25th-75th Percentile Research Articles

207. Ex vivo Assessment of Cefepime (FEP) Clearance during Continuous Renal Replacement Therapy (CRRT) and Clinical Validation of Optimized Dosing Regimens

Abstract Background Optimal antibiotic dosing in critically ill patients receiving CRRT is crucial. Drug clearance (CL) can be affected by multiple factors such as CRRT mode, effluent rate (ER) or filter type. We investigated FEP transmembrane CL (CLTM) in an ex vivo CRRT model to inform optimal dosing regimens and validate these regimens by re-simulation in a clinical cohort of CRRT patients. Methods CLTM was determined ex vivo in hemofiltration and hemodialysis modes with M100 and HF1400 filters. Bovine blood spiked with FEP was sampled from pre-, post-filter and effluent fluids at 10, 30, and 60 minutes in duplicate runs at ER of 1, 2 and 3 L/h. CLTM was calculated via sieving (SC) and saturation coefficients (SA). A multiple linear regression was performed to describe CLTM as a function of ER, filter, and mode. Monte Carlo Simulations (MCS; n=1000) using the equation CL= non-renal CL + CLTM and distribution parameters from a published population pharmacokinetic (popPK) model were executed for ascending ER (1-5 L/h). The resulting FEP regimens were selected by probability of target attainment (PTA) for 70%fT > MIC (MIC = 8mg/L CLSI susceptible breakpoint) and mean AUC within the 25th-75th percentile of a non-CRRT cohort. Selected regimens were validated by re-simulating fT > MIC and AUC using popPK defined Bayesian parameters in Pmetrics for R from 10 CRRT patients receiving FEP in clinical practice. Results Mean (SD) ex vivo SC/SA were 1.01 (0.08). ER was the main predictor (p< 0.001) for CLTM (CLTM= 0.139+0.841*ER) with no effect from mode or filter type. MCS of FEP 1g and 2g q8h provided 100% PTA at 8 mg/L with AUCs similar to the non-CRRT comparator for ER of 1-2.4 and 2.5-5 L/h respectively. Mean (SD) popPK parameter estimates of the validation cohort were CL, 3.8 (1.1); Vc, 17.3 (15.3) L; k12, 5.0 (3.1) h-1; and k21, 6.4 (7.6) h-1. Selected regimens tested in the validation cohort demonstrated good performance with the algorithm (Figure 1). Conclusion These are the first data to translate the findings of ex vivo CRRT CLTM in a dosing algorithm based on CRRT ER to achievable exposure in patients receiving FEP. For CRRT ER of 1-2.4 L/h and 2.5-5 L/h FEP 1g and 2g 8h as 0.5h infusions achieve 70% fT > MIC, respectively, while retaining AUC in range with safe exposures in non-CRRT patients. Disclosures Christina Konig, PhD, Gilead Inc.: Honoraria|Pfizer Inc.: Honoraria|Shionogi Inc.: Honoraria David P. Nicolau, PharmD, CARB-X: Grant/Research Support|Innoviva: Grant/Research Support|Innoviva: Honoraria|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Shionogi: Honoraria|Venatorx: Grant/Research Support Joseph L. Kuti, PharmD, Abbvie: Advisor/Consultant|bioMerieux: Grant/Research Support|Merck: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi Inc: Advisor/Consultant|Shionogi Inc: Grant/Research Support|Shionogi Inc: Honoraria|Venatorx: Grant/Research Support

Determining chlorophyll-a thresholds for characterizing algal bloom conditions: An ocean colour remote sensing approach.

The Indian coast has been experiencing an increase in algal bloom events over the decades. Owing to the regional and seasonal dynamics of algal biomass (proxy: chlorophyll-a, hereafter chl-a), a multitude of thresholds of chl-a has been defined for different parts of the global seas to determine algal bloom conditions. However, no such clear definition is given for the Indian coastal waters. The current study defined chl-a thresholds to demarcate algal bloom conditions for the coastal waters of India, accounting for the variability at hotspots (in accordance with reported events: secondary data), causative species, and satellite-retrieved long-term trends. The secondary data analysis identified nine bloom hotspots along the east and west coasts of India. Among the blooms, diatoms prevailed the most, compared to dinoflagellates and cyanobacteria. Quartile analysis was employed on satellite-retrieved daily chl-a anomaly to determine specific bloom thresholds. Consequently, these quartile thresholds were utilized to classify various bloom phases, such as the 25th percentile (Likely to Bloom), 50th percentile (Bloom), 75th percentile (Intense Bloom), and 90th percentile (Extreme Bloom). As per this percentile-based classification, the 'Bloom' category corresponds to a chl-a range of 0.89-0.94mgm-3 and 0.76-2.87mgm-3, for the identified hotspots along the east and west coasts, respectively. Likewise, during the 'Intense Bloom' phase, the chl-a concentration exceeds 0.99-1.47 and 1.12-4.46mgm-3 at the hotspots along the east and west coasts, respectively. The seasonality of blooms revealed an increasing trend during the pre-southwest monsoon period on the central east coast of India. On the west coast, significant upwelling during the southwest monsoon period has been substantiated to be conducive for blooms. This study provides an avenue towards utilization of the threshold criteria in detecting different phases of bloom using satellite data in coastal waters where field observations are limited due to various factors.

