in NFIB-transfected cells. This may indicate that lower CLZ levels in CT carriers result from decreased NFIB-mediated inhibition of transporter expression. However, further in vivo studies are needed to clarify NFIB's role in CLZ transport mechanisms. SIGNIFICANCE STATEMENT: This study shows that the NFIB rs28379954 T>C variant causes reduced clozapine serum levels and hence increased dose requirements to reach therapeutic levels for optimal clinical response. However, this effect seems to be independent of metabolic changes, suggesting alternative pharmacokinetic mechanisms at play. In vitro experiments further indicate that NFIB may regulate the expression of intestinal efflux transporters. Both findings provide a future foundation for genotype-guided dosing of clozapine in patients suffering from treatment-resistant schizophrenia.

PMID:40554316 | DOI:10.1016/j.dmd.2025.100100

Am J Pharm Educ. 2025 Jun 17:101436. doi: 10.1016/j.ajpe.2025.101436. Online ahead of print.

ABSTRACT

OBJECTIVE: To describe student pharmacists' experience with using PharmTutorAI.com's Gene Counsel artificial intelligence (AI) tool for simulated pharmacogenetic counseling sessions in a third-year skills laboratory course.

METHODS: Third-year pharmacy students completed three PharmTutorAI.com pharmacogenetic counseling cases on cardiovascular, psychiatry, and epilepsy during the Fall semester of the 2023-2024 academic term. The three cases were graded and scored by AI out of 40 points each. Students were asked to complete an optional survey about perceptions of utilizing AI in this learning simulation and if they would recommend its use. Open-ended survey questions were also asked. Data analysis was conducted using KNIME (KoNstanz Information MinEr) and Python. Descriptive statistics were also utilized.

RESULTS: A total of 71 out of the 72 (98.6%) students in the third-year cohort completed all three PharmTutorAI.com pharmacogenetic cases on Gene Counsel AI and the associated survey. Scores (out of 40 total points) were 38.2 ± 1.5 for the cardiovascular case, 38.1 ± 1.9 for the psychiatry case, and 37.3 ± 4.9 for the epilepsy case. When asked about counseling preference, 65.2% of students preferred to have both human counseling subjects and the PharmTutorAI.com cases, 24.6% preferred AI alone, and 10% preferred human only.

CONCLUSION: Students performed well on the AI pharmacogenetic counseling cases and expressed predominantly positive perceptions of the activity. The Gene Counsel AI tool successfully reduced faculty workload by eliminating the need for multiple facilitators per session while enabling students to practice multiple pharmacogenetic counseling scenarios rather than just one.

PMID:40553755 | DOI:10.1016/j.ajpe.2025.101436

Clin Pharmacol Ther. 2025 Jun 24. doi: 10.1002/cpt.3749. Online ahead of print.

ABSTRACT

The Ubiquitous Pharmacogenomics consortium (www.upgx.eu) has recently completed and published the Preemptive Pharmacogenomic Testing for Preventing Adverse Drug Reactions (PREPARE) study on the implementation of panel-based pharmacogenetic testing. PREPARE has provided interesting lessons for the design, execution, and interpretation of future clinical implementation studies. In this paper, we share our experience and lessons learned from the PREPARE study for future pharmacogenetic implementation studies. Issues addressed are the study population, intervention, endpoint, randomization, blinding, crossover, ethics, real-world changes during the study, and data analysis and reporting.

PMID:40552566 | DOI:10.1002/cpt.3749

Blood Neoplasia. 2024 Sep 5;1(4):100040. doi: 10.1016/j.bneo.2024.100040. eCollection 2024 Dec.

ABSTRACT

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm. Although the prognosis of pediatric T-ALL has improved with intensified chemotherapy regimens, this benefit has largely not translated to the adult T-ALL population. Development of new treatments requires understanding the mechanisms driven by specific mutations. DNMT3A mutations are identified in ∼10% to 18% of adult patients with T-ALL and are associated with poor clinical outcomes. Here, using primary human specimens, we show that cells from patients with T-ALL with DNMT3A mutations are resistant to apoptosis and certain chemotherapies. Elevated JAK/STAT signaling drove prosurvival programs in patients with mutant DNMT3A, and JAK/STAT inhibition restored sensitivity to chemotherapy. The prosurvival gene BIRC5 was upregulated in patients with DNMT3A-mutant T-ALL, and these cells were specifically sensitive to the Baculoviral IAP Repeat Containing 5 (BIRC5) inhibitor YM155. Genetic inhibition of BIRC5 in vivo lead to rapid depletion of DNMT3A-mutant T-ALL cells in patient-derived xenografts, positioning BIRC5 as a precision medicine target for these patients.

