An end-to-end workflow for nondestructive 3D pathology.

Recent advances in 3D pathology offer the ability to image orders of magnitude more tissue than conventional pathology methods while also providing a volumetric context that is not achievable with 2D tissue sections, and all without requiring destructive tissue sectioning. Generating high-quality 3D pathology datasets on a consistent basis, however, is not trivial and requires careful attention to a series of details during tissue preparation, imaging and initial data processing, as well as iterative optimization of the entire process. Here, we provide an end-to-end procedure covering all aspects of a 3D pathology workflow (using light-sheet microscopy as an illustrative imaging platform) with sufficient detail to perform well-controlled preclinical and clinical studies. Although 3D pathology is compatible with diverse staining protocols and computationally generated color palettes for visual analysis, this protocol focuses on the use of a fluorescent analog of hematoxylin and eosin, which remains the most common stain used for gold-standard pathological reports. We present our guidelines for a broad range of end users (e.g., biologists, clinical researchers and engineers) in a simple format. The end-to-end workflow requires 3-6 d to complete, bearing in mind that data analysis may take longer.

Aneurysm and Artery Dissection After Oral VEGFR-TKI Use in Adults With Cancer.

Importance: The association of tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR-TKIs) with aneurysm and artery dissection (AAD) has been frequently reported in spontaneous reporting databases. Objective: To investigate the risk and incidence of AAD occurrence in patients with cancer treated with oral VEGFR-TKIs, with capecitabine as an active comparator. Design, Setting, and Participants: This national, historical cohort study was conducted using national claims data from the National Health Insurance Service in Korea from 2007 to 2020, with a 1-year follow-up. Patients with cancer aged 40 years or older prescribed oral VEGFR-TKIs or capecitabine were enrolled. Data were analyzed from September 2022 through April 2023. Exposure: Oral VEGFR-TKIs (sorafenib, regorafenib, vandetanib, sunitinib, lenvatinib, axitinib, and pazopanib) or capecitabine as a comparator. Main Outcomes and Measures: Hazard ratios (HRs) were used to investigate the association between VEGFR-TKI use and AAD after propensity score matching. The primary outcome was AAD, and secondary outcomes were aortic aneurysm and dissection and AAD with rupture. Outcomes were defined using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnosis codes. Results: Among 127 710 patients with cancer eligible for the study (80 386 males [62.9%]; mean [SD] age, 62.6 [10.9] years), 37 308 patients received VEGFR-TKIs and 90 402 patients received capecitabine. Among 27 535 matched patients receiving VEGFR-TKIs, the incidence of AAD within 1 year of treatment initiation was 6.0 per 1000 person-years. The median (IQR) time to AAD onset in the matched AAD group was 114 (67-257) days after treatment initiation, with the highest incidence observed during the first 3 months (45 incidents vs 31, 17, and 16 incidents during 3- to 6-month, 6- to 9-month, and 9- to 12-month periods, respectively). Cox regression modeling showed that the risk of AAD occurrence was significantly higher among patients prescribed VEGFR-TKIs than those receiving capecitabine (HR, 1.48; 95% CI, 1.08-2.02); similar results were obtained among females (HR, 2.08; 95% CI, 1.26-3.42), older adults (aged ≥65 years; HR, 1.42; 95% CI, 1.01-1.99), and patients with dyslipidemia (HR, 1.58; 95% CI, 1.11-2.24). Conclusions and Relevance: In this study, the use of oral VEGFR-TKIs was associated with an increased risk of AAD occurrence. These findings elucidate vascular toxic effects and may provide a substantial reference for reducing the socioeconomic burden of adverse events associated with VEGFR-TKI use.

Comparison of Humoral Response between Third and Fourth Doses of COVID-19 Vaccine in Hemodialysis Patients.

