Cts-Clinical and Translational Science最新文献

{"title":"Reply to: \"Promising Drugs Require Proper Testing\": Let's Not Confuse Pharmacodynamics With Clinical Efficacy.","authors":"Inès Ben Ghezala, Marc Bardou","doi":"10.1111/cts.70567","DOIUrl":"10.1111/cts.70567","url":null,"abstract":"","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"19 5","pages":"e70567"},"PeriodicalIF":2.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13127101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147788114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Urinary Exosomal microRNAs Associated With Subclinical Acute T-Cell-Mediated Rejection in Kidney Transplant Recipients.","authors":"Soichiro Tajima, Miori Ono, Yuto Kawazoe, Hiroshi Noguchi, Tomohiro Shigematsu, Takashi Ogino, Shoji Nakamura, Takahiro Nakamura, Keizo Kaku, Takeshi Hirota, Ichiro Ieiri, Mayako Uchida","doi":"10.1111/cts.70572","DOIUrl":"https://doi.org/10.1111/cts.70572","url":null,"abstract":"<p><p>This study aimed to evaluate the diagnostic utility of urinary exosomal microRNAs (miRNAs) in subclinical rejection following kidney transplantation by comparing miRNA expression profiles in urinary exosomes between patients with no evidence of rejection and patients with subclinical T-cell-mediated rejection (sc-TCMR), as confirmed by protocol kidney biopsies performed 3 months after transplantation. To elucidate these differences, a comprehensive miRNA expression analysis was conducted using microarray profiling. Consequently, 38 urinary exosomal miRNAs were detected, among which three were upregulated and five were downregulated in patients with sc-TCMR. To further evaluate the diagnostic value of these miRNAs, quantitative real-time PCR analysis was performed using urinary exosomes collected at the time of protocol biopsy from 70 kidney transplant recipients. This analysis confirmed that miR-5100 and miR-7975 were differentially expressed in patients with sc-TCMR at the time of the 12-month protocol biopsy. Importantly, miR-7975 demonstrated the ability to distinguish among three groups-no evidence of rejection, borderline changes, and sc-TCMR-with high diagnostic accuracy, as indicated by an area under the receiver operating characteristic curve of 0.825. In vitro, exposure of proximal tubular epithelial cells to transforming growth factor-beta 1 resulted in a reduction in miR-7975 expression within urinary exosomes, implicating these cells as a potential source of exosomal miR-7975. Collectively, these findings suggest that urinary exosomal miR-7975 may serve as a promising noninvasive biomarker for diagnosing and monitoring sc-TCMR, offering valuable insights for future research and clinical applications.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"19 5","pages":"e70572"},"PeriodicalIF":2.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13134950/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147823137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methodological Considerations for AI-Powered Chatbots in Oral Cancer Awareness: Stakeholder Diversity, Instrument Transparency, and Safety Auditing.","authors":"Carlos Fernando Mourão, Luiz Eduardo Juliasse, Rodrigo Dos Santos Pereira","doi":"10.1111/cts.70566","DOIUrl":"https://doi.org/10.1111/cts.70566","url":null,"abstract":"","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"19 5","pages":"e70566"},"PeriodicalIF":2.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13111917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147788138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Individual and Combined Cytochrome P450 Activity Scores on Symptom Improvement and Side Effects in Youth Treated With Sertraline.","authors":"Samuel Gerlach, Abdullah Al Maruf, Sarker M Shaheen, Ryden McCloud, Madison Heintz, Laina McAusland, Paul D Arnold, Chad A Bousman","doi":"10.1111/cts.70590","DOIUrl":"https://doi.org/10.1111/cts.70590","url":null,"abstract":"<p><p>Sertraline is commonly used to treat mental health conditions in youth. However, its tolerability and efficacy vary between individuals, partly due to interindividual differences in drug metabolism. This study assessed the individual and combined impact of genetic variation in cytochrome P450 drug-metabolizing enzymes on patient-reported side effects and symptom improvement in 347 youth, aged 6-24, receiving sertraline treatment. Participants reported sertraline dose, duration, adherence, concomitant medications, side effects, and symptom improvement. DNA was extracted from saliva samples and genotyped for CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Individual activity scores and a weighted combinatorial CYP450 activity score were created. Binomial logistic regression models were used to assess the impact individual and combined