PMID:40552132 | PMC:PMC12182843 | DOI:10.1016/j.bneo.2024.100040

JAMA Netw Open. 2025 Jun 2;8(6):e2516296. doi: 10.1001/jamanetworkopen.2025.16296.

ABSTRACT

IMPORTANCE: Therapeutic responses in acute myeloid leukemia (AML) demonstrate considerable variability both across and within established risk stratifications and age groups. Moreover, significant racial disparities persist, with Black patients experiencing inferior survival outcomes compared with their White counterparts.

OBJECTIVE: To validate the association of the previously reported 10 single nucleotide variant (SNV)-based ara-C pharmacogenomics score (ACS10) with survival outcomes in a large cohort of pediatric AML patients; to evaluate whether ACS10 remains relevant in an adolescent and young adult (AYA) population of patients with AML treated with similar intensive induction chemotherapy protocols; and to assess the association of ACS10 with race and treatment outcomes in both cohorts.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study included patients from the Children's Oncology Group's AAML1031 trial, a multicenter, open-label randomized clinical trial that enrolled pediatric patients with newly diagnosed, treatment-naive primary AML from June 2011 to July 2017 (aged 0 to 29.5 years) and from the Alliance for Clinical Trials in Oncology frontline protocols, which included AYA patients from 9 different trials that enrolled patients with newly diagnosed AML from 1992 to 2010. Data were analyzed from September 2022 to March 2025.

EXPOSURES: Patients in the AAML1031 trial were randomized to 2 arms, standard chemotherapy alone or standard chemotherapy with the addition of bortezomib. Patients in the Alliance for Clinical Trials in Oncology cohorts were treated with similar intensive induction chemotherapy protocols.

MAIN OUTCOMES AND MEASURES: ACS10 scores were evaluated for association with outcomes according to race, treatment arm, and hematopoietic stem cell transplant (HSCT) status.

RESULTS: The study included 1086 patients with AML. There were 717 patients from the pediatric AML cohort (median [range] age, 9.6 [0.04-29.2 years]; 379 [53%] male; 33 [5%] Asian, 84 [12%] Black, and 522 [73%] White) and 369 AYA patients with AML from the Alliance for Clinical Trials in Oncology group (median [range] age, 30 [17-39] years; 196 [53%] male; 7 [2%] Asian, 32 [9%] Black, and 288 [78%] White). Within the standard treatment arm of AAML1031, patients in the low ACS10 group had significantly worse event-free survival (EFS) compared with those in the high ACS10 group (all patients: hazard ratio [HR], 1.42; 95% CI, 1.05-1.95; P = .02; non-HSCT cohort: HR, 1.48; 95% CI, 1.06-2.07; P = .02). The ACS10 score remained significantly associated with EFS in multivariable analysis after adjusting for age, race, risk group and white blood cell count, within the standard treatment arm (HR, 1.44; 95% CI, 1.03-2.02; P = .03). In the Alliance for Clinical Trials in Oncology AYA non-HSCT cohort, the low ACS10 score group had significantly inferior overall survival (OS) and a higher point estimate for EFS compared with patients with a high ACS10 score (OS: HR, 1.50; 95% CI, 1.05-2.14; P = .03; EFS: HR, 1.32; 95% CI, 0.95-1.83; P = .10). A higher number of early deaths was observed in the low ACS10 group compared with the high ACS10 group, but the difference was not statistically significant (death within 30 days of treatment initiation: 6 of 112 [5%] vs 2 of 257 [1%]; P = .07). Across both cohorts, a low ACS10 score was significantly more abundant in Black patients compared with White patients (eg, in Alliance for Clinical Trials in Oncology cohort, 27 of 32 Black patients [84%] had low ACS10 scores compared with 64 of 288 White patients [22%]; P < .001) and inferior survival was observed in Black patients (eg, OS of Black compared with White patients in AAML1031 cohort: HR, 1.47; 95% CI, 1.02-2.13; P = .04). In the AAML1031 cohort, there were no significant differences in EFS or OS between Black and White patients receiving augmented treatment, suggesting that the addition of bortezomib was associated with benefit for Black patients.