Dialysis patients are more likely to die or become hospitalized from coronavirus disease 2019 (COVID-19). Currently, only a few studies have evaluated the efficacy of a fourth booster vaccination in hemodialysis (HD) patients and there is not enough evidence to recommend for or against a fourth booster vaccination. This study compared the humoral response and disease severity of patients on HD who received either three or four doses of COVID-19 vaccine. A total of 88 patients were enrolled. Humoral response to vaccination was measured by quantifying immunoglobulin G levels against the receptor binding domain of SARS-CoV-2 (anti-RBD IgG) at five different times and plaque reduction neutralization tests (PRNT) at two different times after vaccination over a period of 18 months. Antibody levels were measured at approximately two-month intervals after the first and second dose, then four months after the third dose, and then one to six months after the fourth dose of vaccine. PRNT was performed two months after the second and four months after the third dose of vaccine. We classified patients into four groups according to the number of vaccine doses and presence of COVID-19 infection. Severe infection was defined as hospital admission for greater than or equal to two weeks or death. There was no difference in antibody levels between naïve and infected patients except after a fourth vaccination, which was effective for increasing antibodies in infection-naïve patients. Age, sex, body mass index (BMI), dialysis vintage, and presence of diabetes mellitus (DM) did not show a significant correlation with antibody levels. Four patients who experienced severe COVID-19 disease tended to have lower antibody levels prior to infection. A fourth dose of SARS-CoV-2 vaccine significantly elevated antibodies in infection-naïve HD patients and may be beneficial for HD patients who have not been previously infected with SARS-CoV-2 for protection against severe infection.

An end-to-end workflow for non-destructive 3D pathology.

Recent advances in 3D pathology offer the ability to image orders-of-magnitude more tissue than conventional pathology while providing a volumetric context that is lacking with 2D tissue sections, all without requiring destructive tissue sectioning. Generating high-quality 3D pathology datasets on a consistent basis is non-trivial, requiring careful attention to many details regarding tissue preparation, imaging, and data/image processing in an iterative process. Here we provide an end-to-end protocol covering all aspects of a 3D pathology workflow (using light-sheet microscopy as an illustrative imaging platform) with sufficient detail to perform well-controlled preclinical and clinical studies. While 3D pathology is compatible with diverse staining protocols and computationally generated color palettes for visual analysis, this protocol will focus on a fluorescent analog of hematoxylin and eosin (H&E), which remains the most common stain for gold-standard diagnostic determinations. We present our guidelines for a broad range of end-users (e.g., biologists, clinical researchers, and engineers) in a simple tutorial format.

Pre-Attentional Effects on Global Precedence Processing in Children with Autism Spectrum Disorder and Those with Typical Development on a Tablet-Based Modified Navon's Paradigm Task.

This study aimed to characterize the pre-attentional effects on global precedence processing in children with autism spectrum disorder (ASD) and those with typical development (TD). A sample of 17 participants, comprising eight children with ASD and nine TD children, were recruited for the study. A tablet-based assessment utilizing a global and local visual processing paradigm task was developed to investigate the participant's abilities. The task consisted of verbal instructions to locate and touch either a global or local figure, presented in five conditions: neutral, congruent, and incongruent. The percentage of correct answers and reaction time (RT) for each task were measured and analyzed statistically. Results revealed that children with ASD exhibited statistically significant differences in both the percentage of correct scores and RT among various conditions, while TD children displayed differences in RT but not in the percentage of correct answers. These findings suggest that conflicting processes affect both behavioral and cognitive processes in children with ASD, and that cognitive effort is still involved for children with TD, but does not affect behavioral processes. In children with ASD, the RT was the shortest in the congruent (report local figure) condition; in children with TD, the RT was the shortest in the congruent (report global figure) condition. This implies that children with TD exhibit a pre-attentive effect on global precedence processing, while children with ASD do not. These visual-processing-function characteristics may aid in screening for visual perception problems in children with ASD.

Predictive Factors and Clinical Impacts of Delayed Isolation of Tuberculosis during Hospital Admission.