CYP450 activity scores had on patient-reported side effects and symptom improvement, both with and without correction for phenoconversion. After adjusting for phenoconversion, other CYP450 activity scores, and covariates, higher activity scores for CYP2D6 (OR = 0.288, 95% CI = 0.091-0.913) and CYP3A4 (OR = 0.002, 95% CI = 0.001-0.375) were nominally associated with reduced odds of symptom improvement. A higher combined CYP450 activity score was associated with reduced odds of symptom improvement (OR = 0.060, 95% CI = 0.004-0.797) and side effects (OR = 0.097, 95% CI = 0.010-0.925). These findings suggest that a combined CYP450 activity score may serve as a marker of symptom improvement and side effects in youth, but validation using sertraline/desmethylsertraline concentrations is required. If validated, these results may inform updates to pharmacogenetic prescribing guidelines for sertraline and support more personalized sertraline use in youth.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"19 5","pages":"e70590"},"PeriodicalIF":2.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147876605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Phase 1 Multiple-Dose, Open-Label, Pharmacokinetic Study of Nirmatrelvir/Ritonavir in Healthy Lactating Women.","authors":"Jacqueline Gerhart, Narayan Cheruvu, Kathleen Pelletier, Kyle Matschke, Haihong Shi, Josué Kunjom Mfopou, Jennifer Hammond, Ravi Shankar P Singh","doi":"10.1111/cts.70552","DOIUrl":"https://doi.org/10.1111/cts.70552","url":null,"abstract":"<p><p>In accordance with the Centers for Disease Control and Prevention recommendations, pregnant women and those with a recent pregnancy (i.e., lactating) are considered at high risk of developing severe COVID-19 and qualify for treatment with nirmatrelvir/ritonavir. However, clinical data are lacking in this population because breastfeeding women were excluded from the nirmatrelvir/ritonavir clinical development program and pivotal Phase 2/3 studies. We report findings from a prospective Phase 1 trial (NCT05441215) designed and conducted in accordance with the US Food and Drug Administration guidance on clinical lactation studies that evaluated the pharmacokinetics and safety of multiple oral doses of nirmatrelvir/ritonavir in healthy lactating women using paired breast milk and maternal plasma data. Eight participants were enrolled and completed the study. After administration of nirmatrelvir/ritonavir 300 mg/100 mg to steady-state, the concentrations of both nirmatrelvir and ritonavir in breast milk were consistently lower than maternal plasma. Based on standard infant breast milk consumption (150 mL/kg/day), the mean absolute daily doses of nirmatrelvir and ritonavir that an infant would receive were 0.1595 and 0.0057 mg/kg/day, respectively, representing 1.8% and 0.19% of the bodyweight-normalized maternal dose. All treatment-emergent adverse events were mild to moderate in severity. No deaths, serious or severe adverse events, dose reductions, interruptions, or discontinuations were reported. In conclusion, nirmatrelvir/ritonavir 300 mg/100 mg was safe and well tolerated in healthy lactating women, with infant exposure considered to be low and well within the acceptability criteria of < 10% of the body weight-normalized maternal dose.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"19 5","pages":"e70552"},"PeriodicalIF":2.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13098356/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147787929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer Biomarker Test Utilization and Reimbursement in Australia: A National Analysis of Medicare Data.","authors":"Leping Kong, Christine Y Lu","doi":"10.1111/cts.70538","DOIUrl":"https://doi.org/10.1111/cts.70538","url":null,"abstract":"<p><p>Biomarker testing plays a critical role in precision oncology by guiding targeted therapy selection. In Australia, public reimbursement for somatic tumor biomarker tests has expanded over the past decade, yet national data on utilization patterns, equity of access, and public expenditure remain limited. We identified all cancer biomarker tests listed in the March 2025 Medicare Benefits Schedule (MBS), defined as tumor-based assays and selected germline tests used to guide systemic cancer therapy. National claims and expenditure (2010-2024) were extracted from publicly available Medicare Item Statistics. Trends were analyzed by test type, sex, age group, and jurisdiction, and standardized to the 2020 cancer incidence as a proxy for population-level testing coverage. We identified 21 reimbursed cancer biomarker test items, of which 19 had claims during the study period. Between 2010 and 2024, annual claims increased nearly fivefold, from 5130 to 25,374, representing 6% of all MBS-funded genetic