Considerable Interpatient Variability Research Articles

Optimal Threshold and Interpatient Variability in Left Atrial Ablation Scar Assessment by Dark-Blood LGE CMR

BackgroundDark-blood late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) has better correlation with bipolar voltage (BiV) to define ablation scar in the left atrium (LA) compared to conventional bright-blood LGE CMR. ObjectivesThis study sought to determine the optimal signal intensity threshold of dark-blood LGE CMR to identify LA ablation scar. MethodsIn 54 patients scheduled for atrial fibrillation ablation, image intensity ratios (IIRs) were derived from preprocedural dark-blood LGE CMR. In 26 patients without previous ablation, the upper limit of normal was derived from the 95th and 98th percentiles of pooled IIR values. In 28 patients with previous atrial fibrillation ablation, BiV was compared with the corresponding IIR. Receiver-operating characteristics analyses were employed to determine the optimal IIR threshold (ie, the point with the smallest distance to the upper left corner of the receiver-operating characteristics) for LA ablation scar (BiV ≤0.15 mV). ResultsUpper limit of normal corresponded to IIR values 1.16 and 1.21, yielding low sensitivities of 0.32 and 0.09 to detect LA ablation scar. Receiver-operating characteristics analysis of IIR and BiV comparison achieved a median area under the curve of 0.77. Median optimal IIR threshold for LA ablation scar was 1.09, with an average sensitivity of 0.73, specificity of 0.75, and accuracy of 0.71. Median IIR thresholds of 1.00 and 1.10 corresponded to 80% sensitivity and 80% specificity, respectively. There was considerable interpatient variability: optimal IIR thresholds per patient ranged from 1.01 to 1.22. ConclusionsThe optimal IIR threshold to identify LA ablation scar by dark-blood LGE CMR is 1.09. Because of interpatient variability, the investigators recommend using a lower (1.00) and upper (1.10) threshold to prevent over- or underestimation of ablation scar.

Quantitative assessment of daratumumab in serum via intact light chain measurement using liquid chromatography-high resolution mass spectrometry: a method suitable for therapeutic drug monitoring.

Daratumumab, a pivotal treatment for multiple myeloma, exhibits considerable inter-patient variability in pharmacological clinical outcomes, likely attributed to serum concentration that may underscore the need for its therapeutic drug monitoring. This study aims to develop and validate a straightforward analytical method for quantifying daratumumab in serum, focusing on intact light chain determination, using liquid chromatography high-resolution mass spectrometry. The sample preparation involved immunoglobulin enrichment using Melon gel followed by a reduction step to dissociate the light from the heavy chains of immunoglobulins. The latter were then separated using a MabPac RP 2.1 × 50 mm chromatographic column and the intact light chains were detected and quantified using a Q Exactive Orbitrap mass spectrometer operating in ESI-positive ion mode at 17 500 resolution. The method demonstrated excellent linearity (R2 > 0.992) across a serum concentration range of 100 to 2000 μg mL-1 and good precision and accuracy: intra- and interday relative errors ranged from -5.1% to 6.5%, with a relative standard deviation of less than 5.8%. Clinical suitability was confirmed by analyzing 80 clinical samples from multiple myeloma patients treated with 1800 mg of daratumumab. 99% of the samples fell within the analytical range with a mean daratumumab concentration evaluated before the next administration (Ctrough) of 398 μg mL-1. These findings highlighted that intact light chain monoclonal antibody quantification could be a valid and robust alternative to either immunoassays or to LC-MS/MS targeting peptides for measuring daratumumab in clinical samples, positioning it as a suitable method for therapeutic drug monitoring applications.

Optimizing cyclosporine A dose post allogeneic hematopoietic stem cell transplantation in paediatric cancer patients.

Cyclosporine A (CSA) dosing has been complicated by considerable intra-patient and inter-patient variability in pharmacokinetics, which is affected by different factors. We aimed to assess the various factors that might affect the CSA dose and its plasma level. This retrospective study included paediatric cancer patients who underwent allogeneic hematopoietic stem cell transplant at the Children's Cancer Hospital Egypt 57357 from matched related donors with CSA as graft versus host disease prophylaxis. The CSA initial dose was 1.5 mg/kg IV Q12H. Then, it was titrated according to the level and drug toxicity. Cyclosporine A trough levels were assessed two to three times per week using the Emit 2000 cyclosporine-specific assay. Moreover, factors that may affect cyclosporine levels, such as age, sex, weight and the antifungal used, were analyzed to determine their effect on CSA plasma levels. There were 119 patients included in the study. The median age was 10 years; and 43% of them used voriconazole as a prophylactic antifungal. The multivariate analysis revealed that female patients, those >9 years or on voriconazole reached the target level at low initial CSA doses. A higher probability (93%) of reaching the desired plasma level with doses 1.5 mg/kg IV Q12H was observed among patients >9 years, and on voriconazole. While those who were ≤9 years and not on voriconazole required doses >1.5 mg/kg IV Q12H, with an 89% probability of reaching the desired level. This study suggests that the initial CSA dose should consider the patient's age and the antifungal used. Patients >9 years and/or on voriconazole may require lower initial CSA doses and could start with 1.5 mg/kg IV Q12H.

Real-Time Personalised Pharmacokinetic-Pharmacodynamic Modelling in Propofol Anesthesia through Bayesian Inference.

