Cts-Clinical and Translational Science最新文献

{"title":"Translational PK–PD model for in vivo CAR-T-cell therapy delivered using CAR mRNA-loaded polymeric nanoparticle vector","authors":"Se Jin Kim,&nbsp;Ganesh M. Mugundu,&nbsp;Aman P. Singh","doi":"10.1111/cts.70101","DOIUrl":"10.1111/cts.70101","url":null,"abstract":"<p>Autologous chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable response rates, yet its widespread implementation is hindered by logistical, financial, and physical constraints. Additionally, challenges such as poor persistence and allorejection are associated with allogeneic cell therapies. An innovative approach involves in vivo transduction of endogenous T-cells through the administration of CAR mRNA encapsulated in polymeric nanoparticles (NPs), resulting in transient CAR surface expression on circulating T-cells. This method presents a promising alternative, although the dose–exposure–response relationship of in vivo CAR-Ts remains poorly elucidated. The transient nature of CAR expression may necessitate repeated dosing, potentially introducing additional hurdles like cost and patient compliance. To address this issue, we have devised a translational pharmacokinetic–pharmacodynamic (PK–PD) model that characterizes the transient surface CAR expression following mRNA-encapsulated NP administration, leveraging in vitro and in vivo data alongside critical binding kinetic parameters sourced from literature. Our model adequately captures the transient surface CAR expression in both settings, while incorporating known physiological parameter values and exhibiting precise estimation of unknown parameters (coefficient of variation &lt; 30%). Global sensitivity analyses underscore the significance of intracellular mRNA stability, highlighting the sensitivity of parameters linked to free intracellular mRNA concentration. Model-based simulations indicate that optimizing dose and dosing frequency can achieve sustained CAR expression, despite the transient protein expression characteristic of mRNA-based therapies. This mechanistic PK–PD model holds potential for integration into physiologically-based pharmacokinetic models, facilitating the translation of in vivo CAR-T-cell therapies from preclinical studies to human applications.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 12","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70101","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856522","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":"Long-term benefit of SGLT2 inhibitors to prevent heart failure hospitalization in patients with diabetes, with potential time-varying benefit","authors":"Yasuo Takahashi,&nbsp;Kimino Minagawa,&nbsp;Takuya Nagashima,&nbsp;Takashi Hayakawa,&nbsp;Hayato Akimoto,&nbsp;Satoshi Asai","doi":"10.1111/cts.70088","DOIUrl":"10.1111/cts.70088","url":null,"abstract":"<p>SGLT2 inhibitors show promise in reducing hospitalization for heart failure in diabetics, but their long-term effects and time-dependency remain unclear. We conducted a retrospective nested case–control study within a large type 2 diabetic cohort (<i>n</i> = 11,209) using electronic health records. Cases (heart failure hospitalization, <i>n</i> = 352) were matched to controls (<i>n</i> = 1372) based on age, sex, cohort entry date, and diabetes duration. Matched-set conditional logistic regression was used to estimate hazard ratios (HRs) for antidiabetic drug class and heart failure hospitalization risk. SGLT2 inhibitors were associated with a significant reduction in heart failure hospitalization risk (adjusted HR 0.56, 95% CI 0.38–0.82, <i>p</i> = 0.028). This protective effect appeared more pronounced with a longer duration of treatment, suggesting a potential cumulative benefit. Time-varying analysis within propensity score-matched cohorts revealed a progressive decrease in hospitalization risk with continued SGLT2 inhibitor use, indicating a strengthening effect over time (greedy nearest neighbor: HR 0.52, CI 0.31–0.87, <i>p</i> = 0.015; optimal matching: HR 0.54, CI 0.34–0.85, <i>p</i> = 0.008). While promising, further investigation with larger datasets is warranted to definitively confirm these findings.