Association of serum vitamin D level and live birth rate in women undergoing frozen embryo transfer-a retrospective cohort study.

To assess the association of serum vitamin D level and the live birth rate in women undergoing frozen embryo transfer (FET). This is a retrospective cohort study involving 1489 infertile women who had frozen embryo transfer at two tertiary reproductive medicine centres from 2019 to 2021. Only the first frozen embryo transfer was included for women who had repeated transfers during the period. Archived serum samples taken at LH surge or before the start of progestogens for FET were analysed for 25(OH)D levels using mass spectrometry. The main outcome measure was the live birth rate. Vitamin D deficiency was defined as serum 25(OH)D < 50nmol/l (< 20ng/ml) based on the Endocrine Society Clinical Practice guidelines. The median age was 36 (25th-75th percentile 34-38) years. 37.7% (561/1489) women had cleavage stage embryo transfer and 62.3% (928/1489) women had blastocyst transfer. When analysing the results based on the threshold in the Endocrine Society guideline of 50 nmol/l (20 ng/ml) for vitamin D deficiency, there were no statistically significant differences in the live birth rate in the vitamin D deficient and non-deficient groups [151/489 (30.9%) vs 341/998 (34.2%), OR 0.861, 95% CI 0.683-1.086 P = 0.205]. There were no statistically significant differences in the pregnancy rates, ongoing pregnancy rates, and miscarriage rates between the two groups. Serum vitamin D is not associated with birth rate in women undergoing FET.

Exploring offshore particle motion soundscapes.

Fishes and aquatic invertebrates utilize acoustic particle motion for hearing, and some additionally detect sound pressure. Yet, few underwater soundscapes studies report particle motion, which is often assumed to scale predictably with pressure in offshore habitats. This relationship does not always exist for low frequencies or near reflective boundaries. This study compared particle motion and sound pressure from hydrophone arrays near the seafloor at six sites on the U.S. Mid and South Atlantic Outer Continental Shelf and assessed predictability of sound pressure and particle motion levels by environmental indicators (wind, vessels, temperature, currents). Unidentified fish sounds (100-750 Hz) had particle motion magnitudes 4.8-12.6 dB greater than those predicted from single hydrophone (pressure) measurements, indicating that these sounds were received in the near field. Excess particle motion attributed to hydrodynamic flow noise (<100 Hz) was also present at all sites. Most sounds (25th-75th percentile) from other sources received in the far field (vessels, mammals), had measured particle motion within ±3 dB of that predicted from single hydrophone measurements. The results emphasize for offshore soundscapes the importance of particle motion measurement for short-time (1 min) and near field signals, and that pressure measurement is sufficient for long-term (1 year) predictive modeling.

Health literacy in pediatric thrombosis: a landscape analysis.

Health literacy can influence self-management, leading to improved health outcomes in pediatric patients with venous thrombotic events (VTEs). To assess general health literacy in adolescents and parents/caregivers of children diagnosed with VTE, and their perception and satisfaction with overall thrombosis-related knowledge, thrombosis knowledge compared to that of other conditions, and beliefs regarding thrombosis knowledge importance. Patients aged 10 to 18 years with VTE history and parents/caregivers of patients aged 0 to 18 years with VTE attending clinic were recruited in this cross-sectional study. Health literacy was measured using the Rapid Estimate of Literacy in Medicine Short Forms (Adolescent and Adult), the Health Literacy Assessment Scale for Adolescents, and the e-Health Literacy Scale. Self-reported perception, satisfaction, comparative knowledge, and beliefs regarding thrombosis knowledge were assessed using researcher-generated questions. In total, 101 participants (50 adolescents, 51 parents/caregivers) were recruited at a median of 27 months (25th-75th percentile; 12-62 months) post-VTE diagnosis. Overall, 74% of adolescents and 59% of parents/caregivers had ≥1 measure indicating low general health literacy. Only half the participants thought their thrombosis knowledge was similar to that of other diseases. Satisfaction with thrombosis-related knowledge was 44%; 96% agreed that learning about thrombosis was important. Adolescents reported higher satisfaction with their knowledge than parents/caregivers, but satisfaction was not associated with demonstrated thrombosis knowledge. Most participants had low general health literacy levels, and more than half were not satisfied with their thrombosis-related knowledge. Adolescents tended to overestimate their knowledge. Effective strategies to support health literacy in this population are needed.