Pharmacological models describe a patient's response to the administration of a medicinal drug based on parameters derived from population studies. However, considerable inter-patient variability exists, such that population models may underperform when used to predict the actual response of a specific individual. In applications which demand predictive accuracy-such as target-controlled infusion of anesthetic agents-modeling uncertainty may reduce system dependability and introduce clinical risk. Our work investigates the use of Bayesian inference, implemented through a particle filter algorithm, to refine a prior model of propofol pharmacokinetics-pharmacodynamics and estimate patient-specific parameters in real-time. We report here on an observational clinical study conducted on 40 adults undergoing general anesthesia, where we evaluated the performance of Bayesian inference-personalized models in forecasting forward trends of depth of anesthesia (Bispectral Index) measurements and compared it with that of a traditional population-based pharmacological model. Our results show a significant reduction in prediction error metrics for the patient-specific models. Our study demonstrates the viability and practical implementability of Bayesian inference as a tool for real-time intra-operative estimation of personalized pharmacological models in anesthesia applications.

Polygenic risk of anthracycline-related cardiomyopathy in childhood cancer survivors: Report from children’s oncology group and childhood cancer survivor study.

12090 Background: Considerable inter-patient variability in anthracycline-related cardiomyopathy (aCM) risk exists among childhood cancer survivors (CCS). A polygenic risk score (PRS) that accounts for combined effects of multiple genetic variants is established in other clinical situations, but remains understudied in anthracycline-exposed CCS. Methods: For discovery, a case-control set of 278 anthracycline-exposed non-Hispanic White (NHW) CCS (129 aCM cases; 149 controls) matched on primary cancer diagnosis, year of diagnosis and duration of follow-up was included from a Children’s Oncology Group study (COG-ALTE03N1). Genomic DNA underwent whole exome sequencing (100X depth). We searched Medline and Embase databases between 2005 and 2022 to curate evidence for published single nucleotide polymorphisms (SNPs) associated with CM. We identified 1,156 SNPs on 343 genes with minor allele frequency [MAF] ≥0.05 in white populations. We constructed a weighted PRS using sequenced SNPs that were linkage disequilibrium pruned, yielding a final list of 279 independent SNPs. Conditional logistic regression models adjusted for anthracycline dose, age at diagnosis, sex, chest radiation and cardiovascular risk factors (CVRFs; diabetes, hypertension, dyslipidemia) were used to estimate PRS-aCM associations. An independent population of 475 anthracycline-exposed NHW CCS from the Childhood Cancer Survivor Study (CCSS: 96 cases; 379 matched controls) was used to replicate the PRS-aCM association. Area under the receiver operating characteristic curve (AUC) was used to evaluate the performance of a model including the PRS. Results: Median age at primary cancer diagnosis was 7y for cases and controls in the Discovery and 11y in the Replication set. Mean anthracycline dose was higher for cases (Discovery: 312 v 186 mg/m2; Replication: 333 v 289 mg/m2). Cases were more likely to have received chest radiation (Discovery: 35.7% v 24.8%; Replication: 34.3% v 23.2%); and were more likely to have a CVRF (Discovery: 37.2% v 8.7%; Replication: 55.2% v 31.9%). PRScontinuous was significantly associated with aCM (aOR = 2.09, 95%CI: 1.1-4.0, p = 0.024) in the Discovery set. Compared to a model with clinical variables only, a model including the PRS had significant predictive performance: AUCclin= 0.72, 95% CI: 0.65-0.79. v AUCclin+PRS= 0.91, 95% CI: 0.87-0.95, p < 0.001. In the Replication set, the top PRS quartile (top 25%) was significantly associated with aCM (aOR = 2.14, 95%CI: 1.05-4.37, p = 0.036; reference: lowest PRS quartile). Conclusions: The significant association between this comprehensively curated PRS and aCM in CCS could serve as an important tool to identify survivors at increased risk for CM and inform targeted interventions.

Putting square pegs in round holes: Why traditional pharmacokinetic principles cannot universally be applied to iron-carbohydrate complexes

Intravenous iron-carbohydrate complexes are nanomedicines that are commonly used to treat iron deficiency and iron deficiency anemia of various etiologies. Many challenges remain regarding these complex drugs in the context of fully understanding their pharmacokinetic parameters. Firstly, the measurement of the intact iron nanoparticles versus endogenous iron concentration fundamentally limits the availability of data for computational modeling. Secondly, the models need to include several parameters to describe the iron metabolism which is not completely defined and those identified (e.g. ferritin) exhibit considerable interpatient variability. Additionally, modeling is further complicated by the lack of traditional receptor/enzyme interactions. The known parameters of bioavailability, distribution, metabolism, and excretion for iron-carbohydrate nanomedicines will be reviewed and future challenges that currently prevent the direct application of physiologically-based pharmacokinetic or other computational modeling techniques will be discussed.