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 12","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70088","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848226","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":"Endogenous plasma riboflavin is not a viable BCRP biomarker in human","authors":"John P. Savaryn,&nbsp;Ryota Kikuchi,&nbsp;Yuli Qian,&nbsp;Qin C. Ji,&nbsp;Gary J. Jenkins,&nbsp;Daniel A. J. Bow,&nbsp;Mohamed-Eslam F. Mohamed","doi":"10.1111/cts.70109","DOIUrl":"10.1111/cts.70109","url":null,"abstract":"<p>Recent reports suggest that plasma riboflavin may serve as a biomarker for BCRP inhibition in humans. However, the clinical data supporting this claim have been limited, with only two studies showing modest increases in riboflavin levels after administration of a BCRP inhibitor. We have recently demonstrated that co-administration of 375 mg once daily (q.d.) cedirogant, an in vitro BCRP inhibitor, significantly increased rosuvastatin (an OATP1B1/1B3 and BCRP substrate) exposures but did not change the levels of the OATP1B endogenous biomarker coproporphyrin-I, demonstrating that cedirogant is a clinical BCRP inhibitor. Samples from this same cedirogant clinical drug–drug interaction study were utilized to test the hypothesis that endogenous plasma riboflavin is a biomarker of BCRP inhibition. Plasma riboflavin levels in the absence of cedirogant ranged from 1 to 10 ng/mL across the 11 participants analyzed with minimal (&lt;20%) intrasubject variability over a 24-hour interval. Contrary to expectations, 375 mg q.d. oral administration of cedirogant did not increase riboflavin levels. These data strongly suggest that endogenous plasma riboflavin is not a viable biomarker for BCRP inhibition in humans.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 12","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70109","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142840040","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":"Association of liver fibrosis scores with all-cause and cardiovascular mortality in patients with heart failure","authors":"Ziyu Guo,&nbsp;Zixiang Ye,&nbsp;Qinfeng Xu,&nbsp;Yike Li,&nbsp;Jingang Zheng","doi":"10.1111/cts.70104","DOIUrl":"10.1111/cts.70104","url":null,"abstract":"<p>The aim of this study was to examine the relationship of liver fibrosis (determined via fibrosis scores) with all-cause mortality and cardiovascular mortality in HF patients. The study examined demographic and clinical data were collected from NHANES database (1999 to 2018). A total of 1356 HF patients were enrolled in our analysis. During a median follow-up time of 70 months, 455 patients died. Compared to the survivors, the death group showed significantly elevated LFSs levels. RCS analysis revealed a linear relationship between various LFSs and all-cause and cardiovascular mortality. KM curves and Cox regression models indicated that higher FIB-4 (≥ 1.637), NFS (≥ −0.064), and AST/ALT ratio (≥ 1.172) were linked to higher risk of all-cause mortality [Cox model 2: FIB-4 adjusted hazard ratio (aHR), 1.24; 95% CI, 1.04–1.48; NFS aHR, 1.19; 95% CI, 1.01–1.38; AST/ALT ratio aHR, 1.25; 95% CI, 1.07–1.47] and cardiovascular mortality in heart failure patients (FIB-4 aHR, 1.28; 95% CI, 1.07–1.67; AST/ALT ratio aHR, 1.39; 95% CI, 1.08–1.79). ROC curves indicated that FIB-4, NFS, and the AST/ALT ratio were important predicators of all-cause mortality (AUC: 0.715, 0.707, and 0.715, respectively) and cardiovascular mortality (AUC: 0.658, 0.657, and 0.659, respectively) in heart failure patients. Random survival forests showed that FIB-4, AST/ALT ratio, and NFS emerged as important factors potentially influencing mortality of HF. Consistent associations were observed in subgroup analysis. Liver fibrosis scores (FIB-4, NFS, and AST/ALT ratio) were strongly linked to all-cause and cardiovascular mortality in heart failure patients.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 12","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70104","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142839834","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":"Longitudinal correlation of cerebrospinal fluid GFAP and the progression of cognition decline in different clinical subtypes of Parkinson's disease","authors":"Yumei Liu,&nbsp;Jing Wang,&nbsp;Fangbo Ning,&nbsp;Guojun Wang,&nbsp;Anmu Xie","doi":"10.1111/cts.70111","DOIUrl":"10.1111/cts.70111","url":null,"abstract":"<p>Glial fibrillary acidic protein (GFAP) is an intermediate filament protein expressed mainly in astrocytes of the central nervous system (CNS), a potential biomarker of cognitive decline in Parkinson's disease (PD). The central motor subtypes of PD include tremor-dominant (TD), postural instability and gait disorder (PIGD), and indeterminate subtypes, whose different course of disease requires the development of biomarkers that can predict progression based on motor subtypes. In