CONCLUSIONS AND RELEVANCE: In this study of 717 pediatric and 369 AYA patients with AML, the ACS10 score was associated with EFS in pediatric and AYA patients when treated with a standard induction regimen. There was a higher abundance of low ACS10 scores in Black patients, and Black patients treated with augmented therapy (ie, the addition of bortezomib) seemed to have improved outcomes. Integrating the ACS10 score into a prospective clinical trial to personalize induction therapy based on an individual's genetic profile has the potential to improve treatment outcomes.

PMID:40549387 | DOI:10.1001/jamanetworkopen.2025.16296

Aliment Pharmacol Ther. 2025 Jun 23. doi: 10.1111/apt.70232. Online ahead of print.

ABSTRACT

BACKGROUND: The clinical utility and cost-effectiveness of pre-thiopurine NUDT15 pharmacogenetic testing in European and admixed populations are unknown.

AIMS: To report the prevalence, penetrance, expressivity, and pathogenicity of NUDT15 variant allele carriage and the diagnostic accuracy and cost-effectiveness of an inexpensive loop-mediated isothermal amplification (LAMP) test.

METHODS: Retrospective case-matched cohort study of rates of severe myelosuppression in patients with and without loss-of-function NUDT15 variant allele(s) treated with a thiopurine.

RESULTS: Overall, 1.3% of Europeans and 11.7% of South Asians carried a variant allele. Severe myelosuppression was associated with NUDT15 variant allele carriage (11.3% vs 0.95%; p < 0.001). Carriage of a single *3, *6 or *9 variant allele was associated with a shorter time to severe myelosuppression. Numbers needed to genotype to prevent myelosuppression in Europeans and South Asians were 786 and 23. Variant calling using the LAMP assay was fully concordant with Sanger sequencing (n = 154). It improved the safety of thiopurine dosing and was cost-effective when used to reduce the frequency and cost of thiopurine blood monitoring for patients without risk variants.

CONCLUSION: We recommend TPMT and NUDT15 genetic testing in patients of Asian and admixed ancestry. In Europeans, reflex NUDT15 testing should be considered in patients with reduced TPMT activity or loss-of-function genotype. Thiopurines should be avoided in patients with > 1 NUDT15 variant allele and in patients with both NUDT15 and TPMT variant alleles. In patients with a single NUDT15 variant allele, we recommend thiopurine dose reduction (< 1 mg/kg/day) and intensified blood test monitoring.

PMID:40548539 | DOI:10.1111/apt.70232

IJID Reg. 2025 May 8;15:100665. doi: 10.1016/j.ijregi.2025.100665. eCollection 2025 Jun.

ABSTRACT

OBJECTIVES: First-line anti-tuberculosis (TB) medications are effective for drug-susceptible TB but are commonly associated with hepatotoxicity, which can compromise treatment adherence and contribute to drug resistance. This study aimed to determine the frequency of anti-TB drug-induced hepatotoxicity and identify associated risk factors among patients at Chiang Mai University Hospital.

METHODS: A retrospective cross-sectional study was conducted among patients with drug-susceptible pulmonary TB receiving standard treatment. Liver function tests were monitored biweekly during the first 2 months to detect hepatotoxicity. The risk factors evaluated included body mass index (BMI), age, alcohol use, N-acetyltransferase 2 (NAT2) acetylator status, and concomitant statin use. Adverse drug reactions were assessed by physicians using severity grading. Binary logistic regression and multivariate analysis were performed to identify independent predictors of hepatotoxicity. Adjusted odds ratios (ORs), 95% confidence intervals (CIs), and P-values were reported.

RESULTS: The incidence of hepatotoxicity was 41.97%. The multivariate analysis showed significant associations between hepatotoxicity and the following: age >70 years (OR = 41.72, P = 0.001), underweight BMI (OR = 56.48, P = 0.001), current alcohol use (OR = 10.95, P = 0.001), and slow NAT2 acetylator status (OR = 78.18, P = 0.001).

CONCLUSIONS: Hepatotoxicity is a common complication of TB treatment. Older age, low BMI, alcohol use, slow NAT2 genotype, and statin co-administration significantly increase risk. Targeted monitoring and consideration of NAT2 genotyping in high-risk patients may help prevent treatment interruptions and improve clinical outcomes.