test volume and 10% of total expenditure. Median reimbursement per test rose from AU$339 in 2014 to AU$667 in 2024, reflecting increased use of multigene panel tests. Uptake tripled among adults aged 75-84 years, while remaining below 3% among individuals under 35 years. Women accounted for 67% of claims in 2024, down from 88% in 2014. Geographic disparities were marked, with test uptake highest in New South Wales (23.8% of incident cancers) and lowest in the Northern Territory (8.7%). Although national funding for cancer biomarker testing has increased, utilization in Australia remains uneven across demographic and geographic lines. These findings highlight the need to ensure equitable access to genomic diagnostics as part of routine cancer care.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"19 5","pages":"e70538"},"PeriodicalIF":2.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13100301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147787999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-World Efficacy and Safety of Tofacitinib for Patients With Alopecia Areata: A Retrospective Multi-Center Cohort Study.","authors":"Yifan Jin, Juanmei Cao, Sai Yang, Yinghui Liu, Rong Tang, Yufang Zeng, Changzheng Huang, Ying Luo","doi":"10.1111/cts.70544","DOIUrl":"https://doi.org/10.1111/cts.70544","url":null,"abstract":"<p><p>The approval of baricitinib and ritlecitinib for alopecia areata (AA) marks the beginning of the Janus kinase (JAK) inhibitor era in AA treatment. Tofacitinib, a first-generation JAK1/3 inhibitor, has theoretical potential to treat AA; however, real-world evidence, particularly on comparative outcomes across patient subgroups and patient-reported outcomes, remains limited. In this multi-center, retrospective cohort study, we evaluated the efficacy and safety of tofacitinib in refractory AA using objective clinical assessments, including SALT scores and four-point eyebrow and eyelash scales, alongside patient-reported outcomes, namely DLQI/CDLQI and VAS scores. After 12 weeks of treatment, tofacitinib substantially reduced SALT scores and promoted eyebrow and eyelash regrowth, accompanied by meaningful improvements in patient-reported outcomes. Efficacy was greater in patients with severe AA than in those with non-severe AA and was consistent across pediatric and adult populations. Some patients experienced transient disease worsening, which was manageable without treatment escalation. Despite the study's small sample size and retrospective design, tofacitinib demonstrated significant efficacy in both objective and patient-reported measures, supporting its use as a viable therapeutic option for severe AA and underscoring the value of incorporating patient-reported outcomes in real-world studies.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"19 5","pages":"e70544"},"PeriodicalIF":2.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13098360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147788055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Placebo Effect in Rare Disease Clinical Trials: Measurement, Impact, and Statistical Approaches for Patient-as-Own-Control Designs.","authors":"Marshall L Summar, Janet Woodcock","doi":"10.1111/cts.70550","DOIUrl":"10.1111/cts.70550","url":null,"abstract":"<p><p>A frequently cited concern regarding patient-as-own-control trial designs in rare disease is the potential for placebo and related effects to inflate apparent treatment efficacy. Whether this concern is disqualifying or manageable has not been systematically evaluated. We reviewed meta-analyses quantifying placebo effect magnitude by endpoint type, reporter modality, and trial duration and evaluated statistical methods available for post-trial placebo adjustment in own-control designs. Placebo effects depend heavily on endpoint type. For objective endpoints (enzyme activity, serum biomarkers, imaging volumetrics)-which constitute the majority of primary endpoints in approved rare disease therapies-placebo effects are consistently small and in most meta-analyses statistically indistinguishable from zero (standardized mean difference [SMD] < 0.10). For subjective endpoints (patient-reported pain, caregiver-rated function), effects are larger (SMD 0.20-0.50) but well-characterized and correctable. Placebo effects peak early and decay over weeks, providing a temporal signature distinguishable from sustained pharmacological effects. Multiple complementary analytical methods-including temporal trajectory modeling, objective-subjective concordance analysis, Bayesian informative priors, extended run-in observation designs, and blinded outcome assessment-are available to quantify and manage placebo contributions. Importantly, the randomized controlled trial's structural advantage in canceling placebo is itself degraded in small samples, where asymmetric allocation of placebo responders can distort between-arm comparisons. The placebo objection to own-control designs is manageable rather than disqualifying. For objective endpoints, correction is minimal. For subjective endpoints, a rich analytical toolkit supports credible decomposition of drug and placebo components. These findings support the broader adoption of own-control designs in rare disease clinical trials.