Faculty Bibliography

As American universities become increasingly diverse, students often encounter cross-cultural challenges. Chinese students represent a substantial international U.S. student community, with distinctive pragmatic norms and values. This study investigates Chinese international and American graduate students"™ intercultural pragmatic strategies towards a face-threatening critical incident: expressing disagreement to a professor. Our mixed-methods design revealed quantitative and qualitative differences in participants"™ strategies and judgments of alternatives, demonstrating distinctive underlying norms and values. Many American participants preferred to express different opinions in class, while Chinese students privileged more indirect options, though each group included participants with alternate preferences. Implications for cross-cultural communication and pedagogy are offered.

Mismatch repair-deficient (dMMR) endometrial cancer is an inflamed phenotype with poor outcomes when meeting high-risk criteria and limited treatment options in the adjuvant setting. We report protocol-prespecified subgroup analysis of patients with dMMR tumors from the phase 3 ENGOT-en11/GOG-3053/KEYNOTE-B21 study (NCT04634877) in newly-diagnosed, high-risk endometrial cancer after surgery with curative intent. Patients were randomized to pembrolizumab 200mg or placebo (6 cycles) plus carboplatin-paclitaxel (4-6 cycles) Q3W, then pembrolizumab 400mg or placebo Q6W (6 cycles), respectively. MMR status was a stratification factor. Patients received radiotherapy at investigator discretion. Investigator-assessed disease-free survival (DFS) was a primary endpoint. No formal hypothesis testing was performed for subgroup analysis. In the intention-to-treat population, 141 patients in the pembrolizumab arm and 140 in the placebo arm had dMMR tumors. At this interim analysis, hazard ratio for DFS favored pembrolizumab (0.31; 95%CI, 0.14-0.69); median DFS was not reached in either group. Two-year DFS rates were 92.4% (95%CI, 84.4%-96.4%) and 80.2% (95%CI, 70.8%-86.9%), respectively. No new safety signals occurred. Longer-term follow-up of outcomes will be evaluated at final analysis. Preplanned subgroup analysis based on the study's stratification factors suggests that pembrolizumab plus chemotherapy improves DFS and is clinically relevant for patients with dMMR tumors in the curative-intent setting.

BACKGROUND:Resection of glioblastoma (GBM) in eloquent regions depends on functional mapping to limit perioperative neurological morbidity. When neurological deficits preclude reliable mapping, neurosurgeons should explore potential mitigation strategies. The authors present the case of a patient with a large left cystic temporoinsular GBM and aphasia, for whom the authors used intraoperative language mapping and a staged approach to enable safe tumor resection. OBSERVATIONS/METHODS:A 49-year-old female presented with progressive mixed aphasia for 1 month and new-onset right facial droop. Magnetic resonance imaging (MRI) revealed a large, heterogeneously enhancing, left temporoinsular tumor with a significant cystic component. Her aphasia was profound, and resection without reliable language mapping was deemed unsafe. An initial stereotactic tumoral cyst aspiration was performed, which reduced local mass effect and improved her language function. Cyst decompression thereby enabled both task-based functional MRI and intraoperative awake speech mapping, resulting in a safe resection of her GBM. LESSONS/CONCLUSIONS:Safe resection of eloquently localized GBM is compromised when neurological deficits prohibit intraoperative functional mapping. This case demonstrates a mitigation strategy specific to cystic lesions in which an initial-stage stereotactic cyst aspiration is aimed at generating sufficient interval neurological improvement, such that intraoperative functional mapping can be performed during a second-stage resection. https://thejns.org/doi/10.3171/CASE24362.

Juvenile polyposis syndrome lies within the family of hamartomatous polyposis syndromes characterized by polyps that appear benign but harbor an increased risk of colorectal and gastric cancer. This 27-year-old man with severe ulcerative colitis was discovered to have concomitant juvenile polyposis syndrome during diagnostic workup for gastrointestinal bleeding. The implications of this rare association complicate both diagnostic and treatment modalities since both diseases confer an increased risk of cancer.