PMID:40547509 | PMC:PMC12179635 | DOI:10.1016/j.ijregi.2025.100665

EClinicalMedicine. 2025 Jun 5;84:103277. doi: 10.1016/j.eclinm.2025.103277. eCollection 2025 Jun.

ABSTRACT

BACKGROUND: The risks and benefits of colchicine use among patients with atherosclerotic cardiovascular disease (ASCVD) have been widely reported. Our umbrella review aimed to systematically analyse and synthesise the available causal evidence on the therapeutic effects and safety profile of colchicine in patients with ASCVD.

METHODS: We searched PubMed, Embase, Web of Science, and Cochrane Library from database inception to December 4, 2024, to identify systematic reviews and meta-analyses of randomised controlled trials (RCTs) investigating colchicine use among patients with ASCVD. The primary endpoints were physical adverse events, MACEs, and CV disorder. The quality of systematic reviews was evaluated using A Measurement Tool to Assess Systematic Reviews (AMSTAR), and the certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) system. Risk of bias was evaluated using Cochrane Systematic Review criteria. Inconsistency was flagged if heterogeneity (I 2 ) exceeded 50%, or 75% without explanation. Publication bias was detected via funnel plot asymmetry or Egger's test. Subgroup analyses were done according to colchicine dose, treatment duration, geographical region, participant age and disease of patients. This study is registered with PROSPERO (CRD 42025631311).

FINDINGS: This review analysed 47 unique outcomes from 48 systematic reviews and meta-analyses of RCTs. Among 271 associations, 95 were supported by high-certainty evidence. For primary outcomes, compared with placebo treatment, colchicine exhibited therapeutic efficacy in coronary heart disease [relative risk (RR): 0.73, 95% confidence interval (CI): 0.64-0.83, I 2 : 0%] and acute coronary syndromes (OR: 0.72, 95% CI: 0.58-0.89, I 2 : 0%), demonstrating secondary prevention benefits in major adverse cardiovascular events (RR: 0.56, 95% CI: 0.47-0.67, I 2 : 0%). Common adverse effects included gastrointestinal reactions and hepatic toxicity, with dose-dependent associations of drug discontinuation (RR: 4.63, 95% CI: 2.06-10.38, I 2 : 36%). Evidence of publication bias was identified in 18 of 271 tested associations. Subgroup analyses indicated that optimal clinical application required consideration of patient age, geographic variance in pharmacogenomics, and protocol adjustments (recommended dose ≤0.5 mg/day for more than a month) to balance efficacy-risk profiles.

INTERPRETATION: High-certainty evidence supported the therapeutic and secondary preventive benefits of colchicine in patients with ASCVD when dose and duration were appropriately controlled. Future studies could focus on identifying ASCVD subgroups with pharmacogenomic and ethnographic predictors of colchicine response heterogeneity to guide precision therapy.

FUNDING: This work was supported by the Liaoning Revitalization Talents Program, Outstanding Youth Scientific Talent Project of Dalian, and Outstanding Scientific Fund of Shengjing Hospital.

PMID:40547439 | PMC:PMC12179638 | DOI:10.1016/j.eclinm.2025.103277

Neuropsychopharmacology. 2025 Jun 21. doi: 10.1038/s41386-025-02147-7. Online ahead of print.

ABSTRACT

While numerous studies have examined the subjective response to alcohol as an intermediate phenotype to understand its variability, heritability, and predictive capacity for alcohol-related disorders, in-depth analyses linking alcohol reactivity indicators to genetic factors within a large cohort have been absent. Our study aimed to quantify the exact contribution of each genetic variant relevant to the alcohol metabolism to the variability in alcohol response. Specifically, we focused on two primary genes involved in alcohol metabolism (ALDH2 and ADH1B) and three additional loci (ALDH1B1, ALDH1A1, and GCKR) that have been shown to have significant associations with drinking behaviors in Japanese individuals. We conducted the first study to assess the relationship between subjective response to alcohol (SR), evaluated by various assessment subscales, and genetic factors using an intravenous clamp technique in 429 healthy Japanese young adults. By reducing the dimensionality of the data to assess similarity structures, we identified three distinct clusters of SRs and participants. Each participant cluster exhibited a distinct alcohol response profile shaped by specific genetic contributions. Participant cluster 1 demonstrated the strongest response, followed by participant cluster 2, and then participant cluster 3. Participant cluster 1 may also be the most strongly influenced by the allelic status of ALDH2 and ADH1B. SR patterns varied accordingly, and the enrichment of the ALDH2*2 and ADH1B*2, differed across both participant and subscale clusters. Notably, the three participant clusters closely aligned with the three subscale clusters, highlighting a consistent genotype-phenotype relationship. Furthermore, the proportion of variance explained by these genes also varied across subscale clusters. Contrary to known functions, ADH1B showed associations at later timings when ALDH2 associations attenuate. Our three-cluster classification may improve prevention by enabling early identification of individuals at health risk.