Harmonizing multisite neonatal diffusion-weighted brain MRI data for developmental neuroscience.

Large diffusion-weighted brain MRI (dMRI) studies in neonates are crucial for developmental neuroscience. Our aim was to investigate the utility of ComBat, an empirical Bayes tool for multisite harmonization, in removing site effects from white matter (WM) dMRI measures in healthy infants born at 37 gestational weeks+ 0 days-42 weeks+ 6 days from the Theirworld Edinburgh Birth Cohort (n = 86) and Developing Human Connectome Project (n = 287). Skeletonized fractional anisotropy (FA), mean, axial and radial diffusivity (MD, AD, RD) maps were harmonized. Differences between voxel-wise metrics, skeleton means and histogram widths (5th-95th percentile) were assessed before and after harmonization, as well as variance associated with gestational age at birth and scan. Before harmonization, large cohort differences were observed. Harmonization removed all voxel-wise differences from MD maps and all metric means and histogram widths, however small voxel-wise differences (<1.5 % of voxels) remained in FA, AD and RD. We detected significant relationships between GA at birth and all metrics. When comparing single site and multisite harmonized datasets of equal sample sizes, harmonized data resulted in smaller standardized regression coefficients. ComBat could enable unprecedented sample sizes in developmental neuroscience, offering new horizons for biomarker discovery and validation, understanding typical and atypical brain development, and assessing neuroprotective therapies.

Interoceptive Awareness Is Associated With Impaired Awareness of Hypoglycemia in Adults With Type 1 Diabetes.

To assess the association between impaired awareness of hypoglycemia (IAH) and interoceptive awareness in type 1 diabetes. A total of 154 adults with type 1 diabetes completed IAH surveys and the Multidimensional Assessment of Interoceptive Awareness, Version 2 (MAIA-2). Logistic regression was performed for assessment of associations between IAH and MAIA-2, accounting for covariates. Significant relationships were observed between IAH and two MAIA-2 scales. Each 1-point increase on the Not-Worrying subscale was associated with 87% increased odds of IAH (odds ratio 1.87, CI 1.01-3.46) and on the Attention Regulation subscale was associated with 72% decreased odds of IAH (0.28, 0.12-0.66). Compared with scoring >90th percentile for Attention Regulation, scoring <10th percentile and scoring in the 10th-90th percentiles were associated with 71-fold (71.26, 3.42-1482.10) and 12-fold (12.73, 1.19-135.57) increased odds of IAH, respectively. Less worry about and reduced ability to sustain and control attention to body sensations were associated with significantly increased odds of IAH.

Associations of Traumatic Brain Injury and Hearing: Results From the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS).

To examine associations of traumatic brain injury (TBI) with self-reported and clinical measures of hearing function. Four US communities. A total of 3176 Atherosclerosis Risk in Communities Study participants who attended the sixth study visit in 2016-2017, when hearing was assessed. Prospective cohort study. TBI occurring prior to the hearing assessment was defined using self-reported questions and "International Classification of Diseases-9th/10th Edition" (ICD-9/10) codes. Hearing function was assessed by self-reported questionnaires and clinically measured indices (audiometry [4-frequency pure tone average for each ear] and speech-in-noise testing). Linear, logistic, and multinomial logistic models adjusted for sociodemographics, vascular risk factors, and occupational noise exposure were used to examine associations. Participants were a mean age of 79years, 59% were female, 21% were of self-reported Black race, and 33% had a history of TBI (median time from first TBI to hearing assessment: 39years (25th-75th percentile=19-63years). Compared to participants without TBI, participants with prior TBI had higher age-adjusted prevalence of self-reported hearing loss (42.3% vs 35.3%), tinnitus (28.0% vs 23.8%), hearing aid use (23.4% vs 17.8%), pure tone average>40dB (30.6% vs 24.8%), and presence in the lowest quartile of speech-in-noise performance (27.6% vs 22.8%). With further adjustment, and particularly with adjustment for occupational noise exposure, associations with hearing measures were largely no longer statistically significant. In secondary analyses of associations of TBI frequency and severity with hearing function, results were similar to our main analyses, without evidence of dose-dependent associations. In this community-based cohort, prior TBI was associated with impaired hearing on both self-reported and clinically measured assessments, but these associations were attenuated after adjustment for occupational noise exposure. These results underscore the importance of the consideration of loud noise exposures, which may confound associations of TBI with hearing, in future studies.

