Faculty Bibliography

The management of drug-resistant epilepsy (DRE) in the pediatric population using neurostimulation of the centromedian (CM) nucleus of the thalamus (CMN) has been reported to be effective and safe. We present a case series of pediatric patients treated with responsive neurostimulation (RNS) and report on contact localization in relation to preliminary outcomes, specifically seizure reduction rates. Thirteen pediatric patients treated with RNS underwent direct targeting of the CMN based on Magnetization-Prepared 2 Rapid Gradient-Echo (MP2RAGE) scans, using ClearPoint neuronavigation. The implanted electrodes were co-registered to a probabilistic anatomical model of the thalamic nuclei (Freesurfer) for secondary confirmation of contact localization. Ten out of the 12 patients with extra-temporal multifocal or generalized DRE (83.3%) had over 50% reduction in seizures, benefiting from an 80.4% seizure reduction rate. The average follow-up interval was 25.2 months, with no patients experiencing stimulation-related side effects. The analysis of post-operative images revealed that out of the 24 CM-processed electrodes, 23 (95.8%) had at least two contacts in the nucleus, based on patient-specific segmentation of the thalamus. The preliminary outcomes suggest a robust response to central neurostimulation and no stimulation-related side effects in pediatric patients suffering from multifocal or generalized DRE when implementing high-accuracy direct targeting. PLAIN LANGUAGE SUMMARY: We are reporting our experience in the management of the most challenging types of pediatric epilepsy, involving seizures originating from multiple and/or poorly defined brain areas. We surgically implanted a responsive neurostimulation device (RNS) in central areas of the brain that function as connection hubs between different brain regions. These devices are designed to detect early signs of abnormal brain activity, and respond with electrical pulses to prevent progression to clinical seizures. Using our approach, we reduced the seizure rates by an average of 80% in 83% of the pediatric patients who received this treatment.

Xenotransplantation of genetically-modified pig kidneys offers a solution to the scarcity of organs for end-stage renal disease patients.¹ We performed a 61-day alpha-Gal knock-out pig kidney and thymic autograft transplant into a nephrectomized brain-dead human using clinically approved immunosuppression, without CD40 blockade or additional genetic modification. Hemodynamic and electrolyte stability and dialysis independence were achieved. Post-operative day (POD) 10 biopsies revealed glomerular IgM and IgA deposition, activation of early complement components and mesangiolysis with stable renal function without proteinuria, a phenotype not seen in allotransplantation. On POD 33, an abrupt increase in serum creatinine was associated with antibody-mediated rejection and increased donor-specific IgG. Plasma exchange, C3/C3b inhibition and rabbit anti-thymocyte globulin (rATG), completely reversed xenograft rejection. Pre-existing donor-reactive T cell clones expanded progressively in the circulation post-transplant, acquired an effector transcriptional profile and were detected in the POD 33 rejecting xenograft prior to rATG treatment. This study provides the first long-term physiologic, immunologic, and infectious disease monitoring of a pig-to-human kidney xenotransplant and indicates that pre-existing xenoreactive T cells and induced antibodies to unknown epitope(s) present a major challenge, despite significant immunosuppression. It also demonstrates that a minimally gene-edited pig kidney can support long-term life-sustaining physiologic functions in a human.