Continuous Shoulder Activity Tracking after Open Reduction and Internal Fixation of Proximal Humerus Fractures

Postoperative shoulder activity after proximal humerus fracture treatment could influence the outcomes of osteosynthesis and may depend on the rehabilitation protocol. This multi-centric prospective study aimed at evaluating the feasibility of continuous shoulder activity monitoring over the first six postoperative weeks, investigating potential differences between two different rehabilitation protocols. Shoulder activity was assessed with pairs of accelerometer-based trackers during the first six postoperative weeks in thirteen elderly patients having a complex proximal humerus fracture treated with a locking plate. Shoulder angles and elevation events were evaluated over time and compared between the two centers utilizing different standard rehabilitation protocols. The overall mean shoulder angle ranged from 11° to 23°, and the number of daily elevation events was between 547 and 5756. Average angles showed longitudinal change <5° over 31 ± 10 days. The number of events increased by 300% on average. Results of the two clinics exhibited no characteristic differences for shoulder angle, but the number of events increased only for the site utilizing immediate mobilization. In addition to considerable inter-patient variation, not the mean shoulder angle but the number of elevations events increased markedly over time. Differences between the two sites in number of daily events may be associated with the different rehabilitation protocols.

Model-Informed Estimation of Acutely Decreased Tacrolimus Clearance and Subsequent Dose Individualization in a Pediatric Renal Transplant Patient With Posterior Reversible Encephalopathy Syndrome.

Considerable interpatient and interoccasion variability has been reported in tacrolimus pharmacokinetics (PK) in the pediatric renal transplant population. This study investigated tacrolimus PK in a 2-year-old post-renal transplant patient and a known CYP3A5 expresser who developed posterior reversible encephalopathy syndrome (PRES) and had significantly elevated tacrolimus blood concentrations during tacrolimus treatment. A model-informed PK assessment was performed to assist with precision dosing. Tacrolimus clearance was evaluated both before and after the development of PRES on post-transplant day (PTD) 26. A retrospective chart review was conducted to gather dosing data and tacrolimus concentrations, as part of a clinical pharmacology consultation service. Individual PK parameters were estimated by Bayesian estimation using a published pediatric PK model. Oral clearance (CL/F) was estimated for 3 distinct periods-before CNS symptoms (PTD 25), during the PRES event (PTD 27-30), and after oral tacrolimus was restarted (PTD 93). Bayesian estimation showed an estimated CL/F of 15.0 L/h in the days preceding the PRES event, compared with a population mean of 16.3 L/h (95% confidence interval 14.9-17.7 L/h) for CYP3A5 expressers of the same age and weight. Samples collected on PTD 27-30 yielded an estimated CL/F of 3.6 L/h, a reduction of 76%, coinciding with clinical confirmation of PRES and therapy discontinuation. On PTD 93, an additional assessment showed a stable CL/F value of 14.5 L/h 1 month after reinitiating tacrolimus and was used to recommend a continued maintenance dose. This is the first report to demonstrate acutely decreased tacrolimus clearance in PRES, likely caused by the downregulation of metabolizing enzymes in response to inflammatory cytokines. The results suggest the ability of model-informed Bayesian estimation to characterize an acute decline in oral tacrolimus clearance after the development of PRES and the role that PK estimation may play in supporting dose selection and individualization.

Loss of Cyb5R3 Function Silences Fetal Hemoglobin and Hematocrit Responses to Hydroxyurea in Patients with Sickle Cell Anemia

BACKGROUND: Hydroxyurea (HU) is the first FDA-approved and most widely prescribed drug for sickle cell (SS) patients due to its beneficial effects (decreased Hb polymerization, pain crises and hospitalization) and relative safety profile. While the clinical benefits of HU have been found to associate with increased nitric oxide (NO) and fetal hemoglobin (HbF) in most SS patients, there has been considerable interpatient variability in HbF response to the drug. From this standpoint, HU is imperfectly understood mechanistically. Cytochrome b5 reductase 3 (Cyb5R3), also known as methemoglobin reductase, is an enzyme known to modulate redox signaling in erythrocytes and vascular cells by catalyzing one electron transfer reactions using reduced nicotinamide adenine dinucleotide (NADH) as an electron donor. Functionally, membrane-associated CYB5R3 exerts antioxidant properties by modulating heme iron reduction, plasma membrane coenzyme Q reduction, elongation and unsaturation of fatty acids, cholesterol biosynthesis and drug metabolism, while the soluble form of CYB5R3 reduces red blood cell methemoglobin. Unremitting oxidation of the soluble guanylate cyclase (sGC) heme iron in the absence of sufficient Cyb5R3 activity in vascular smooth muscle has been shown to explain some NO resistance that characterizes pulmonary arterial hypertension and other vasculopathy associated with SCD. More than 40 variants of Cyb5R3 have been identified. Of particular interest is a Cyb5R3 variant (T117S) that contains a threonine to serine substitution in the flavoprotein, which lessens the reductase's activity by roughly 50% compared to wild-type. This variant occurs with high frequency (0.23 minor allele) in persons of African ancestry but is rare (<1%) in all other races. Nothing is known about the role of Cyb5R3 in the anemia of sickle cell disease. We hypothesized that Cyb5R3 may act as a modifier of HbF induction by HU in sickle cell anemia. METHODS: Male and female SS patients (n=633, 12-70 years of age) from the Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (walk-PHaSST) trial were recruited for genetic analysis (University of Pittsburgh IRB Protocol Study 19060255). Genotyping of rs1800457 (T117S SNP) was performed using Taqman genotyping assay. One-way ANOVA and Holms Sidak were used for multiple comparisons of HbF levels by Cyb5R3 genotype and HU treatment status. Intrapatient correlation analyses of HbF and hematocrit (HCT) were conducted using Pearsons r. RESULTS: Comparisons of HbF levels by Cyb5R3 genotype (CC, wild-type; CG, heterozygous wild-type and T117S; GG, homozygous T117S) and HU treatment status (treated vs. untreated) at time of study enrollment (baseline) show that HU is a less potent HbF inducer in the GG group (4.32 mean diff, P=0.344) versus the CC and CG patient groups (CC: 6.027 mean diff, P<0.0001 and CG: 6.914 mean diff, P<0.0001). Correlation analyses showed that as HbF levels increased among HU-untreated patients, the trend was for HCT to decrease. This was true for all SS patients, irrespective of Cyb5R3 genotype (CC: r = -0.336, P<0.0001, n=320; CG: r = -0.437 P<0.0001, n=120; GG: r = -0.253, P=0.136, n=36). However, with HU therapy, the inverse relationship between HbF and HCT was less negative in SS patients carrying at least one copy of the wild-type Cyb5R3 gene (CC or CG). In these individuals, increasing levels of HbF (up to 10%) correlated with positive gains in HCT at HbF greater than 5-6% (CC: r = -0.161, P=0.097, n=107) and 6-7% (CG: r = -0.186, P=0.25, n=40). In patients homozygous for T117S, HCT continued trending downward as HbF increased (GG: r = -0.419, P=0.228, n=10). These data indicate that the positive relationship between HbF and HCT is subject to uncoupling by loss of Cyb5R3 function. In vitro studies with human erythroleukemic K562 cells reveal loss of gamma globin induction by HU treatment when wild-type Cyb5R3 is knocked down by siRNA, indicating a requirement for Cyb5R3 in HU-stimulated HbF induction. SUMMARY andCONCLUSION: Loss of Cyb5R3 activity negatively impacts HbF and HCT in HU treated SS patients. We conclude that the T117S variant may be a useful marker for predicting which SS patients will incur beneficial HbF and HCT responses to HU, thereby improving clinical decision-making about best drug choices for preventing HbS polymerization and treating anemia in SS patients.