Delayed isolation of tuberculosis (TB) can cause unexpected exposure of healthcare workers (HCWs). This study identified the predictive factors and clinical impact of delayed isolation. We retrospectively reviewed the electronic medical records of index patients and HCWs who underwent contact investigation after TB exposure during hospitalization at the National Medical Center, between January 2018 and July 2021. Among the 25 index patients, 23 (92.0%) were diagnosed with TB based on the molecular assay, and 18 (72.0%) had a negative acid-fast bacilli smear. Sixteen (64.0%) patients were hospitalized via the emergency room, and 18 (72.0%) were admitted to a non-pulmonology/infectious disease department. According to the patterns of delayed isolation, patients were classified into five categories. Among 157 close-contact events in 125 HCWs, 75 (47.8%) occurred in Category A. Twenty-five (20%) HCWs had multiple TB exposures (n = 57 events), of whom 37 (64.9%) belonged to Category A (missed during emergency situations). After contact tracing, latent TB infection was diagnosed in one (1.2%) HCW in Category A, who was exposed during intubation. Delayed isolation and TB exposure mostly occurred during pre-admission in emergency situations. Effective TB screening and infection control are necessary to protect HCWs, especially those who routinely contact new patients in high-risk departments.

Individual Differences in Categorical Judgment of L2 Stops: A Link to Proficiency and Acoustic Cue-Weighting.

This study investigated individual differences in Korean adult learners' categorical perception of L2 English stops with an aim to explore the relationship of gradient categorizations to perceptual sensitivity to acoustic cues and L2 proficiency. Korean young adult L2 learners of English (N = 49) participated in two speech perception tasks (visual analog scaling and forced-choice identification) in which they listened to English voiced and voiceless stops and Korean lax and aspirated stops with Voice Onset Time (VOT) and F0 manipulated to form a continuum. It was found that in both L1 and L2 stop perception, listeners' gradient category judgment was associated with greater reliance on language-specific redundant cues (i.e., F0 in L2 English and VOT in L1 Korean) and that in the perception of L2 stops, categorical listeners who tended to be less sensitive to F0 were the ones with a higher level of L2 English proficiency. The results suggest that the categorical manner of judging L2 stops reflects learners' better knowledge of L2-specific acoustic cue-weightings, based on which less relevant acoustic information is effectively suppressed.

Innovations in Remote Teaching of Engineering Design Teams.

The University of Washington's Engineering Innovation in Health program is a yearlong engineering design course sequence where senior undergraduate and graduate engineering students across different disciplines work in teams with health professionals to address their unmet needs. With the onset of the COVID-19 pandemic, these team- and project-based courses shifted from an in-person to remote course environment. Here, we share innovative teaching strategies for a team-based, remote course environment. We show how this shift affected productivity by comparing survey results from before (in person) and during (remote) the pandemic. Preliminary results show that overall project outcomes and productivity were as high or, in some cases, higher during the pandemic than prior to the pandemic. These findings suggest that the innovative remote teaching strategies implemented by the teaching team provided effective options in the absence of certain hands-on experiences that are considered critical to engineering capstone design courses. A discussion on these teaching strategies in the context beyond the pandemic are considered in the discussion.

Dose Optimization of Meropenem in Patients on Veno-Arterial Extracorporeal Membrane Oxygenation in Critically Ill Cardiac Patients: Pharmacokinetic/Pharmacodynamic Modeling.

Background: Our objective was to determine an optimal dosage regimen of meropenem in patients receiving veno-arterial extracorporeal membrane oxygenation (V-A ECMO) by developing a pharmacokinetic/pharmacodynamic (PK/PD) model. Methods: This was a prospective cohort study. Blood samples were collected during ECMO (ECMO-ON) and after ECMO (ECMO-OFF). The population pharmacokinetic model was developed using nonlinear mixed-effects modeling. A Monte Carlo simulation was used (n = 10,000) to assess the probability of target attainment. Results: Thirteen adult patients on ECMO receiving meropenem were included. Meropenem pharmacokinetics was best fitted by a two-compartment model. The final pharmacokinetic model was: CL (L/h) = 3.79 × 0.44CRRT, central volume of distribution (L) = 2.4, peripheral volume of distribution (L) = 8.56, and intercompartmental clearance (L/h) = 21.3. According to the simulation results, if more aggressive treatment is needed (100% fT > MIC target), dose increment or extended infusion is recommended. Conclusions: We established a population pharmacokinetic model for meropenem in patients receiving V-A ECMO and revealed that it is not necessary to adjust the dosage depending on V-A ECMO. Instead, more aggressive treatment is needed than that of standard treatment, and higher dosage is required without continuous renal replacement therapy (CRRT). Also, extended infusion could lead to better target attainment, and we could provide updated nomograms of the meropenem dosage regimen.

