Systematic clinical phenotyping using Human Phenotype Ontology (HPO) is central to rare disease diagnosis. However, current disease prioritization (ranking candidate diseases from HPO for a patient) methods face key challenges: they often fail to account for the hierarchical structure of HPO terms, ignore dependencies among correlated terms, and do not adjust for batch effects arising from systematic differences in phenotype documentation across cohorts, institutions, or clinicians. We aim to develop a scalable and statistically principled framework to address these limitations for rare disease prediction and patient stratification. We developed PhenoSS, a Gaussian copula-based framework that models disease-specific marginal prevalence of HPO terms while capturing their joint dependencies through a multivariate normal distribution. Phenotype frequencies were estimated using external curated resources, including OARD (Open Annotations for Rare Diseases) and HPO annotations. PhenoSS supports both pair-wise phenotype similarity calculation for patient clustering and posterior odds estimation for patient-specific disease prioritization. A batch-effect correction module mitigates systematic phenotyping differences across datasets. Across diverse simulation scenarios, PhenoSS demonstrated robust disease-prediction performance and consistently improved accuracy after batch-effect correction. In real electronic health record (EHR) data, PhenoSS identified clinically meaningful patient clusters and effectively distinguished patients with different rare diseases. In disease prioritization tasks, PhenoSS achieved competitive performance with existing methods, particularly for patients exhibiting sparse or noisy phenotype annotations. PhenoSS provides a statistically interpretable framework for modeling phenotypic heterogeneity in rare disease research and is adaptable to other structured clinical vocabularies such as SNOMED-CT and ICD codes.

Vaccinia-related kinase 1 (VRK1) is a promising therapeutic target in gliomas and glioblastomas where VRK2 is silenced by promoter methylation, rendering VRK1 essential for accurate nuclear envelope reassembly following mitosis. Small-molecule ATP-site drug discovery for VRK1 has been hindered by the absence of robust and reproducible biochemical assays. Through virtual screening, we identified previously unreported VRK1-binding scaffolds and validated them in biochemical kinase assays, yielding an 82 nM inhibitor with high selectivity for VRK1 over VRK2. During characterization of this compound, we found that a commonly used commercial time-resolved fluorescence resonance energy transfer VRK1 activity assay is dependent on purification tag-mediated VRK1 dimerization. Leveraging the new inhibitor, we developed fluorogenic tool compounds that increase in fluorescence intensity upon binding to the active site of VRK1 and do not require artificial dimerization of VRK1. The top probe exhibits a Kd of 180 nM and is useful for ligand displacement assays using both fluorescence enhancement and time-resolved fluorescence resonance energy transfer readouts. Together, these results introduce new chemical scaffolds for targeting VRK1, define an assay artifact that has complicated VRK1 inhibitor discovery, and deliver fluorogenic tool compounds for high-throughput screening of ATP-site VRK1 inhibitors, enabling future drug discovery efforts against this emerging cancer vulnerability.

Plastic and reconstructive surgery (PRS) encompasses a wide range of procedures, and postoperative complications remain a persistentchallenge. While preoperative laboratory values (PLVs) are routinely assessed, their predictive value for postoperative outcomes inPRS is unclear. This study evaluates the association between PLVs and postoperative morbidity to enhance risk stratification. The ACS-NSQIP database (2008-2022) was analyzed for PRS patients. PLVs included sodium, blood urea nitrogen, creatinine, albumin, bilirubin, SGOT, alkaline phosphatase, white blood cell count, hematocrit, platelets, partial thromboplastin time, international normalized ratio, and prothrombin time (PT). Multivariate logistic regression identified independent predictors of complications, while decision tree analysis established risk thresholds, validated through cross-validation. A total of 200,015 patients with a mean age of 50.3±14.5 years and a mean BMI of 29.1±6.8 kg/m2 were included in this study. Albumin levels emerged as the strongest predictor for the occurrence of any complications. Patients with albumin ≤ 3.3 g/dL had a 36.5% risk for the occurrence of any complication compared to 10.4% in those with higher levels. In the high-risk group, prolonged PT (> 16.2s) further increased risk for the occurrence of any complications. Also, in the lower-risk group (albumin > 3.3 g/dL), prolonged PT (> 13.7 s) were found to significantly influence complication occurrence. Further, multivariate analysis confirmed reduced albumin (OR 0.460) as the strongest independent predictors for any complication occurrence. Albumin and PT are key predictors of 30-day postoperativecomplications in PRS. Preoperative optimization of these values can enhance patient safety and surgical outcomes. Findings support integrating targeted preoperative evaluations into clinical practice. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Early recognition of postpartum nerve injury is critical for timely intervention and recovery. However, diagnosis is challenging because deficits may mimic residual epidural anesthesia, nerve root injury, or epidural hematoma. Anesthesiologists, often first consulted, are pivotal in early evaluation and diagnosis. Figure 1 shows fat-suppressed T2-weighted pelvic magnetic resonance imaging obtained on postpartum day 7 from a 35-yr-old primiparous woman who reported difficulty lifting her right leg 1 day after vaginal delivery of a 2,670-g infant at 37 + 6 weeks under uneventful epidural labor analgesia (first stage, 12 h; second stage, 1.5 h with mediolateral episiotomy). This image demonstrates T2 hyperintensity in the right pectineus with normal contralateral signal—findings consistent with acute denervation edema and early peripheral neuropathy. Focused examination on postpartum day 1 revealed right hip flexion weakness (3/5) and unexpected adduction weakness (3/5), impairing leg crossing. Reflexes and sensation, including assessment of the obturator nerve’s medial thigh territory, were intact (Supplemental Digital Content fig. S1, https://links.lww.com/ALN/E356). Given that the pectineus may receive obturator nerve innervation, the imaging findings aligned with the adduction weakness and raised suspicion for obturator neuropathy, later confirmed by needle electromyography at 6 weeks, showing spontaneous activity in the right adductor magnus. With conservative management, hip flexion recovered from 4/5 at 1 week to 5/5 by 2 months, and adduction progressed from 4/5 at 1 month to full recovery by 3 months (Supplemental Digital Content video S1, https://links.lww.com/ALN/E357).Fig. 1.: Axial (A) and coronal (B) fat-suppressed T2-weighted fast spin echo pelvic magnetic resonance imaging obtained on postpartum day 7. Yellow arrows indicate increased T2 signal intensity in the right pectineus, with normal signal on the contralateral side (white arrows), consistent with early denervation changes.Electrodiagnostic testing is critical for evaluating peripheral nerve injury but limited within the first 1 to 2 weeks, as denervation signs typically appear 10 to 28 days after injury.1 In contrast, magnetic resonance imaging can detect muscle denervation as early as 24 h,2 is readily available, and visualizes surrounding structures to promptly exclude compressive lesions, making it a valuable tool for early diagnosis and management. Postpartum obturator neuropathy is rare, often due to fetal head or positional compression.3 Anesthesiologists should begin evaluation with a detailed peripartum history and a focused neurologic examination, carefully testing hip adduction, as subtle or compensated deficits may aid localization. Serial assessments clarify symptom evolution, guiding to the underlying cause. If deficits persist or worsen, then early magnetic resonance imaging is essential for differential diagnosis and timely rehabilitation. Competing Interests The authors declare no competing interests. Supplemental Digital Content Supplemental Figure 1. Schematic of medial thigh sensory innervation, https://links.lww.com/ALN/E356 Supplemental Video S1. Serial assessment of right lower limb function over the first 8 weeks postpartum, https://links.lww.com/ALN/E357