this study, we aimed to assess the predictive value of cerebrospinal fluid (CSF) GFAP for PD motor subtypes in PD. Two hundred and sixteen PD patients were recruited in our study from the progression markers initiative. Patients were subgrouped into TD, PIGD, and indeterminate subtypes. Longitudinal relationships between baseline CSF GFAP and cognitive function and CSF biomarkers were assessed using linear mixed-effects models. Cox regression was used to detect cognitive progression in TD patients. The baseline and longitudinal increases in CSF GFAP were associated with a greater decline in episodic memory, CSF α-syn, and a greater increase of CSF NfL in TD and TD-male subtypes. Cox regression showed that higher baseline CSF GFAP levels were corrected with a higher risk of developing mild cognitive impairment (MCI) over a 4-year period in the PD with normal cognition (NC) group (adjusted HR = 1.607, 95% CI 1.907–2.354, <i>p</i> = 0.01). CSF GFAP might be a promising predictor of cognition decline in TD.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 12","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70111","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830298","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":"Interindividual variability in CYP3A-mediated venetoclax metabolism in vitro and in vivo in patients with chronic lymphocytic leukemia","authors":"Jonghwa Lee,&nbsp;Jessica L. Beers,&nbsp;Isabel Cheng,&nbsp;Vivian Truong,&nbsp;Zachary Brown,&nbsp;Benyam Muluneh,&nbsp;Catherine C. Coombs,&nbsp;Klarissa D. Jackson","doi":"10.1111/cts.70106","DOIUrl":"10.1111/cts.70106","url":null,"abstract":"<p>Venetoclax is a first-in-class orally administered B-cell lymphoma-2 inhibitor used to treat chronic lymphocytic leukemia (CLL). Venetoclax is primarily metabolized in the liver by cytochrome P450 (CYP) 3A4 to its major metabolite M27, via M5, and M2, M3, and M4 via oxidation. Although venetoclax is a breakthrough in CLL treatment, managing drug safety and toxicity remains a clinical challenge. The objectives of this study were to investigate how individual CYP3A activity and protein expression affect hepatic venetoclax metabolism in vitro and examine whether plasma 4β-hydroxycholesterol (4β-HC)/cholesterol ratio can predict venetoclax metabolism in vitro and in vivo. In human liver microsomes (<i>n</i> = 20) and primary human hepatocytes (<i>n</i> = 15), venetoclax metabolite formation varied widely between donors and significantly correlated with CYP3A activity (midazolam 1′-hydroxylation) and CYP3A4 protein expression. Venetoclax metabolite formation positively correlated with 4β-HC/cholesterol ratio in plasma samples from the matched non-infant donors (<i>n</i> = 14, ages 3–63 years). In an observational pilot study of real-world patients with CLL (<i>n</i> = 12, ages 56–84 years) treated with venetoclax, the plasma M3/venetoclax metabolic ratio negatively correlated with plasma 4β-HC/cholesterol ratio and positively correlated with patient age. Plasma 4β-HC/cholesterol ratio negatively correlated with patient age. Differences between the in vitro data, which showed a positive association between venetoclax metabolism, hepatic CYP3A markers, and plasma 4β-HC/cholesterol ratio, and the in vivo findings in patients with CLL could be due to age or other factors regulating plasma 4β-HC/cholesterol and/or venetoclax disposition. Future studies with larger sample sizes are needed to investigate age-related changes in venetoclax metabolism and plasma 4β-HC/cholesterol ratio.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 12","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11645475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824728","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":"Pharmacogenomic variation and sedation outcomes during early intensive care unit admission: A pragmatic study","authors":"Moataz E. Mohamed,&nbsp;Tam T. Nguyen,&nbsp;Jared Larson,&nbsp;Beatrice Schwake,&nbsp;Zachary Rivers,&nbsp;Greg Beilman,&nbsp;Debra J. Skaar,&nbsp;Pamala A. Jacobson","doi":"10.1111/cts.70107","DOIUrl":"10.1111/cts.70107","url":null,"abstract":"<p>Unpredicted responses to sedatives and analgesics are common in critically ill patients on mechanical ventilation (MV) and may be attributed to genetic variation. Our primary aim was to investigate the association between the pharmacogenomic (PGx) variation and sedation outcomes. The secondary aim was to capture intensive care unit (ICU) participants' perceptions of PGx. This was a prospective, observational PGx association