Assessment of MGMT and TERT Subtypes and Prognosis of Glioblastoma by Whole Tumor Apparent Diffusion Coefficient Histogram Analysis.

Adult glioblastomas (GBMs) are associated with high recurrence and mortality. Personalized treatment based on molecular markers may help improve the prognosis. We aimed to evaluate whether apparent diffusion coefficient (ADC) histogram analysis can better predict MGMT and TERT molecular characteristics and to determine the prognostic relevance of genetic profile in patients with GBM. MRI, clinical, and pathological data of 79 patients with GBM were retrospectively collected. The ADC values based on histogram analysis were described using 10th percentile (p10), 90th percentile (p90), mean, median, minimum, maximum, skewness, kurtosis, and entropy. The independent-sample t test, linear correlation analysis, receiver operating characteristics (ROC) curve analysis, Kaplan-Meier analysis, and Cox proportional hazard regression were performed. MGMT promoter methylation and TERT promoter mutation were detected in 53.2% and 44.3% of GBM patients, respectively. The ADCp10 in MGMT promoter unmethylated group was significantly lower than that in the MGMT promoter methylated group (p=0.005). There were significant differences in ADCmin, ADCp10, ADCmean, and entropy between TERT promoter mutant and wild-type groups. Entropy showed the best diagnostic performance in differentiating between positive and negative TERT groups (AUC=0.722, p=0.001). Overall survival (OS) showed a positive correlation with ADCmin. The TERT promoter mutation was the only independent prognostic factor for GBM. ADC histogram analysis may be a potential noninvasive biomarker for differentiating MGMT and TERT molecular markers and providing prognostic information for GBM patients.

Left ventricular systolic function after percutaneous coronary intervention: patterns of change and prognosis according to clinical presentation of coronary artery disease.

Whether there are differences in the left ventricular ejection fraction change (ΔLVEF) after percutaneous coronary intervention (PCI) and its association with long-term prognosis according to coronary artery disease (CAD) presentations is unknown. We assessed ΔLVEF after PCI and its association with 5-year mortality in various CAD presentations. This study included 8181 patients with paired (before and 6-8months after PCI) angiographic LVEF measurements: 4582 patients with chronic coronary disease (CCD), 1972 patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) and 1627 patients with ST-segment elevation myocardial infarction (STEMI). ΔLVEF (LVEF at 6-8months minus baseline LVEF) was classified as follows: decline (ΔLVEF < 0), moderate improvement (ΔLVEF > 0 to < 10%) and large improvement (ΔLVEF ≥ 10%). The primary endpoint was 5year mortality. In patients with CCD, NSTE-ACS and STEMI, ΔLVEF (median [25th-75th percentiles]) was 0.0% [-3.0%; 4.0%], 1.0% [-2.0%; 5.0%] and 3.0% [-2.0%; 10.0%], respectively (P < 0.001). In patients with a decline, moderate improvement and large improvement of LVEF, 5-year mortality was 10.0%, 10.4% and 12.3% in patients with CCD, 10.8%, 10.7% and 18.1% in patients with NSTE-ACS and 10.6%, 8.2% and 5.2% in patients with STEMI. After adjustment, ΔLVEF was associated with 5-year mortality in patients with CCD (adjusted hazard ratio [HR] = 0.90, 95% confidence interval [0.83-0.97]) and STEMI (adjusted HR = 0.85 [0.75-0.95]) but not in patients with NSTE-ACS (adjusted HR = 0.97 [0.85-1.10]), with all 3 risk estimates calculated for 5% increment in the ΔLVEF. The type of CAD presentation appears to impact both LVEF change after PCI and its association with 5-year mortality.

The risk of death according to left ventricular ejection fraction and right ventricular dilatation in 17 321 adults with heart failure from 40 high-, middle- and low-income countries-A Global Congestive Heart Failure (G-CHF) study.