Performance evaluation of biodegradable polymer sirolimus and ascorbic acid eluting stent systems.

The purpose of this study was to evaluate the performance of biodegradable polymer sirolimus and ascorbic acid eluting stent systems with four commercially available drug-eluting stents (DES). We investigated the characterization of mechanical properties by dimension, foreshortening, recoil, radial force, crossing profile, folding shape, trackability, and dislodgement force. Additionally, we identify the safety and efficacy evaluation through registry experiments. Each foreshortening and recoil of D + Storm® DES is 1.3 and 3.70%, which has better performance than other products. A post-marketing clinical study to evaluate the performance and safety of D + Storm® DES is ongoing in real-world clinical settings. Two hundred one patients were enrolled in this study and have now completed follow-up for up to 1 month. No major adverse cardiovascular event (MACE) occurred in any subjects, confirming the safety of D + Storm® DES in the clinical setting. An additional approximately 100 subjects will be enrolled in the study and the final safety profile will be assessed in 300 patients. In conclusion, this study reported the objective evaluation of DES performance and compared the mechanical responses of four types of DES available in the market. There is little difference between the four cardiovascular stents in terms of mechanical features, and it can help choose the most suitable stent in a specific clinical situation if those features are understood. Graphical abstract.

Sodium-Glucose Cotransporter-2 Inhibitors Could Help Delay Renal Impairment in Patients with Type 2 Diabetes: A Real-World Clinical Setting.

This study compared the renoprotective effects of sodium−glucose cotransporter-2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes mellitus (T2DM). We performed a retrospective cohort study using electronic medical records of patients with T2DM. The primary outcome was the first occurrence of an estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2 after the index date. We analyzed changes in repeatedly measured laboratory data, such as eGFR and serum uric acid (SUA). We included 2396 patients (1198 patients in each group) in the present study. The rate of renal events was significantly lower in the SGLT2 inhibitors group than that in the DPP-4 inhibitors group (hazard ratio, 0.46; 95% CI, 0.29 to 0.72; p = 0.0007). The annual mean change in the eGFR was significantly smaller in the SGLT2 inhibitors group than that in the DPP-4 inhibitors group, with a between-group difference of 0.86 ± 0.18 mL/min/1.73 m2 per year (95% CI, 0.49 to 1.23; p < 0.0001). Moreover, the mean change in SUA was lower in the SGLT2 inhibitors group. Considering the lower incidence of renal impairment, the slower decline in eGFR, and reduced SUA, SGLT2 inhibitors could help delay renal impairment in patients with T2DM.

Severe Acute Respiratory Syndrome Coronavirus 2 Antibody Response After Heterologous Immunizations With ChAdOx1/BNT162b2 in End-Stage Renal Disease Patients on Hemodialysis.

The Korean government decided to schedule heterologous vaccinations on dialysis patients for early achievement of immunization against Coronavirus disease 2019(COVID-19). However, the effects of heterologous immunizations in hemodialysis (HD) patients are unclear. One hundred (HD) patients from Gangdong Kyung Hee University Hospital and Kyung Hee Medical Center and 100 hospital workers from Gangdong Kyung Hee University Hospital were enrolled in this study. The HD patients received the mixing schedule of ChAdOx1/BNT162b2 vaccinations at 10-week intervals, while hospital workers received two doses of ChAdOx1 vaccines at 12-week intervals. Serum IgG to a receptor-binding domain (RBD) of the S1 subunit of the spike protein of SARS-CoV-2 was measured 1 month after the first dose, 2 months and 4 months after the second dose. The median [interquartile range] anti-RBD IgG was 82.1[34.5, 176.6] AU/ml in HD patients and 197.1[124.0, 346.0] AU/ml in hospital workers (P < 0.001) after the first dose. The percentage of positive responses (IgG > 50 AU/ml) was 65.0% and 96.0% among the both group, respectively (P < 0.001). The anti-RBD IgG levels increased significantly by 2528.8 [1327.6, 5795.1] AU/ml with a 100.0% positive response rate in HD patients 2 months after the second dose, which was higher than those in hospital workers 981.4[581.5, 1891.4] AU/ml (P < 0.001). Moreover, anti-RBD IgG remains constantly high, and positive response remains 100% in HD patients 4 months after the second dose. This study suggests that heterologous vaccinations with ChAdOx1/BNT162b2 can be an alternative solution on HD patients for early and strong induction of humoral response.