PMID:40544219 | DOI:10.1038/s41386-025-02147-7

J Am Acad Dermatol. 2025 Jun 19:S0190-9622(25)02362-X. doi: 10.1016/j.jaad.2025.06.037. Online ahead of print.

ABSTRACT

Genetic testing enhances the accuracy of diagnosing and managing complex autoinflammatory skin diseases. Advancements in diagnostic methodologies, including next-generation sequencing, whole exome sequencing, and whole genome sequencing, have improved the detection of rare genetic variants, facilitating personalized treatment approaches and optimizing patient outcomes. While techniques such as microarray analysis and targeted sequencing panels contribute to the identification of disease-associated variants, NGS provides a broader scope, enabling the simultaneous detection of multiple genetic alterations. This article examines the distinctions between genetic tests for somatic and germline mutations, highlights the role of genetic counseling, and discusses how genetic testing informs tailored therapeutic strategies.

PMID:40543673 | DOI:10.1016/j.jaad.2025.06.037

J Clin Pharmacol. 2025 Jun 20. doi: 10.1002/jcph.70065. Online ahead of print.

ABSTRACT

Racial and ethnic differences in drug disposition and response may have a significant impact on its risk-benefit balance. Therefore, it is important to examine whether an investigational drug has characteristics that make the pharmacokinetics (PK), safety, and efficacy likely to be affected by intrinsic and extrinsic ethnic factors based on ethnic sensitivity assessment. This assessment is recommended by the latest Japanese guideline (issued in December 2023) for Japanese phase 1 studies before participation in multi-regional clinical trials (MRCTs). To comprehensively understand characteristics and ethnic sensitivity of drugs that seem to have racial/ethnic differences in its disposition and response, we investigated 620 new molecular entities (NMEs) approved by the United States Food and Drug Administration (FDA) between 2008 and 2023. Of those, only 6.5% (40 NMEs) reported racial/ethnic differences in the PK (5.0%), safety (1.6%), and/or efficacy (0.6%) in the FDA drug labeling, with only one NME (0.16%) having a clinically significant PK difference which requires a reduced starting dose in East Asian patients. Additionally, 4.4% of 620 NMEs reported differences in the pharmacogenetics for drug-metabolizing enzymes. The comprehensive evaluation of characteristics and ethnic sensitivity of 40 NMEs with racial/ethnic differences in the PK, safety, and/or efficacy indicated two key findings. First, participation in MRCTs from various regions as early as possible is much more important than conduct of an additional phase 1 study in a specific region/country. Second, more attention and deeper evaluation of Asian PK would be needed for drugs with low bioavailability in the overall drug development.

PMID:40542466 | DOI:10.1002/jcph.70065

Commun Med (Lond). 2025 Jun 20;5(1):241. doi: 10.1038/s43856-025-00955-y.

ABSTRACT

Pharmacogenomics studies how a person's inherited genes influence response to therapeutic drugs. Many drugs do not work in all patients and pharmacogenomics can assist in the identification of patients who are better suited to particular drugs or patients who need adjusted drug doses to reach better treatment outcomes. This stratification of patients could be beneficial in Africa as it would allow drugs that would ordinarily be discontinued due to toxicity on a proportion of the populations to be used in a directed manner in people for whom it is not toxic. However, there has been limited use of pharmacogenomics. One of the key issues has been the need to demonstrate the economic benefits of adopting pharmacogenomics implementation and the impact on healthcare cost drivers. Integration of pharmacogenomics into clinical practice has huge potential in Africa due to the large genetic diversity in African populations. This Perspective article explores the current pharmacogenomics landscape, the health economics associated with its implementation, and future directions for pharmacogenomics research translation in Africa.

PMID:40542221 | DOI:10.1038/s43856-025-00955-y