Preclinical Development and Screening of a Quinone-Nitroalkene Molecule for Sickle Cell Anemia

Background: Sickle cell anemia (SCA) is a hereditary disorder caused by the formation of hemoglobin S (HbS). HbS undergoes polymerization and generates sickled red blood cells (RBCs). Along with having reduced oxygen carrying capacity, sickled RBCs are also prone to frequent hemolysis releasing the pro-oxidant heme in the circulation. Oxidative stress created by the free heme leads to sterile inflammation, vaso-occlusion and cardiovascular complications. The prevalence of SCA is greatest in the poorer regions of Sub-Saharan Africa and there are around 100,000 new incidents of SCA every year in the USA alone. Although a number of therapeutic options are currently FDA-approved for the treatment of SCA patients, there is considerable interpatient variability in terms of their efficacy and safety, along with high morbidity and mortality rates. We have developed a novel quinone-nitroalkene hybrid molecule called CP50 (figure 1), which has been shown to activate two important proteins: 1) nuclear factor erythroid 2-related factor 2 (Nrf2), a transcriptional regulator of cellular resistance to oxidants and 2) cytochrome b5 reductase 3 (CYB5R3), an anti-stress enzyme in the cardiovascular system. Methodology and results: Primary human aortic endothelial cells (HAECS) were incubated with 5 µM CP50 for 6 hours to perform a genomic screening. The mRNA expression profile revealed that CP50 differentially regulated pathways associated with oxidative balance, inflammation, and erythropoiesis. CP50 was associated with upregulation of genes responsible for counteracting stress, including heat shock protein family, HSPA6, HSPA1A, HSPA1B and heme-oxygenase 1 (HMOX-1) (n=5, p<0.05). CP50 downregulated genes that inhibit effective erythropoiesis, such as ZFP36 Ring Finger Protein Like 2 (ZFP36L2) and Growth/differentiation factor 15 (GDF15), thus imparting a positive effect on the process (n=5, p<0.05). Immunoblotting for heme-oxygenase 1 (HO-1) using wild type and Nrf2-knockdown HAECs demonstrated that HO-1 was induced by 5 µM CP50 by 5 fold (±1.36) after 24 hours of exposure, in a Nrf2 dependent manner (n=3, p<0.0001). CYB5R3 activity measured by its impact on myoglobin reduction rate, was also found to increase dose-dependently by CP50 (n=3, p<0.001). Afterwards, CD34+ hematopoietic stem cells (HSCs, n=3) were cultured with 5 µM CP50 and 50 µM hydroxyurea (HU) to observe the effect on erythropoiesis, using CD71, CD235a and fetal hemoglobin (HbF) as markers for flow cytometry. CP50 augmented the percentage of HbF-expressing F cells by 1.7 fold (±0.54) in comparison to 2.21 fold (±0.89) by HU on day 9. F cells are known to impart resilience against sickling and hemolysis in sickle cell anemia. We then observed the effect of CP50 administered by osmotic pump implantation on hematopoiesis in Townes HbSS mice (vehicle, 5mg/kg/day, 15mg/kg/day, n=3/4 in each group). After a period of 4 weeks, we collected whole bone marrow from the mice and using flow cytometry checked for HSCs. CP50 (15 mg/kg/day) significantly increased (p<0.001) the HSC pool by 59% in comparison to vehicle. Additionally, it also enhanced the differentiation of megakaryocyte-erythroid progenitors (MEP) in bone marrow cells by 11% (p<0.05). In a separate experiment, peripheral blood samples from Townes HbSS mice were collected and incubated with 5 µM CP50 before chemically inducing oxidative hemolysis. CP50 reduced hemolysis by 73.68% in comparison to vehicle. Conclusion: Together, our studies indicate that CP-50 has the potential to correct oxidative imbalance by activating antioxidant genes, reverse anemia by inducing hematopoiesis, and inhibit hemolysis by increasing F cell percentage. Thus, we can conclude that CP50 is a prospective drug candidate with the promise to satisfy the unmet need for additional safe and effective therapeutic options for patients with sickle cell anemia. Legend (figure 1): The quinone head group in CP50 serves as an antioxidant, whereas the nitro group in the fatty acid side chain acts as an electrophile. The electrophile modifies the cysteine maintaining the Keap1-Nrf2 interaction and releases the Nrf2. Nrf2 enters the nucleus and initiates the expression of genes that counteract oxidative stress. Keap1: Kelch-like ECH-associated protein 1 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical correlates of movement disorders in adult Niemann-Pick type C patients measured via a Personal KinetiGraph