Successful Treatment of Thrombotic Thrombocytopenic Purpura in a Patient with Mixed Connective Tissue Disease.

BACKGROUND: Although the survival rate of thrombocytopenic purpura (TTP) has increased significantly due to the introduction of therapeutic plasma exchange (TPE). TTP in patients with mixed connective tissue disease (MCTD) has a very high mortality rate and a very small number of reported cases. In TTP, daily TPE is administered until a treatment response is achieved; however, in practice, TPE is often not performed for such long durations. METHODS: We report a case of TTP with MCTD in a female patient. She had developed thrombocytopenia and hemolytic anemia 9 months after delivery. She had status epilepticus and lapsed into a coma. RESULTS: The patient was successfully treated with extended sessions of TPE with corticosteroids and rituximab. CONCLUSIONS: Although the TTP regimen has not yet been established and remains controversial, this report demonstrates the importance of continuing daily TPE until achieving a treatment response.

Prostate Cancer Risk Stratification via Nondestructive 3D Pathology with Deep Learning-Assisted Gland Analysis.

Prostate cancer treatment planning is largely dependent upon examination of core-needle biopsies. The microscopic architecture of the prostate glands forms the basis for prognostic grading by pathologists. Interpretation of these convoluted three-dimensional (3D) glandular structures via visual inspection of a limited number of two-dimensional (2D) histology sections is often unreliable, which contributes to the under- and overtreatment of patients. To improve risk assessment and treatment decisions, we have developed a workflow for nondestructive 3D pathology and computational analysis of whole prostate biopsies labeled with a rapid and inexpensive fluorescent analogue of standard hematoxylin and eosin (H&E) staining. This analysis is based on interpretable glandular features and is facilitated by the development of image translation-assisted segmentation in 3D (ITAS3D). ITAS3D is a generalizable deep learning-based strategy that enables tissue microstructures to be volumetrically segmented in an annotation-free and objective (biomarker-based) manner without requiring immunolabeling. As a preliminary demonstration of the translational value of a computational 3D versus a computational 2D pathology approach, we imaged 300 ex vivo biopsies extracted from 50 archived radical prostatectomy specimens, of which, 118 biopsies contained cancer. The 3D glandular features in cancer biopsies were superior to corresponding 2D features for risk stratification of patients with low- to intermediate-risk prostate cancer based on their clinical biochemical recurrence outcomes. The results of this study support the use of computational 3D pathology for guiding the clinical management of prostate cancer. SIGNIFICANCE: An end-to-end pipeline for deep learning-assisted computational 3D histology analysis of whole prostate biopsies shows that nondestructive 3D pathology has the potential to enable superior prognostic stratification of patients with prostate cancer.

Population Pharmacokinetics and Dosing Optimization of Piperacillin-Tazobactam in Critically Ill Patients on Extracorporeal Membrane Oxygenation and the Influence of Concomitant Renal Replacement Therapy.