The aim of this study was to describe the prognostic importance of left ventricular ejection fraction (LVEF) versus right ventricular (RV) dilatation and dysfunction in patients with heart failure (HF) from countries of different income levels. We enrolled 17 321 participants with HF from 40 countries. Participants were followed for a median (25th-75th percentile) of 2.1 (2.0-4.6) years. Cox proportional hazards models were performed with adjustment for age, sex, HF aetiology, diabetes, atrial fibrillation, chronic obstructive pulmonary disease, tobacco and alcohol use, functional class, and the use of HF medications, blood pressure, serum creatinine and HF duration. During follow-up, 5738 (33%) participants died and 3569 (21%) were hospitalized for HF. Compared with LVEF ≥50%, the hazard ratios (HR) for death were 0.88 (95% confidence interval [CI] 0.80-0.97, p = 0.009) in patients with LVEF 40-49%, 0.96 (95% CI 0.88-1.05, p = 0.40) for LVEF 30-39%, and 1.18 (95% CI 1.08-1.29, p < 0.0001) for LVEF <30%. RV enlargement was associated with an increased risk of death (HR 1.35, 95% CI 1.26-1.44, p < 0.0001). The relationship between LVEF and death differed according to HF aetiology (interaction p = 0.0010). In ischaemic HF and idiopathic dilated cardiomyopathy, there was a continuous inverse association between LVEF and the risk of death, but in hypertensive, valvular and other HF types, there was no association between LVEF and the risk of mortality. Reduced LVEF was associated with worse prognosis in ischaemic and idiopathic dilated cardiomyopathy but not in HF of other causes. RV enlargement was associated with a more marked increase in the risk of death.

Prediction of SPT-07A Pharmacokinetics in Rats, Dogs, and Humans Using a Physiologically-Based Pharmacokinetic Model and In Vitro Data.

Background/Objectives: SPT-07A, a D-borneol, is currently being developed in China for the treatment of ischemic stroke. We aimed to create a whole-body physiologically-based pharmacokinetic (PBPK) model to predict the pharmacokinetics of SPT-07A in rats, dogs, and humans. Methods: The in vitro metabolism of SPT-07A was studied using hepatic, renal, and intestinal microsomes. The pharmacokinetics of SPT-07A in rats were simulated using the developed PBPK model and in vitro data. Following validation using pharmacokinetic data in rats, the developed PBPK model was scaled up to dogs and humans. Results: Data from hepatic microsomes revealed that SPT-07A was primarily metabolized by UDP-glucuronosyltransferase (UGTs). Glucuronidation of SPT-07A also occurred in the kidney and intestine. The in vitro to in vivo extrapolation analysis showed that hepatic clearance of SPT-07A in rats, dogs, and humans accounted for 62.2%, 87.3%, and 76.5% of the total clearance, respectively. The renal clearance of SPT-07A in rats, dogs, and humans accounted for 32.6%, 12.7%, and 23.1% of the total clearance, respectively. Almost all of the observed concentrations of SPT-07A following single or multi-dose to rats, dogs, and humans were within the 5th-95th percentiles of simulations from 100 virtual subjects. Sensitivity analysis showed that hepatic metabolic velocity, renal metabolic velocity, and hepatic blood flow remarkably affected the exposure to SPT-07A in humans. Dedrick plots were also used to predict the pharmacokinetics of SPT-07A in humans. Prediction accuracy using the PBPK model is superior to that of Dedrick plots. Conclusions: We elucidate UGT-mediated SPT-07A metabolism in the liver, kidney, and intestine of rats, dogs, and humans. The pharmacokinetics of SPT-07A were successfully simulated using the developed PBPK model.

A Risk Score Using a Cell-based Assay Predicts Long-term Over-immunosuppression Events in Kidney Transplant Recipients.

Infections and cancer are major causes of premature death in organ recipients. However, there have been few advances in personalized immunosuppressive therapy. We previously reported that a cell-based assay measuring CD14+16+tumor necrosis factor-α+ monocytes after peripheral blood mononuclear cell (PBMC) incubation with Epstein-Barr virus peptides has a high sensitivity for detecting over-immunosuppression (OIS) events in kidney recipients in the short term. We aimed to develop a risk score for predicting long-term events. We studied 551 PBMC samples from 118 kidney recipients. Following random allocation to a testing and training set, we derived a risk function for the delineated tertiles of low, intermediate, and high risk of OIS based on age and CD14+16+tumor necrosis factor-α+ cells. Patients were followed for a median of 6.3 y (25th-75th percentiles: 3.7-8.3 y). Of these, 40 (34%) experienced an OIS event. The validation indicated that the risk score was well calibrated, with an absolute risk of 21%, 41%, and 61% in the low-, intermediate-, and high-risk categories, respectively (P = 0.03). In sensitivity analyses, the risk score was robust to alternative definitions of OIS ranging from mild to severe. In particular, when restricted to life-threatening OIS, the proportion of events varied from 5% to 27% among the low- and high-risk categories, respectively (P = 0.01). Using a combination of age and in vitro PBMC response to Epstein-Barr virus peptides allows a substantial shift in the estimated risk of OIS events.