BACKGROUND AND OBJECTIVES/UNASSIGNED:As the population of U.S. service members (SMs) who have sustained concussions and more severe traumatic brain injuries (TBIs) during military service ages, understanding the long-term outcomes associated with such injuries will provide critical information that may promote long-term assessment, support, and rehabilitation following military service. The objective of this research was to examine whether concussion and more severe TBIs are associated with greater risk of precursors to dementia (i.e., mild cognitive impairment, memory loss), early-onset dementia, and any dementia. METHODS/UNASSIGNED: = 1,211,972). Diagnoses of concussion and more severe TBI during active duty service recorded in inpatient settings between 1980 and 2020 and in outpatient settings from 2001 to 2020 were identified. Focal outcomes of interest included memory loss, mild cognitive impairment, Alzheimer's, Lewy Body dementia, frontotemporal dementia, and vascular dementia. Dementia diagnoses before age 65 were labeled early-onset. RESULTS/UNASSIGNED:Those with (vs. without) concussion diagnoses during military service were significantly more likely to be diagnosed with memory loss and mild cognitive impairment and any of the dementias examined. However, they were not at greater risk of being diagnosed with early-onset dementia. DISCUSSION/UNASSIGNED:Military SMs diagnosed with concussion may be at elevated risk for long-term neurodegenerative outcomes including memory loss, mild cognitive impairment, and dementia. As the population of SMs who sustained TBI during the Global War on Terror continue to age, the prevalence of dementia will increase and may bring a unique burden to the VHA.

Muscle-specific kinase (MuSK) is essential for the formation, function, and preservation of neuromuscular synapses. Activation of MuSK by a MuSK agonist antibody may stabilize or improve the function of the neuromuscular junction (NMJ) in patients with disorders of the NMJ, such as congenital myasthenia (CM). Here, we generated and characterized ARGX-119, a first-in-class humanized agonist monoclonal antibody specific for MuSK, that is being developed for treatment of patients with neuromuscular diseases. We performed in vitro ligand-binding assays to show that ARGX-119 binds with high affinity to the Frizzled-like domain of human, nonhuman primate, rat, and mouse MuSK, without off-target binding, making it suitable for clinical development. Within the Fc region, ARGX-119 harbors L234A and L235A mutations to diminish potential immune-activating effector functions. Its mode of action is to activate MuSK, without interfering with its natural ligand neural Agrin, and cluster acetylcholine receptors in a dose-dependent manner, thereby stabilizing neuromuscular function. In a mouse model of DOK7 CM, ARGX-119 prevented early postnatal lethality and reversed disease relapse in adult Dok7 CM mice by restoring neuromuscular function and reducing muscle weakness and fatigability in a dose-dependent manner. Pharmacokinetic studies in nonhuman primates, rats, and mice revealed a nonlinear PK behavior of ARGX-119, indicative of target-mediated drug disposition and in vivo target engagement. On the basis of this proof-of-concept study, ARGX-119 has the potential to alleviate neuromuscular diseases hallmarked by impaired neuromuscular synaptic function, warranting further clinical development.

Due to femoral head-neck deformities and hip joint incongruence, patients with Legg-Calvé-Perthes Disease (LCPD) commonly require total hip arthroplasty (THA) in the fifth and sixth decades of life. These patients present additional challenges to arthroplasty surgeons not only because of their complicated hip anatomy but also because patients may have undergone prior operative procedures in childhood and thus present with pre-existing proximal femoral deformities. THA in LCPD patients can be associated with peri-operative complications such as fracture or nerve injury, and the rate of reoperation has been reported to be higher in the LCPD population as compared to the general population undergoing THA. Despite this, multiple case reports and studies have shown the relative long-term success of THA in patients with history of LCPD. In particular, uncemented modular stems are a commonly used implant choice in such cases. This article reviews and discusses the technical considerations for THA in patients with LCPD and highlights three such cases.

Optimizing immunologic compatibility in organ transplantation extends beyond the conventional approach of Human Leukocyte Antigen (HLA) antigen matching, which exhibits significant limitations. A broader comprehension of the roles of classical and non-classical HLA genes in transplantation is imperative for enhancing long-term graft survival. High-resolution molecular HLA genotyping, despite its inherent challenges, has emerged as the cornerstone for precise patient-donor compatibility assessment. Leveraging understanding of eplet biology and indirect immune activation, eplet mismatch calculators and the PIRCHE-II algorithm surpass traditional methods in predicting allograft rejection. Understanding minor histocompatibility antigens may also present an opportunity to personalize the compatibility process. While the application of molecular matching in deceased donor organ allocation presents multiple technical, logistical, and conceptual barriers, rendering it premature for mainstream use, several other areas of donor-recipient matching and post-transplant management are ready to incorporate molecular matching. Provision of molecular mismatch scores to physicians during potential organ offer evaluations could potentially amplify long-term outcomes. The implementation of molecular matching in living organ donation and kidney paired exchange programs is similarly viable. This article will explore the current understanding of immunologic matching in transplantation and the potential applications of epitope and non-epitope molecular biology and genetics in clinical transplantation.