In children undergoing craniotomy, the impact of postoperative pain on recovery is receiving growing recognition. While opioids are often the primary treatment, their administration requires a delicate balance between achieving sufficient analgesia and mitigating side effects like sedation, nausea, vomiting, and respiratory depression. We review the emerging adjunct treatment modality regional scalp block (RSB) infiltration for post-craniotomy pain. Postoperative pain after pediatric craniotomy can be challenging to manage and may contribute to unnecessary suffering as well as the development of long-term neurocognitive and psychological sequelae. Pain during the PICU stay is also a major risk factor for post-PICU syndrome, which involves persistent impairments in children's physical, cognitive, or mental health persisting beyond acute hospitalization. Despite increasing awareness and treatment strategies for post-craniotomy pain in adults, significant gaps remain in understanding its assessment and management in children. This review examines the current literature surrounding post-craniotomy pain management in children with a special emphasis on RSB, a treatment option increasingly used in adults and children. RSB has been shown in randomized trials to reduce postoperative pain and opioid use. However, while pediatric perioperative trials support its safety and feasibility, robust clinical evidence supporting RSB's efficacy for post-craniotomy pain in children remains limited, hindering wider translation into clinical standard. RSB infiltration is an emerging and promising technique for pediatric post-craniotomy pain management. Early evidence suggests it is both safe and effective, with potential to enhance postoperative recovery and to be integrated into clinical practice. Further research is critical to validate initial findings and better define the benefits across diverse pediatric populations.

BACKGROUND AND OBJECTIVE/OBJECTIVE:Only a minority of renal oncocytic tumors are aggressive. These tumors' behavior is difficult to predict by histopathological evaluation; consequently, many patients experience anxiety upon diagnosis and may undergo unnecessary treatment. Our aim was to derive genomic and epigenomic signatures to distinguish clinically indolent renal oncocytic tumors from aggressive chromophobe renal cell carcinoma (ChRCC). METHODS:We performed molecular profiling of nephrectomies from 68 patients: 44 with indolent renal oncocytic tumors (19 renal oncocytoma, two oncocytic renal neoplasm of low malignant potential, and 23 indolent ChRCC) and 24 with aggressive ChRCC. We performed targeted exome sequencing, gene expression profiling, and whole-genome methylation sequencing of formalin-fixed, paraffin-embedded (FFPE) samples. We also analyzed The Cancer Genome Atlas Kidney Chromophobe data from 66 ChRCC patients in silico. Genomic and epigenomic signatures linked to aggressive ChRCC-obtained from sampling morphologically nonsarcomatoid foci-from both cohorts were derived using the least absolute shrinkage and selection operator method. KEY FINDINGS AND LIMITATIONS/UNASSIGNED:Aggressive ChRCC was distinguished from indolent ChRCC and other indolent renal oncocytic tumors using a focused seven- to 11-gene expression signature (ten-fold cross-validation [CV] area under the curve [AUC] = 0.77-0.85) with an external validation AUC of 0.88, and an eight-CpG methylation signature (ten-fold CV AUC = 0.86) with an external validation AUC of 0.91. TP53 and PTEN mutations substantially increased the probability of aggressive ChRCC. Limitations include the small sample size. CONCLUSIONS AND CLINICAL IMPLICATIONS/CONCLUSIONS:Focused genomic and epigenomic signatures from routinely processed FFPE tumor tissues can help distinguish aggressive ChRCC from indolent renal oncocytic tumors, including indolent ChRCC. This forms the basis for replication studies to inform appropriate patient management, provide reassurance, and guide follow-up.

METHODS:This study assessed the safety of the lateral femoral cutaneous and over the hip (LOH) block, a regional anesthetic, in anticoagulated hip fracture patients while maintaining efficacy. A retrospective review of patients diagnosed with hip fractures (AO/OTA 31A/B) who presented to a single academic medical center and level 1 trauma center actively using oral anticoagulants. Patients were grouped based on anesthesia type: LOH block (LOH) versus general anesthesia (GA) and LOH versus spinal anesthesia (SA). LOH patients were matched based on anticoagulant type, OTA/AO classification, and risk (STTGMA) score with a 3:1 ratio to GA and a 1:1 ratio to SA. Outcome comparisons included: time to surgery, operative and anesthesia time, and bleeding complications, demographics (age, sex, race, BMI, CCI, and STTGMA), postoperative complications, 90-day readmission rates, mortality within 1 year, and discharge location. RESULTS:A total of 135 patients: 27 LOH, 27 SA, and 81 GA, were analyzed. Compared to GA, LOH block patients had a shorter time to surgery (1.31 ± 0.082 vs. 0.89 ± 0.69, p = 0.014), lower rates of 90-day readmission (3.7% vs. 19.8%, p = 0.047), and a greater discharge to home with health services rate (33.3% vs. 8.6%, p = 0.024). The GA population trended-toward more major complications (p = 0.077) and mortality within 1 year (p = 0.077). Compared to SA, LOH patients were slightly underweight (25.1 ± 4.19 vs. 22.7 ± 4.16, p = 0.035) and got to surgery faster (0.89 ± 0.69 vs 1.54 ± 1.48, p = 0.039). Across all groups, there were no differences in the need for blood transfusion or other quality markers. CONCLUSION/CONCLUSIONS:The LOH block was safe and effective for use in anticoagulated hip fracture patients. This technique provided an intraoperative safety profile similar to other anesthetic choices, allowed for less delay to surgery compared to spinal anesthesia and improved discharge parameters compared to GA. LEVEL OF EVIDENCE III/METHODS:Prognostic Level III.