Daily glucose variability is associated with intrahepatic fat content, β cell sensitivity, and biomarkers of glycolysis in youth with obesity.

Pediatric obesity is associated with insulin resistance, which, in turn, impacts glucose and lipid metabolism. This study sought to assess how glucose variability relates to intrahepatic fat content, β cell insulin sensitivity, and glycolysis in youth with obesity. A total of 27 youth with obesity (11 girls, BMI percentile, median [25th-75th percentiles]: 99.0 [97.9-99.0]) wore a continuous glucose monitoring device for 10 days and underwent a 3-h oral glucose tolerance test. β cell function was assessed using the oral minimal model, and liver proton density fat fraction was measured by magnetic resonance imaging. Average sensor-derived glucose and glucose standard deviation (STDEV) and coefficient of variation (CV) were associated with liver proton density fat fraction(p = 0.0130, p = 0.0005, and p = 0.0028, respectively). First-phase insulin secretion, basal insulin secretion, and insulin sensitivity were associated with STDEV (p = 0.0344, p = 0.0091, and p = 0.0031, respectively) and CV (p = 0.0128, p = 0.0012, and p = 0.0022, respectively). STDEV and CV were also associated with 2-h glucose (p = 0.0067 and p = 0.0324, respectively) and plasma lactate (p = 0.0030 and p = 0.0123, respectively). Daily glucose variability is associated with the degree of intrahepatic fat content, postprandial glucose, and plasma lactate concentrations.

Transition of patients with systemic lupus erythematosus from pediatric to adult-oriented rheumatology care.

The transition from pediatric to adult-oriented care for individuals with juvenile-onset systemic lupus erythematosus (SLE) poses significant challenges. This study aimed to assess the outcomes of transitioning patients with juvenile-onset SLE from pediatric to adult-oriented care. Patients with juvenile-onset SLE were included in the study. They were transferred in face-to-face meetings where at least one pediatric rheumatologist and one adult rheumatologist were present (transition time: October-December 2020). The median (25th-75th percentile) age at diagnosis and the time of the first examination in an adult-oriented rheumatology department of the included 65 SLE patients were 14.3 (10.9-15.1) years and 19.2 (18.5-20.4) years, respectively (female/male ratio: 7.1). There was no difference in clinical findings related to SLE between the last pediatric care visit and the last adult-oriented care visit other than constitutional symptoms being more prevalent in adult-oriented care (p = 0.039). There was a higher rate of low medication adherence in the post- than pretransition period (p = 0.003). The number of patients admitted to the emergency department during follow-up in adult-oriented care was higher (p = 0.009). Additionally, patients were more likely to miss at least one scheduled appointment in the post- than pretransition period (p = 0.002). We observed that patients with juvenile-onset SLE had more constitutional symptoms, lower medication compliance, higher rates of emergency department visits, and more missed appointments in the posttransition period despite a face-to-face structured transition process. We hope that future studies will offer solutions to the problems in transitional care.

Real-world evidence of Trastuzumab Deruxtecan (T-DXd) Efficacy in HER2-expressing gynecological malignancies

Human epidermal growth factor receptor 2 (HER2) overexpression emerges as an attractive therapeutic target in gynecological malignancies. Recently, Trastuzumab-Deruxtecan (T-DXd) has shown substantial efficacy in HER2 overexpressing carcinomas, most prominently in ovarian, endometrial and cervical patients. We have examined the efficacy of T-DXd in patients with metastatic endometrial, ovarian and cervical malignancies that were treated in the Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens.MethodsPatients with gynecological malignancies with HER2 expression 2 + /3 + as assessed by immunohistochemistry (IHC) that were treated with T-DXd were retrospectively identified. Patients received T-DXd intravenously at a dose of 5.4 mg/kg every 3 weeks until disease progression or unacceptable toxicity.ResultsIn total, 10 patients treated with T-DXd for recurrent/metastatic disease were identified. Regarding histology, there were 5 patients with uterine neoplasms (serous carcinoma (n = 3), uterine carcinosarcoma (n = 1), uterine leiomyosarcoma (n = 1)), 1 patient with squamous cervical carcinoma and 4 patients with ovarian cancer (ovarian carcinosarcoma (n = 2), high-grade serous carcinoma (n = 1) and mucinous ovarian carcinoma (n = 1)). Median age was 65.4 years (25th-75th percentile, 58.1–75.2 years). 5 patients had HER2 expression 3 + by IHC and 5 patients had HER2 expression 2 + . Median number of previous lines of therapy was 4 (range 2–6), 2 patients with uterine serous carcinoma were pretreated with trastuzumab and 4 patients had already received immunotherapy. In the entire cohort median progression-free survival (PFS) was 5.4 months (95%CI 0.8–9.8 months). Regarding responses, 5 patients had partial response (including 2 patients that were pretreated with trastuzumab), 1 patient had stable disease at 12 weeks and 4 patients had disease progression at initial assessment. All patients but one that derived clinical benefit had HER2 3 + expression.DiscussionIn the real-world setting, T-DXd showed activity in a cohort of heavily pre-treated patients with HER2-expressing gynecological malignancies.