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"19 5","pages":"e70550"},"PeriodicalIF":2.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13128525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147788106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of a High-Fat Meal on the Pharmacokinetics of Olverembatinib in Patients With Chronic Myeloid Leukemia.","authors":"Hengbang Wang, Yun Yang, Zi Chen, Min Yu, Lixin Jiang, Lichuang Men, Hua Yan, Dajun Yang, Yifan Zhai","doi":"10.1111/cts.70545","DOIUrl":"10.1111/cts.70545","url":null,"abstract":"<p><p>Olverembatinib is approved in China to treat patients with chronic- or accelerated-phase chronic myeloid leukemia (CML-CP or CML-AP) with T315I mutations and CML-CP that is resistant and/or intolerant to first- and second-generation tyrosine kinase inhibitors. The objective of this study was to determine the effects of a high-fat meal on the pharmacokinetics of olverembatinib in patients with CML. Twelve participants were enrolled and received olverembatinib treatment over two periods, with a washout of 7 days between consecutive doses. Pharmacokinetics and safety were assessed in all participants. When olverembatinib was administered with a high-fat meal, the maximum plasma concentration (C_max) and area under the plasma concentration versus time curve from time 0 to infinity (AUC_0-∞) of olverembatinib increased by 105.74% and 69.74%, respectively, compared to fasting conditions. The median time to maximum plasma concentration (T_max) of olverembatinib was not affected when it was administered with a high-fat meal, and the geometric mean terminal plasma half-life (t_1/2) was comparable between high-fat meal and preprandial conditions (26.8 vs. 31.1 h). The safety profile of olverembatinib was consistent with observations from previous studies; all treatment-related adverse events were mild, and no serious adverse event was reported. These results indicate that consumption of a high-fat meal 30 min before administering olverembatinib can increase its plasma exposure to some extent.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"19 5","pages":"e70545"},"PeriodicalIF":2.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13157130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147864759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of a Therapeutic Drug Monitoring Strategy for Adalimumab in Psoriasis: A Prospective Pharmacokinetic-Pharmacodynamic Study.","authors":"Shan Pan, Teresa Tsakok, Ruoheng Wei, Nick Dand, Floris C Loeff, Karien Bloem, Annick de Vries, David Baudry, Michael Duckworth, Angela Pushpa-Rajah, Alice Russell, Ali Alsharqi, Gabrielle Becher, Ruth Murphy, Shyamal Wahie, Andrew Wright, Christopher E M Griffiths, Nick J Reynolds, Jonathan Barker, Richard B Warren, A David Burden, Theo Rispens, Satveer K Mahil, Joseph F Standing, Catherine H Smith","doi":"10.1111/cts.70563","DOIUrl":"10.1111/cts.70563","url":null,"abstract":"<p><p>Using a real-world psoriasis cohort, we established the pharmacokinetic-pharmacodynamic (PKPD) relationship for the biologic therapy adalimumab and evaluated the clinical utility and cost-effectiveness of a proactive therapeutic drug monitoring (TDM) strategy. A total of 543 patients on adalimumab monotherapy for psoriasis provided 946 pharmacokinetic samples and 1700 Psoriasis Area Severity Index (PASI) disease severity measurements. To describe the PASI change over time, a one-compartment linear PK model with first-order absorption and elimination was linked to a turnover mechanism of skin lesions. Based on the PKPD relationship and a predefined therapeutic range, real-time stochastic simulation was performed for a proactive TDM strategy, where trough levels guided dose escalation or reduction. Compared to the standard care, the TDM strategy improved PASI90 and PASI75 by 37.5% and 12.8%, respectively, with a 25.9% increase in drug costs. In the future, incorporating the PKPD model into a Bayesian therapeutic monitoring algorithm could facilitate individualized adalimumab dosing.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"19 5","pages":"e70563"},"PeriodicalIF":2.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13129494/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147787987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}