BACKGROUND:Some pulse oximeters perform worse in people with darker skin, and this may be due to inadequate diversity of skin pigment in device development study cohorts. Guidance is needed to accurately and equitably characterize skin pigment to ensure diversity in research cohorts. We tested multiple methods for characterizing skin pigment to assess comparability and impact on cohort diversity. OBJECTIVES/OBJECTIVE:Assess reliability and comparability of common skin pigment measurement methods Compare findings from different anatomical sites Demonstrate that pigment cannot be assumed from US National Institutes for Health (NIH) race categories. METHODS:We used three subjective methods (perceived Fitzpatrick pFP, Monk Skin Tone MST and Von Luschan VL) and two objective methods (Konica Minolta CM-700d spectrophotometer and Delfin Skin Color Catch DSCC colorimeter) for individual typology angle (ITA), across multiple measurement sites in adults. We calculated ΔE to estimate operator perceptibility thresholds for subjective methods and to determine reproducibility for objective methods. We used each method to categorize participants as 'light, medium, or dark' and compared the impact of method selection on cohort diversity. RESULTS:We studied 789 participants, with 33,856 assessments. The MST had the widest luminosity range, and VL had the least discernible adjacent categories. With 'dark' defined as ITA <-30°, 14% of participants were categorized 'dark' as compared to 26% by pFP or 16% by MST. Approximately half of the 'dark' cohort had an ITA <-50°. With an ITA threshold <-50°, only 7% of the cohort was categorized as 'dark.' When 'Black or African American' self-identification was used to define 'dark', 23% of the cohort was categorized as such. Each self-assigned NIH race category included a wide range of ITA and subjective scale categories. Both ITA and L* from the KM-700d and DSCC demonstrated strong correlation (⍴ > 0.7). CONCLUSION/CONCLUSIONS:Common methods for skin pigment characterization, especially the use of race or subjective scales, have significant limitations. When applied to the same cohort, different methods yield significantly different results, and some may overestimate diversity. Previously published ITA thresholds for defining 'dark' skin are too light and lead to underrepresentation of people with darker skin.

Theories propose that speech production can be approximated as a temporal reversal of speech perception. For example, phonological code is assumed to precede phonetic encoding in the motor system during speech production. However, empirical neural evidence directly testing the temporal order hypothesis remains scarce, mostly because of motor artifacts in non-invasive electrophysiology recordings and the requirements of both temporal and spatial precision. In this study, we investigated the neural dynamics of speech production using stereotactic electroencephalography (sEEG). In both onset latency analysis and representational similarity analysis (RSA), activation in the auditory region of the posterior superior temporal gyrus (pSTG) was observed before articulation, suggesting the availability of auditory phonological code before production. Surprisingly, the activation in the motor region of the inferior frontal gyrus (IFG) preceded that of pSTG, suggesting that the phonological code in the auditory domain may not necessarily be activated before the encoding in the motor domain during speech production.