NT-proBNP and Cardiac Troponin I, but Not Cardiac Troponin T, Are Associated With 7-Year Changes in Cardiac Structure and Function in Older Adults: The ARIC Study.

Higher circulating concentrations of NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI) are associated with left ventricular remodeling and with incident heart failure. The associations of these cardiac biomarkers with changes in cardiac structure and function over time are uncharacterized. Among 2006 participants in the ARIC prospective cohort study (Atherosclerosis Risk in Communities) who were free of overt cardiovascular disease and underwent echocardiography at study visits 5 (2011- 2013) and 7 (2018-2019), we assessed the associations of NT-proBNP, hs-cTnT, and hs-cTnI concentrations at visit 5 with changes in left ventricular structure and function between visits 5 and 7 (≈7-year change) using multivariable linear regression with the biomarkers modeled as restricted cubic splines. Models were adjusted for age, sex, race, body mass index, smoking, diabetes, hypertension, and renal function at visit 5; blood pressure and heart rate at both visits; and the baseline value of the echocardiographic parameter of interest. Mean±SD age was 74±4 years at visit 5; 61% were women; and 23% were Black adults. Median (25th-75th percentile) concentrations at visit 5 of NT-proBNP, hs-cTnT, and hs-cTnI were 87 ng/L (50-157 ng/L), 9 ng/L (6-12 ng/L), and 2.6 ng/L (1.9-3.9 ng/L). In adjusted models, elevated baseline concentrations of NT-proBNP and hs-cTnI were significantly associated with 7-year decline in left ventricular systolic function (ejection fraction, longitudinal and circumferential strain) and worsening diastolic indices. In contrast, elevated baseline concentrations of hs-cTnT were not significantly associated with 7-year changes in cardiac structure, systolic function, or diastolic function (all P>0.05). Higher concentrations of NT-proBNP and hs-cTnI, but not hs-cTnT, were associated with greater declines in left ventricular function over ≈7 years in late life independently of traditional cardiovascular risk factors.

SCAT Symptom Evolution in the Acute Concussion Phase: Findings from the NCAA-DoD CARE Consortium.

The Sport Concussion Assessment Tool (SCAT) is the most widely used tool following sport-related concussion (SRC). Initial SCAT symptom burden is a strong predictor of recovery in collegiate athletes; however, it is unknown if symptom presentation varies within the acute (<48 h) post-SRC phase. The purpose of this cohort study was to examine acute SRC symptom presentation among the National Collegiate Athletic Association (NCAA) athletes. Concussed NCAA varsity athletes (n = 1,780) from 30 universities across the United States, which participated in the Concussion Assessment, Research, and Education (CARE) Consortium, were included. Time of injury occurrence and SCAT administration data were recorded, from which time-to-SCAT (hours, continuous) was calculated. The main outcome was SCAT total symptom severity [(TSS), 0-126]. Multivariable negative binomial regression was used to examine the association between time (hours) since injury and TSS. Covariates included sex, previous concussion, sport contact level, amnesia/loss of consciousness, immediate reporting of injury, and injury situation. A random effect (person level) accounted for multiple assessments. TSS score ratios (SR) with associated 95% confidence intervals (CI) were provided. The SCAT was administered an average of 14 (25th-75th percentile: 1.2-24) hours post-SRC, and average TSS was 27.35 ± 21.28 across all participants. Time-to-SCAT was associated with a 1% decrease in TSS after adjusting for covariate effects (SR: 0.99, 95% CI: 0.99-0.99, p < 0.001). Overall, we observed a small, but significant decrease in TSS with each hour post-SRC. Assessing a concussed athlete once in the acute phase will likely provide a sufficient sense of their symptomatic well-being, as measures did not fluctuate dramatically. Future research should aim to examine how acute symptom evolution influences recovery metrics.