BackgroundNiemann-Pick type C (NPC) is an autosomal recessive progressive neurodegenerative disorder caused by mutations in the NPC1 or NPC2 genes. Patients with this disorder have variable phenotypic presentations that often include neuropsychiatric manifestations, cognitive decline, and movement disorders. There is considerable interpatient variation in movement disorders, with limited quantitative measurements describing the movements observed. Objective measurements using wearable sensors provide clinically applicable monitoring of patients with Parkinson’s disease, and hence may be utilized in patients with NPC.ObjectiveTo explore the relationship between objective measurements of movement obtained via the use of the Personal KinetiGraph (PKG) with the clinical information obtained via questionnaires and clinical rating tools of patients with Niemann-Pick type C.MethodsTwelve patients with Niemann-Pick type C were recruited who wore the PKG for 6 days during regular activities. A 6-day output was provided by the manufacturer, which provided bradykinesia (BK) and dyskinesia (DK) scores. BK and DK scores were further divided into their interquartile ranges. A fluctuation score (FDS), percentage time immobile (PTI), and percent time with tremors (PTT) were also provided. Clinical assessments included Abnormal Involuntary Movement Scale (AIMS), Epworth Sleepiness Score (ESS), Falls, Neuropsychiatric Unit Assessment Tool (NUCOG), Parkinson’s disease questionnaire (PDQ), and modified Unified Parkinson’s Disease Rating Scale (UPDRS) which were performed over telehealth within 2 weeks of PKG use. Pearson’s correlation analyses were utilized to explore the relationship between DK and BK quartiles and clinical measures.ResultsWe found bradykinesia to be a feature among this cohort of patients, with a median BKS of 22.0 (7.4). Additionally, PTI scores were elevated at 4.9 (8.2) indicating elevated daytime sleepiness. Significant correlations were demonstrated between BK25 and Falls (r = − 0.74, 95% CI = [− 0.95, − 0.08]), BK50 and Falls (r = − 0.79, 95% CI = [− 0.96, − 0.19]), and BK75 and Falls (r = − 0.76, 95% CI = [− 0.95, − 0.11]). FDS correlated with PDQ (r = − 0.7, 95% CI = [− 0.92, − 0.18]), UPDRS IV (r = − 0.65, 95% CI = [− 0.90, − 0.09]), UPDRS (r = − 0.64, 95% CI = [− 0.9, − 0.06]), and AIMS (r = − 0.96, 95% CI = [− 0.99, − 0.49]). DK25 in comparison with NUCOG-A (r = 0.72, 95% CI = [0.17, 0.93]) and DK75 in comparison with NUCOG (r = 0.64, 95% CI = [0.02, 0.91]) and NUCOG-A (r = 0.63, 95% CI = [0.01, 0.90]) demonstrated significant correlations. Additionally, duration of illness in comparison with PTI (r = 0.72, 95% CI = [0.22, 0.92]) demonstrated significance.ConclusionsUtilization of PKG measures demonstrated that bradykinesia is under recognized among NPC patients, and the bradykinetic patients were less likely to report concerns regarding falls. Additionally, the FDS rather than the DKS is sensitive to the abnormal involuntary movements of NPC—reflecting a differing neurobiology of this chorea compared to levodopa-induced dyskinesias. Furthermore, dyskinetic individuals performed better in cognitive assessments of attention which may indicate an earlier timepoint within disease progression.

Superior temporal gyrus functional connectivity predicts transcranial direct current stimulation response in Schizophrenia: A machine learning study.