Critical illness and extracorporeal circulation, such as extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT), may alter the pharmacokinetics of piperacillin-tazobactam. We aimed to develop a population pharmacokinetic model of piperacillin-tazobactam in critically ill patients during ECMO or CRRT and investigate the optimal dosage regimen needed to achieve ≥90% of patients attaining the piperacillin pharmacodynamic target of 100% of dosage time above MIC of 16 mg/L. This prospective observational study included 26 ECMO patients, of which 13 patients received continuous venovenous hemodiafiltration (CVVHDF). A population pharmacokinetic model was developed using nonlinear mixed-effects models, and Monte Carlo simulations were performed to evaluate creatinine clearance (CrCL) and infusion method in relation to the probability of target attainment (PTA) in four patient groups according to combination of ECMO and CVVHDF. A total of 244 plasma samples were collected. In a two-compartment model, clearance decreased during ECMO and CVVHDF contributed to an increase in the volume of distribution. The range of PTA reduction as CrCL increased was greater in the order of intermittent bolus, extended infusion, and continuous infusion method. Continuous infusion should be considered in critically ill patients with CrCL of ≥60 mL/min, and at least 12, 16, and 20 g/day was required for CrCL of <40, 40 to 60, and 60 to 90 mL/min, respectively, regardless of ECMO or CVVHDF. In patients with CrCL of ≥90 mL/min, even a continuous infusion of 24 g/day was insufficient to achieve adequate PTA. Therefore, further research on permissible high continuous infusion dose focused on the risk of toxicity is required. (This trial has been registered at ClinicalTrials.gov under registration no. NCT02581280, December 1, 2014.) IMPORTANCE To the best of our knowledge, this is the first large prospective pharmacokinetic/pharmacodynamic (PK/PD) study of piperacillin-tazobactam in ECMO patients. We used piperacillin-tazobactam plasma concentration data from four different cases (concomitant use of ECMO and CVVHDF, receiving ECMO only, weaned from ECMO and receiving CVVHDF, and weaned from ECMO and not receiving CVVHDF) to provide preliminary insights into the incremental effects of critical illness, ECMO, and CVVHDF on PK. Our analysis revealed that volume of distribution increased in patients on CVVHDF and clearance decreased during ECMO and as creatinine clearance was reduced. When targeting 100% fT>MIC (16 mg/L, clinical breakpoint for Pseudomonas aeruginosa), continuous infusions would have achieved the highest percentage of target attainment compared to intermittent bolus or extended infusion if the total daily dose was the same. Continuous infusion should be considered in critically ill patients with creatinine clearance of ≥60 mL/min, regardless of ECMO or CVVHDF.

Implementation and evaluation of team science training for interdisciplinary teams in an engineering design program.

INTRODUCTION: Interdisciplinary academic teams perform better when competent in teamwork; however, there is a lack of best practices of how to introduce and facilitate the development of effective learning and functioning within these teams in academic environments. METHODS: To close this gap, we tailored, implemented, and evaluated team science training in the year-long Engineering Innovation in Health (EIH) program at the University of Washington (UW), a project-based course in which engineering students across several disciplines partner with health professionals to develop technical solutions to clinical and translational health challenges. EIH faculty from the UW College of Engineering and the Institute of Translational Health Sciences' (ITHS) Team Science Core codeveloped and delivered team science training sessions and evaluated their impact with biannual surveys. A student cohort was surveyed prior to the implementation of the team science trainings, which served as a baseline. RESULTS: Survey responses were compared within and between both cohorts (approximately 55 students each Fall Quarter and 30 students each Spring Quarter). Statistically significant improvements in measures of self-efficacy and interpersonal team climate (i.e., psychological safety) were observed within and between teams. CONCLUSIONS: Tailored team science training provided to student-professional teams resulted in measurable improvements in self-efficacy and interpersonal climate both of which are crucial for teamwork and intellectual risk taking. Future research is needed to determine long-term impacts of course participation on individual and team outcomes (e.g., patents, start-ups). Additionally, adaptability of this model to clinical and translational research teams in alternate formats and settings should be tested.

Validation of the Combined Biomarker for Prediction of Response to Checkpoint Inhibitor in Patients with Advanced Cancer.