Population Pharmacokinetic and Pharmacodynamic Study of Palbociclib in Children and Young Adults with Recurrent, Progressive, or Refractory Brain Tumors.

Background/Objectives: Palbociclib, an oral CDK 4/6 inhibitor, was evaluated in a Pediatric Brain Tumor Consortium (PBTC) phase 1 (NCT02255461; PBTC-042) study to treat children and young adults with recurrent, progressive, or refractory brain tumors. The objectives of this study were to characterize the palbociclib population pharmacokinetics in children enrolled on PBTC-042, to conduct a population pharmacodynamic analysis in this patient population, and to perform a simulation study to assess the role of palbociclib exposure on neutropenia and thrombocytopenia. Methods: The palbociclib population pharmacokinetics and pharmacodynamics were characterized in this patient population (n = 34 patients; 4.9-21.6 years old). Population pharmacokinetics were modeled using a one-compartment model with first-order absorption and elimination. Covariate analysis was performed, evaluating demographics, laboratory values, and concomitant medications. A pharmacodynamic model was used to describe the relation between palbociclib plasma exposure and changes in the ANC and platelet counts. Results: The population estimates for the apparent oral volume, apparent oral clearance, and absorption rate constant were 664.5 L/m2, 36.8 L/h/m2, and 0.48 h-1, respectively. The palbociclib apparent oral clearance was decreased in patients with higher AST values (p = 0.0066). The ANC and platelet pharmacodynamic models estimated that the median (5th-95th percentile) time individuals had grade 3 or greater neutropenia was 4 (0, 21) days. Simulations showed that given 75 mg/m2 palbociclib, 49% of the individuals were expected to have grade 3 or greater neutropenia. Conclusions: Palbociclib pharmacokinetics and pharmacodynamics were adequately characterized in this patient population, no unexpected adverse reactions were noted, and the drug was well tolerated.

Growth and Eating Behaviours at 2 Years Corrected Age in Extremely Low-Birthweight Babies; Secondary Cohort Analysis from the ProVIDe Trial.

Early postnatal growth following extremely preterm birth may have long-term effects on growth, eating behaviours and health. Background/Objectives: To determine whether growth to age two years is conditional on growth in the NICU, a conditional growth analysis was performed in a cohort of 330 extremely low-birthweight (ELBW; birthweight < 1000 g) participants in the ProVIDe trial who were followed-up at 2 years corrected age (CA); Methods: We used z-score change for weight, length and head circumference from 36 weeks post-menstrual age to 2 years CA as the end-point-adjusted for birth z-score and z-score change from birth to 36 weeks. Growth and body composition were assessed using bioimpedance analysis. Relationships between eating behaviours and body mass index (BMI) at 2 years CA and growth were assessed using a Child Eating Behaviour Questionnaire (CEBQ) completed by parents at 2 years CA; Results: Growth, or change in z-score, from 36 weeks PMA was conditional upon growth in the NICU, with slower neonatal growth associated with faster early childhood growth (weight: R2 = 0.27, ß-coefficient -0.81 (95% CI: -0.96, -0.66), p < 0.0001; length: R2 = 0.28, ß-coefficient -0.64 (95% CI: -0.76, -0.51), p < 0.0001; head circumference: R2 = 0.18, ß-coefficient -0.61 (95% CI: -0.76, -0.46), p < 0.0001). Fat-free mass index, adjusted for confounding factors, was positively correlated with z-score change from NICU discharge to 2 years CA for weight, but not length (weight: R2 = 0.50, ß-coefficient = 0.87 (95% CI: 0.56, 1.18), p < 0.0001; length: R2 = 0.32, ß-coefficient = 0.01 (95% CI: -0.40, 0.42), p = 0.95). At 2 years CA, CEBQ scores for enjoyment were significantly higher and satiety and slowness significantly lower in children with a BMI ≥ 90th percentile than in children with a BMI ≤ 10th percentile or between the 10th-90th percentile.; Conclusions: Growth from NICU discharge to 2 years CA is conditional upon growth in the NICU, with slower NICU growth linked to faster early childhood growth, and weight z-score changes positively correlated with fat-free mass index. At age 2, children with a BMI ≥ 90th percentile have significantly different eating behaviour assessments by caregivers compared to children with a BMI ≤ 10th percentile or between the 10th-90th percentile; further RCTs are needed to confirm links between nutrition factors and growth outcomes in ELBW infants.