Indiana University – Purdue University Indianapolis

Drug-drug interaction (DDI) management is critical for safe and effective use of oral anticancer drugs (OADs). Our study objectives were to (i) compile clinically relevant pharmacokinetic (PK) DDI mechanisms for OADs and (ii) assess the prevalence of PK potential DDIs (PDDIs) in patients with advanced solid cancers. OADs approved through January 2023 were assigned DDI mechanisms based on studies obtained from drug labels and primary literature showing ≥ 2-fold exposure change or significant adverse health outcomes during co-administration with interacting drugs. Electronic health records of 3,697 solid cancer patients were reviewed retrospectively to detect PDDIs, defined as overlapping prescriptions of OADs with relevant interacting drugs. FDA labels were reviewed for 99 OADs, and 239 studies were extracted from the primary literature, yielding a total of 748 drug-drug pairs for analysis. Eighty-five OADs (85.9%) had ≥ 1 DDI mechanism. The most common DDI mechanisms were victims with metabolic inducers (71.7%), CYP3A substrates (55.6%), CYP3A perpetrators (29.3%), and victims with acid reducers (17.2%). Our primary literature search detected clinically relevant DDI mechanisms without actionable recommendations in the drug labels for 14 drugs. Among patients prescribed ≥ 1 OADs (46.9%), 17.4% had ≥ 1 PDDI, most commonly involving OADs acting as CYP3A (58.9%) or CYP2D6 (32.5%) perpetrators. Most OADs (~86%) had ≥ 1 DDI mechanism, and ~17% of solid tumor board patients had a clinically relevant PDDI.

Although most imaging assessments are made qualitatively, quantitative measurements in orthopedic imaging are becoming more important in detecting subtle findings and assessing degrees of abnormality, which can help direct surgical management. In the knee, patellofemoral maltracking is a common cause of anterior pain, particularly in younger patients. Failure to recognize this pathophysiology may result in accelerated chondral loss and osteoarthritis (OA), and the imaging findings may be subtle. As a result, clinicians and radiologists have developed numerous measurements to detect and quantify patellofemoral alignment. Additional entities, such as femorotibial subluxation or angular abnormalities, may only be detected by using standardized measurements and can help detect ligamentous insufficiency or developmental malalignment, which can lead to instability and OA in the medial and lateral femorotibial compartments. Finally, the proper positioning and hardware selection for knee arthroplasty are critical to preventing early hardware failure and postsurgical pain. This review, which focuses on the knee, is the second in a three-part series discussing the appropriate imaging modalities on which to obtain specific lower extremity measurements as well as proper measurement techniques, grouped by pathology. Furthermore, the normal value or range of values according to current literature is reported, along with the significance of abnormal measurements.

Polyaminopathies are a recently described family of rare genetic neurodevelopmental disorders. Polyaminopathies disrupt the biosynthesis of the primary polyamines: putrescine, spermidine, and spermine. Snyder-Robinson syndrome results from hemizygous loss-of-function variants in the spermine synthase (SMS) gene, resulting in decreased or complete loss of spermine synthase enzyme activity. Bachmann-Bupp syndrome results from heterozygous gain-of-function variants in the ornithine decarboxylase 1 (ODC1) gene, resulting in increased ornithine decarboxylase enzyme activity. Faundes-Banka syndrome results from heterozygous loss-of-function variants in the eukaryotic translation initiation factor 5A (EIF5A) gene, impairing eIF5A protein function. DHPS (deoxyhypusine synthase) deficiency is an autosomal recessive disease and results from bi-allelic hypomorphic variants in the deoxyhypusine synthase (DHPS) gene, which results in reduced deoxyhypusine synthase enzyme activity. Finally, DOHH (deoxyhypusine hydroxylase) disorder is an autosomal recessive disorder caused by bi-allelic loss-of-function variants in the deoxyhypusine hydroxylase (DOHH) gene, which causes decreased deoxyhypusine hydroxylase enzyme activity. Snyder-Robinson syndrome was first described in 1969, while the other four syndromes have only been identified in the past 7 years. A comprehensive phenotypic and genotypic description of these five syndromes is needed. We review the clinical and genetic features of these five polyaminopathies to create an inclusive clinical resource. A systematic keyword search strategy was used to identify all published cases in PubMed, Web of Science, and Scopus databases. The five known syndromes associated with the polyamine pathway share many similar clinical phenotypes, and yet patients with each syndrome present with distinctive syndromic features. This review will serve as a valuable resource for clinicians diagnosing and caring for patients with these rare polyaminopathies.