Although immune checkpoint inhibitors can induce durable responses in patients with multiple types of advanced cancer, only a limited number of patients have a known reliable biomarker. This study aimed to validate the IMmunotherapy Against GastrIc Cancer (IMAGiC) model, which was developed based on a previous study of four-gene and PD-L1 level, to predict immunotherapy response. We developed a clinical assay for formalin-fixed paraffin-embedded samples using quantitative real-time polymerase chain reaction to measure the expression level of the previously published four-gene set. The predictive performance was validated in a cohort of 89 patients with several advanced tumor types. The IMAGiC score was derived from tumor samples of 89 patients consisting of eight cancer types, and 73 out of 89 patients available for clinical response were analyzed with clinicopathological factors. The IMAGiC group (responder vs. non-responder) was determined with a specific value of the IMAGiC score as a cutoff, which was set by log-rank statistics for progression-free survival (PFS) divided the patients into 56 (76.7%) non-responders and 17 (23.3%) responders. Clinical responders (complete response/partial response) were higher in the IMAGiC responder group than in the non-responder group (70.6 vs. 21.4%). The median PFS of the IMAGiC responder group and non-responder was 20.8 months (95% CI 9.1-not reached) and 6.7 months (95% CI 4.9-11.1, p = 0.007), respectively. Among the 17 IMAGiC responders, 11 patients had tumor mutation burden-low and microsatellite-stable tumors. This study validated a predictive model based on a four-gene expression signature. Along with conventional biomarkers, our model could be useful for predicting response to immunotherapy in patients with advanced cancer.

Population pharmacokinetics and dose optimization of vancomycin in neonates.

The pharmacokinetics of vancomycin vary among neonates, and we aimed to conduct population pharmacokinetic analysis to determine the optimal dosage of vancomycin in Korean neonates. From a retrospective chart review, neonates treated with vancomycin from 2008 to 2017 in a neonatal intensive care unit (NICU) were included. Vancomycin concentrations were collected based on therapeutic drug monitoring, and other patient characteristics were gathered through electronic medical records. We applied nonlinear mixed-effect modeling to build the population pharmacokinetic model. One- and two-compartment models with first-order elimination were evaluated as potential structural pharmacokinetic models. Allometric and isometric scaling was applied to standardize pharmacokinetic parameters for clearance and volume of distribution, respectively, using fixed powers (0.75 and 1, respectively, for clearance and volume). The predictive performance of the final model was developed, and dosing strategies were explored using Monte Carlo simulations with AUC0-24 targets 400-600. The patient cohort included 207 neonates, and 900 vancomycin concentrations were analyzed. Only 37.4% of the analyzed concentrations were within trough concentrations 5-15 µg/mL. A one-compartment model with first-order elimination best described the vancomycin pharmacokinetics in neonates. Postmenstrual age (PMA) and creatinine clearance (CLcr) affected the clearance of vancomycin, and model evaluation confirmed the robustness of the final model. Population pharmacokinetic modeling and dose optimization of vancomycin in Korean neonates showed that vancomycin clearance was related to PMA and CLcr, as well as body weight. A higher dosage regimen than the typical recommendation is suggested.

Dose Optimization of Cefpirome Based on Population Pharmacokinetics and Target Attainment during Extracorporeal Membrane Oxygenation.

To obtain the optimal dosage regimen in patients receiving extracorporeal membrane oxygenation (ECMO), we developed a population pharmacokinetics model for cefpirome and performed pharmacodynamic analyses. This prospective study included 15 patients treated with cefpirome during ECMO. Blood samples were collected during ECMO (ECMO-ON) and after ECMO (ECMO-OFF) at predose and 0.5 to 1, 2 to 3, 4 to 6, 8 to 10, and 12 h after cefpirome administration. The population pharmacokinetic model was developed using nonlinear mixed effects modeling and stepwise covariate modeling. Monte Carlo simulation was used to assess the probability of target attainment (PTA) and cumulative fraction of response (CFR) according to the MIC distribution. Cefpirome pharmacokinetics were best described by a two-compartment model. Covariate analysis indicated that serum creatinine concentration (SCr) was negatively correlated with clearance, and the presence of ECMO increased clearance and the central volume of distribution. The simulations showed that patients with low SCr during ECMO-ON had lower PTA than patients with high SCr during ECMO-OFF; so, a higher dosage of cefpirome was required. Cefpirome of 2 g every 8 h for intravenous bolus injection or 2 g every 12 h for extended infusion over 4 h was recommended with normal kidney function receiving ECMO. We established a population pharmacokinetic model for cefpirome in patients with ECMO, and appropriate cefpirome dosage regimens were recommended. The impact of ECMO could be due to the change in patient status on consideration of the small population and uncertainty in covariate relationships. Dose optimization of cefpirome may improve treatment success and survival in patients receiving ECMO. (This study has been registered at ClinicalTrials.gov under identifier NCT02581280.).