Transcranial direct current stimulation (tDCS) is a promising adjuvant treatment for persistent auditory verbal hallucinations (AVH) in Schizophrenia (SZ). Nonetheless, there is considerable inter-patient variability in the treatment response of AVH to tDCS in SZ. Machine-learned models have the potential to predict clinical response to tDCS in SZ. This study aims to examine the feasibility of identifying SZ patients with persistent AVH (SZ-AVH) who will respond to tDCS based on resting-state functional connectivity (rs-FC). Thirty-four SZ-AVH patients underwent resting-state functional MRI at baseline followed by add-on, twice-daily, 20-min sessions with tDCS (conventional/high-definition) for 5 days. A machine learning model was developed to identify tDCS treatment responders based on the rs-FC pattern, using the left superior temporal gyrus (LSTG) as the seed region. Functional connectivity between LSTG and brain regions involved in auditory and sensorimotor processing emerged as the important predictors of the tDCS treatment response. L1-regularized logistic regression model had an overall accuracy of 72.5% in classifying responders vs. non-responders. This model outperformed the state-of-the-art convolutional neural networks (CNN) model—both without (59.41%) and with pre-training (68.82%). It also outperformed the L1-logistic regression model trained with baseline demographic features and clinical scores of SZ patients. This study reports the first evidence that rs-fMRI-derived brain connectivity pattern can predict the clinical response of persistent AVH to add-on tDCS in SZ patients with 72.5% accuracy.

Association of polymorphisms in ARRB2 and clinical response to methadone for pain in advanced cancer.

Background: The prescription of methadone in advanced cancer poses multiple challenges due to the considerable interpatient variation seen in effective dose and toxicity. Previous reports have suggested that ARRB2 influences the response to methadone in opioid substitution therapy. Associations with opioid response for pain management in advanced cancer are conflicting, with no studies including methadone as the primary intervention. Methods: In a prospective, multicenter, open-label dose-individualization study, we investigated whether polymorphisms in ARRB2 were associated with methadone dose requirements and pain severity. Results: Significant associations were found for rs3786047, rs1045280, rs2036657 and pain score. Conclusion: While studies are few and the sample size small, ARRB2 genotyping may assist in individualized management of the most feared symptom in advanced cancer.

Integrative single cell RNA-sequencing descrambles a substantial divergence of adaptive immune cell identities and transcriptional programs in mouse and human atherosclerosis

Abstract Aims The distinct function of immune cells in human atherosclerosis has been mostly defined by preclinical mouse studies. Contrastingly, the immune cell composition of human atherosclerotic plaques and their contribution to disease progression is only poorly understood. It remains uncertain whether genetic animal models allow for valuable translational approaches. Methods and results We performed single cell RNA-sequencing (scRNAseq) to define the immune cell landscape in human carotid atherosclerotic plaques. The human immune cell repertoire was dominated by T cells with a considerable inter-patient variability and an unexpected heterogeneity. We performed bioinformatical integration with 7 mouse data sets and discovered a total of 38 cellular identities, of which some were not conserved between species and exclusively found in mice or humans. Locations, frequencies, and transcriptional programs of immune cells in preclinical mouse models did not resemble the immune cell landscape in human atherosclerosis. In contrast to mice, human plaques were not myeloid- and B cell-dominated and instead contained several T cell phenotypes with hallmarks of T cell memory, dysregulation, exhaustion, and activation. Human immune cells were predominantly enriched for transcriptional programs of hypoxia, glucose, and autoimmunity. In a validation cohort of 43 patients activated immune cell subsets defined by multi-colour flow cytometry associated with cerebral ischemia and coronary artery disease. Conclusion Here, we uncover yet undefined immune cell types associating with clinical disease. This leukocyte atlas of human atherosclerosis builds the conceptual basis for subsequent identification of cellular targets for clinical immunomodulatory therapies and risk prediction. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): ERC Starting Grant

Pretherapeutic Comparative Dosimetry of 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T in Patients with Metastatic Castration-Resistant Prostate Cancer.

Radiohybrid prostate-specific membrane antigen (rhPSMA) ligands allow for labeling with 18F and radiometals for endoradiotherapy. rhPSMA-7.3 has been designated as a lead compound with promising preclinical data for 177Lu-rhPSMA-7.3, which has shown higher tumor uptake than 177Lu-PSMA I&T. In this retrospective analysis, we compared pretherapeutic clinical dosimetry data of both PSMA ligands. Methods: Six patients with metastatic castration-resistant prostate cancer underwent both 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T pretherapeutic dosimetry. Whole-body scintigraphy was performed at 1 h, 4 h, 24 h, 48 h, and 7 d after injection. Regions of interest covering the whole body, organs, bone marrow, and tumor lesions were drawn for each patient. Absorbed doses for individual patients and pretherapeutic applications were calculated using OLINDA/EXM. To facilitate the comparison of both ligands, we introduced the therapeutic index (TI), defined as the ratio of mean pretherapeutic doses to tumor lesions over relevant organs at risk. Results: Mean whole-body pretherapeutic effective doses for 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T were 0.12 ± 0.07 and 0.05 ± 0.03 Sv/GBq, respectively. Mean absorbed organ doses for 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T were, for example, 1.65 ± 0.28 and 0.73 ± 0.18 Gy/GBq for the kidneys, 0.19 ± 0.09 and 0.07 ± 0.03 Gy/GBq for the liver, 2.35 ± 0.78 and 0.80 ± 0.41 Gy/GBq for the parotid gland, and 0.67 ± 0.62 and 0.30 ± 0.27 Gy/GBq for the bone marrow, respectively. Tumor lesions received mean absorbed doses of 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T of 6.44 ± 6.44 and 2.64 ± 2.24 Gy/GBq, respectively. The mean TIs for the kidneys were 3.7 ± 2.2 and 3.6 ± 2.2 for 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T, respectively, and those for the bone marrow were 15.2 ± 10.2 and 15.1 ± 10.2 for 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T, respectively. Conclusion: Pretherapeutic clinical dosimetry confirmed preclinical results of mean absorbed doses for tumors that were 2-3 times higher for 177Lu-rhPSMA-7.3 than for 177Lu-PSMA I&T. Absorbed doses to normal organs also tended to be higher for 177Lu-rhPSMA-7.3, resulting overall in similar average TIs for both radiopharmaceuticals with considerable interpatient variability. 177Lu-rhPSMA-7.3 has promise for a therapeutic efficacy similar to that of 177Lu-PSMA I&T at smaller amounts of injected activity, simplifying radiation safety measurements (especially for large patient numbers or dose escalation regimens).