study. Adult ICU patients receiving acute MV and sedatives/analgesics were enrolled. The number of altered PGx phenotypes in genes relevant to fentanyl, propofol, and midazolam (CYP2D6, CYP3A4/5, COMT, OPRM1, and CYP2B6) were tested with logistic regression for association with achieving ≥60% and ≥70% of time within Richmond Agitation-Sedation Scale (RASS) target range (0 to −2) in the first 24 and 48 h of MV. Participants' perceptions of PGx testing and satisfaction with the return of PGx results were collected. Participants (<i>n</i> = 78) had a median of 2 altered PGx phenotypes. Fentanyl and propofol combination was the most frequently administered regimen. There were non-significant associations of worse sedation outcomes with an increasing number of altered PGx phenotypes (i.e., adjusted odds ratio of achieving target RASS range = 0.46 to 0.96 for each altered phenotype increase at both 24 and 48 h). Individuals participating in the post-discharge survey had positive perceptions toward PGx. There were no associations between sedation outcomes and PGx variants in the studied 6 genes. Larger studies are needed to investigate the impact of these genes and to evaluate additional genes. ICU participants had positive attitudes and perceptions toward PGx.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 12","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11646075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824750","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":"Augmented intelligence in precision medicine: Transforming clinical decision-making with AI/ML and/or quantitative systems pharmacology models","authors":"Sai Phanindra Venkatapurapu,&nbsp;Megan Gibbs,&nbsp;Holly Kimko","doi":"10.1111/cts.70112","DOIUrl":"10.1111/cts.70112","url":null,"abstract":"&lt;p&gt;Effective disease management is becoming increasingly important given the chronic disease burden, which is projected to reach $47 trillion worldwide by 2030 (see Appendix S1). Lifestyle and drug adherence significantly impact chronic disease management, making the doctor-patient relationship a key driver of clinical outcomes. By effectively communicating with the patients and empowering them to focus on self-care, physicians can enable lifestyle changes and improve drug adherence, leading to better outcomes. Digital health is transforming the doctor-patient relationship,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; with patients becoming more proactive in their care, seeking to understand different treatment options, and participating in decision-making. This presents both a challenge and an opportunity—a challenge for the physicians to adapt to evolving patient expectations and an opportunity for physicians empowered with digital tools&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; to not only treat the disease effectively but also impact the overall patient journey. Artificial Intelligence, including machine learning algorithms (AI/ML), spans a broad set of digital tools with great potential to aid physicians in this transformation and revolutionize the care paradigm.&lt;/p&gt;&lt;p&gt;Physicians are increasingly employing AI/ML to improve diagnostics, determine disease prognoses, reduce workload, and support clinical decision-making.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Clinical decision-making involves diagnosing based on patient history, physical examination, and diagnostic tests, followed by determining the optimal treatment plan. Physicians integrate information and evidence from multiple sources to make certain decisions. Despite their expertise, physicians may err due to biases or blind spots, potentially leading to misdiagnosis, or poor treatment choices and suboptimal patient outcomes. AI/ML can help physicians cover their blind spots, eliminate potential biases, and enable data-driven decisions. AI/ML models could also serve as tools to engage patients in discussions about their disease state and update treatment plans to meet their health goals.&lt;/p&gt;&lt;p&gt;AI/ML-based personalization of treatment plans can be achieved by clinical decision support systems (CDSS&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;) powered by models predicting treatment outcomes and risk of complications, and by digital twins&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; mirroring actual patients. A digital twin emulates the behavior of a physical system, here a patient, using real-time data to update itself through its lifecycle. The primary differentiator for digital twin platforms from other predictive models is that the digital twins have a memory of the patient's history, evolve with them, and guide the patient toward their goal. In the following sections, we will explore how predictive models and digital twin platforms personalize treatment plans.