High-throughput transcriptomic technologies have advanced rapidly, enabling genome-wide gene expression profiling. Microarrays, introduced in 1995, laid the foundation for large-scale analysis but were later surpassed in 2008 by RNA sequencing (RNA-seq), which offers single-nucleotide resolution, detects low-abundance transcripts, and does not require prior sequence knowledge. Bulk RNA-seq provides robust insights into global transcriptomic changes but lacks single-cell resolution. Single-cell RNA-seq (scRNA-seq), introduced in 2009, addressed this limitation by revealing cellular heterogeneity and dynamic gene expression. However, its application in bone research is constrained due to difficulties in releasing bone cells called osteocytes from the mineralized matrix, often resulting in low yield and dissociation-induced artifacts. In order to address these challenges, single-nucleus RNA-seq (snRNA-seq), first introduced in 2016 to enable transcriptomic profiling from isolated nuclei, was used in this study. We developed a protocol for snRNA-seq on bone tissue, achieving high-yield recovery of osteocyte nuclei from snap-frozen, marrow-flushed long bones. This approach minimized dissociation bias and enhanced osteocyte representation. We applied this robust method to long bones from young adult male and female mice, generating a high-resolution map of osteocyte gene expression under physiological conditions. Compared to scRNA-seq datasets, where osteocytes represent only 0.18%-6.64% of cells, our snRNA-seq approach increased osteocyte capture and transcriptomic fidelity to 18.5%. We identified an osteocyte transcriptomic signature highlighting the top 30 genes, including Sost, which is typically undetected or lowly-expressed in scRNA-seq. Notably, 23 of these genes have not been well-characterized in osteocytes, including Tg, Kcnq5, Rapgef4os1, Cacna1a, Egr3, Dok5, and Lgr6, which may represent novel regulators of osteocyte biology. This study represents the first application of snRNA-seq specifically for osteocyte analysis in bone tissue, providing a valuable resource for investigating osteocyte biology and skeletal disorders.

The study goal was to evaluate the outcomes associated with albumin use in children with sepsis and shock compared with those without shock, using causal inference analysis in a multicenter cohort. This was a secondary analysis of electronic health record data collected from 13 U.S. PICUs between 2012 and 2018, consisting of children younger than 18 years who met Phoenix sepsis criteria within the first 24 hours of PICU admission. Covariate-balancing propensity score weighting was applied to adjust for indication bias in the albumin use. Patients receiving at least 0.5 g/kg albumin within 24 hours of PICU admission were assigned to the albumin group; others to the control. Only 24-hour survivors were included to address immortal time bias. Overall, 17,307 children with sepsis survived at least 24 hours. Of these, 1,344 patients (7.8%) who received albumin within the first 24 hours, and 9,678 (55.9%) met the criteria for septic shock. A significant interaction between albumin use and shock status was observed (interaction: -0.353, p = 0.007), with albumin administration in pediatric septic shock patients associated with lower in-hospital mortality: odds ratio equals to 0.698 (95% CI, 0.629-0.774), risk ratio equals to 0.746 (95% CI, 0.625-0.891), and hazard ratio equals to 0.688 (95% CI, 0.558-0.848). In contrast, there was no difference in outcomes between the albumin and control groups in the non-shock group. Early albumin administration was associated with improved outcomes in children with septic shock, but not in those without shock. These results highlight the importance of considering clinical heterogeneity, such as the presence of shock, in identifying treatment-responsive subgroups and enabling more targeted interventions in pediatric sepsis. Further prospective validation is warranted.