Healthcare Resource Utilization and Costs in Patients with Geographic Atrophy Secondary to Age-Related Macular Degeneration.

PurposeGeographic atrophy (GA) is an advanced form of nonexudative age-related macular degeneration (AMD) that lacks treatment options. With considerable interpatient variability in the rate of GA progression due to lesion characteristics, information characterizing the disease burden is limited. The aim of this study was to describe the healthcare resource utilization (HCRU) and costs associated with increasing severity levels of GA.Patients and MethodsA retrospective analysis was conducted using claims data from IQVIA’s PharMetrics Plus database. Patients with a prevalent GA diagnosis were identified between October 1, 2016 and June 30, 2017 and classified by disease severity and laterality. Disease-specific HCRU and costs by disease severity were assessed during the 12-month follow-up period, with multivariable analyses performed adjusting for baseline characteristics.ResultsA total of 28,773 GA cases were identified (mean age = 68.7; 58.5% female), of which 24% and 76% had unilateral and bilateral GA, respectively, with varying levels of recorded severity (in increasing order): early or intermediate (EI) AMD, GA without subfoveal involvement (GAwoSF), and GA with subfoveal involvement (GAwSF). Patients with greater baseline severity in the bilateral group had a significantly higher number of outpatient (OP) visits per year (1.98 EI AMD; 2.57 for GAwoSF; 2.63 for GAwSF). Increasing disease severity was associated with higher patient-related costs in the outpatient setting (mean [SD] of $82 [$157], $110 [$559] for unilateral EI AMD and GAwSF, respectively, and $56 [$94], $64 [$97], $59 [$85] for bilateral EI AMD, GAwoSF, GAwSF, respectively). Similarly, higher payer-related costs were seen in patients with bilateral GAwSF compared to bilateral EI AMD (mean [SD] $280 [$325]; $198 [$262]).ConclusionStudy findings demonstrate that patients, with more severe GA at baseline, experience greater HCRU and costs in the outpatient setting. Further research should explore specific contributing factors to the long-term economic burden of GA.

Complex Factors and Challenges that Affect the Pharmacology, Safety and Efficacy of Nanocarrier Drug Delivery Systems.

Major developments in nanomedicines, such as nanoparticles (NPs), nanosomes, and conjugates, have revolutionized drug delivery capabilities over the past four decades. Although nanocarrier agents provide numerous advantages (e.g., greater solubility and duration of systemic exposure) compared to their small-molecule counterparts, there is considerable inter-patient variability seen in the systemic disposition, tumor delivery and overall pharmacological effects (i.e., anti-tumor efficacy and unwanted toxicity) of NP agents. This review aims to provide a summary of fundamental factors that affect the disposition of NPs in the treatment of cancer and why they should be evaluated during preclinical and clinical development. Furthermore, this chapter will highlight some of the translational challenges associated with elements of NPs and how these issues can only be addressed by detailed and novel pharmacology studies.

Population pharmacokinetic modelling of intravenous immunoglobulin in patients with predominantly antibody deficiencies.

There is considerable interpatient variability in the pharmacokinetics (PK) of intravenous immunoglobulin G (IVIG), causing difficulty in optimizing individual dosage regimen. This study aims to estimate the population PK parameters of IVIG and to investigate the impact of genetic polymorphism of the FcRn gene and clinical variability on the PK of IVIG in patients with predominantly antibody deficiencies. Patients were recruited from four hospitals. Clinical data were recorded and blood samples were taken for PK and genetic studies. Population PK parameters were estimated by nonlinear mixed-effects modelling in Monolix®. Models were evaluated using the difference in objective function value, goodness-of-fit plots, visual predictive check and bootstrap analysis. Monte Carlo simulation was conducted to evaluate different dosing regimens for IVIG. A total of 30 blood samples were analysed from 10 patients. The immunoglobulin G concentration data were best described by a one-compartment model with linear elimination. The final model included both volume of distribution (Vd) and clearance (CL) based on patient's individual weight. Goodness-of-fit plots indicated that the model fit the data adequately, with minor model mis-specification. Genetic polymorphism of the FcRn gene and the presence of bronchiectasis did not affect the PK of IVIG. Simulation showed that 3-4-weekly dosing intervals were sufficient to maintain IgG levels of 5gL-1 , with more frequent intervals needed to achieve higher trough levels. Body weight significantly affects the PK parameters of IVIG. Genetic and other clinical factors investigated did not affect the disposition of IVIG.