&lt;/p&gt;&lt;p&gt;Predictive modeling has immense potential to transform treatment decision-making across various disease domai","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 12","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11645444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824722","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":"Pharmacokinetic study of polymyxin B in healthy subjects and subjects with renal insufficiency","authors":"Yu-Wei Fang,&nbsp;Chien-Hsien Huang,&nbsp;Tsrang-Neng Jang,&nbsp;Shih-Sen Lin,&nbsp;Jing-Tong Wang,&nbsp;Yen-Ta Huang,&nbsp;Ming Hsien Tsai","doi":"10.1111/cts.70110","DOIUrl":"10.1111/cts.70110","url":null,"abstract":"<p>Polymyxin B is a viable option for treating antibiotic-resistant infections; however, current data on its pharmacokinetics, particularly in patients with renal insufficiency, remain inconclusive and necessitates further investigation. To address this gap, we conducted an open-label, single-center, single-dose, parallel-group pharmacokinetic study. Participants received an intravenous dose of 0.75 mg/kg of polymyxin B and were categorized based on their renal function: those with normal function (creatinine clearance [CLcr] ≥ 90 mL/min), mild renal insufficiency (CLcr 60–89 mL/min), and end-stage kidney disease patients on intermittent hemodialysis (IHD) (CLcr &lt; 10 mL/min). The pharmacokinetic parameters assessed included the area under the curve (AUC), maximum concentration (<i>C</i>_max), clearance rate (CL), volume of distribution (Vz), and half-life (<i>t</i>_1/2). Results indicated that subjects with mild renal insufficiency exhibited pharmacokinetic profiles similar to healthy individuals. Nevertheless, in patients undergoing long-term IHD, we observed significant differences: the AUC was 58% higher, <i>C</i>_max was 29% lower, CL was 42% lower, Vz was 60% larger, and <i>t</i>_1/2 was extended by 10 h compared to healthy controls. Secondary outcomes revealed good tolerability of polymyxin B across all groups, with no serious adverse effects related to renal function. In summary, while kidney function may have a slight impact on the pharmacokinetic of polymyxin B, it does not compromise the drug's therapeutic effectiveness.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 12","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11645446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824119","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 evidence in the cloud: Tutorial on developing an end-to-end data and analytics pipeline using Amazon Web Services resources","authors":"Wes Anderson,&nbsp;Roopal Bhatnagar,&nbsp;Keith Scollick,&nbsp;Marco Schito,&nbsp;Ramona Walls,&nbsp;Jagdeep T. Podichetty","doi":"10.1111/cts.70078","DOIUrl":"10.1111/cts.70078","url":null,"abstract":"<p>In the rapidly evolving landscape of healthcare and drug development, the ability to efficiently collect, process, and analyze large volumes of real-world data (RWD) is critical for advancing drug development. This article provides a blueprint for establishing an end-to-end data and analytics pipeline in a cloud-based environment. The pipeline presented here includes four major components, including data ingestion, transformation, visualization, and analytics, each supported by a suite of Amazon Web Services (AWS) tools. The pipeline is exemplified through the CURE ID platform, a collaborative tool designed to capture and analyze real-world, off-label treatment administrations. By using services such as AWS Lambda, Amazon Relational Database Service (RDS), Amazon QuickSight, and Amazon SageMaker, the pipeline facilitates the ingestion of diverse data sources, the transformation of raw data into structured formats, the creation of interactive dashboards for data visualization, and the application of advanced machine learning models for data analytics. The described architecture not only supports the needs of the CURE ID platform, but also offers a scalable and adaptable framework that can be applied across various domains to enhance data-driven decision making beyond drug repurposing.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 12","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142820049","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}