Comparison of Individualized Versus MAP-Bayesian Predicted AUC of Busulfan in FluBu4 Treated Patients Undergoing Allogeneic Transplant

Although myeloablative fludarabine/busulfan (FluBu4) has been widely adopted in clinical practice, considerable interpatient variability exists in systemic busulfan exposure (AUC) when using body weight or body surface area based-dosing, leading to decreased efficacy (i.e. relapse) or increased toxicity (i.e., mucositis, veno-occlusive disease). This well-defined dose-exposure-outcome relationship has led to the widespread clinical implementation of therapeutic drug monitoring (TDM). However, individualized TDM can be time and labor intensive as well as potentially biased due to the lack of incorporation of any previously established PK data (Bayesian prior). In contrast, Bayesian maximum a posteriori (MAP) PK models consider the Bayesian prior and individualized TDM to generate a revised probability distribution (Bayes conditional posterior) to more accurately and rapidly estimate the AUC with reduced bias. There are a paucity of data comparing busulfan AUCs using individualized PK versus MAP-Bayesian-based models in adults although these more sophisticated approaches may assist in optimizing dosing of busulfan in this vulnerable population. This was a retrospective, single-center study of patients who received FluBu4 with busulfan TDM between January 1999 and September 2019. 109 patients diagnosed with a hematologic malignancy who received either sequential (n=46) or concurrent (n=63) FluBu4 were analyzed. The median age was 48 (range: 18-66), and were Hispanic (n=38), White (n=46) or African-American (n=14). TDM was performed either after a test dose of 0.8 mg/kg (n=52) or after the first dose (3.2 mg/kg) of busulfan administered during the preparative regimen (n=71), with dosing was based on actual or adjusted body weight. For PK analysis, plasma busulfan concentrations were analyzed via gas chromatography with mass selective detection. Individualized PK data were generated using WinNonlin while the MAP-Bayesian approach utilized the Bayesian prior developed from McCune et al (Clin Cancer Res, 2014). An AUC of 4800 µM˖min/24 hours was targeted based on previous literature. Based on individualized PK data, total recommended busulfan doses ranged from 9.3-21.3 mg/kg (-27.1% to +66.7% compared to FDA labeled dose of 12.8 mg/kg). When first-dose busulfan PK was compared between busulfan given sequentially versus concurrently with fludarabine there was a trend towards a higher AUC with concomitant administration (4651 vs. 4988 µM˖min; p=0.13). A strong correlation between the AUC generated from both the individualized PK an MAP-Bayesian models was observed with both the test dose (R2=0.91) and first dose (R2=0.86) of busulfan. Using the MAP Bayesian model, AUC predictions were on average higher (mean AUC 5069 versus 4886 µM˖min, p&amp;lt;0.0001) compared to the patient-specific individualized PK estimates. Figure 1 shows the Bland Altman plots for comparison of the individualized AUC vs. MAP-Bayesian estimates for test dose and first dose. Our individualized busulfan PK approach generated relatively similar AUC values compared to MAP-Bayesian estimates, although the higher AUC generated via MAP-Bayesian predictions may allow for lower doses of busulfan to be administered thereby potentially reducing toxicity while maintaining efficacy. Further, use of the MAP-Bayesian method may allow for more rapid dose optimization and a decreased number of serum concentrations. Further prospective studies including more patients are warranted to confirm these findings. Figure 1 Disclosures Calip: Flatiron Health: Current Employment. Patel:Janssen: Consultancy; Amgen: Consultancy; Celgene: Consultancy.

MTXPK.org: A Clinical Decision Support Tool Evaluating High-Dose Methotrexate Pharmacokinetics to Inform Post-Infusion Care and Use of Glucarpidase.

Methotrexate (MTX), an antifolate, is administered at high doses to treat malignancies in children and adults. However, there is considerable interpatient variability in clearance of high‐dose (HD) MTX. Patients with delayed clearance are at an increased risk for severe nephrotoxicity and life‐threatening systemic MTX exposure. Glucarpidase is a rescue agent for severe MTX toxicity that reduces plasma MTX levels via hydrolysis of MTX into inactive metabolites, but is only indicated when MTX concentrations are > 2 SDs above the mean excretion curve specific for the given dose together with a significant creatinine increase (> 50%). Appropriate administration of glucarpidase is challenging due to the ambiguity in the labeled indication. A recent consensus guideline was published with an algorithm to provide clarity in when to administer glucarpidase, yet clinical interpretation of laboratory results that do not directly correspond to the algorithm prove to be a limitation of its use. The goal of our study was to develop a clinical decision support tool to optimize the administration of glucarpidase for patients receiving HD MTX. Here, we describe the development of a novel 3‐compartment MTX population pharmacokinetic (PK) model using 31,672 MTX plasma concentrations from 772 pediatric patients receiving HD MTX for the treatment of acute lymphoblastic leukemia and its integration into the online clinical decision support tool, MTXPK.org. This web‐based tool has the functionality to utilize individualized demographics, serum creatinine, and real‐time drug concentrations to predict the elimination profile and facilitate model‐informed administration of glucarpidase.