Faculty Bibliography

In contrast to living organisms, viruses were long thought to lack protein synthesis machinery and instead depend on host factors to translate viral transcripts. Here, we discover that giant DNA viruses encode a distinct and functional IF4F translation-initiation complex to drive protein synthesis, thereby blurring the line between cellular and acellular biology. During infection, eukaryotic IF4F on host ribosomes is replaced by an essential viral IF4F that regulates viral translation, virion formation, and replication plasticity during altered host states. Structural dissection of viral IF4F reveals that the mRNA cap-binding subunit mediates exclusive interactions with viral mRNAs, constituting a molecular switch from translating host to viral proteins. Thus, our study establishes that viruses express a eukaryotic translation-initiation complex for protein synthesis, illuminating a series of evolutionary innovations in a core process of life.

The rate of recurrent instability following primary medial patellofemoral ligament (MPFL) reconstruction has been reported to be as high as 6.7%. However, limited studies have reported on clinical outcomes and complications following revision MPFL reconstruction. Furthermore, the role of previously identified risk factors for primary failure (e.g., patella alta and trochlear dysplasia) warrants further study in this patient population. Therefore, the goal of this study was 2-fold. First, to evaluate the prevalence of anatomic risk factors and technical errors among patients presenting for revision patellofemoral surgery. Second, to report early clinical outcomes following revision MPFL reconstruction. A single-surgeon registry was queried for patients who underwent revision MPFL reconstruction (including prior MPFL imbrication, MPFL reconstruction, tibial tubercle osteotomy [TTO]) from November 2015 to June 2022. Preoperative imaging was evaluated for risk factors including (1) misplacement of the femoral tunnel, (2) Caton-Deschamps index, (3) tibial tubercle-trochlear groove distance (TT-TG), (4) patellar tilt, and (5) trochlear dysplasia. Patient-reported outcomes and complications were obtained at final follow-up (minimum 1 year). The study included 32 patients (72% female, age: 23.9 ± 6.6 years). Mean time from index surgery to revision MPFL reconstruction was 4.8 ± 4.7 years (range 0.6 to 17.9 years). The most prevalent anatomic risk factors were patella alta (72%), TT-TG >15 mm (53%), trochlear dysplasia (Dejour type B, C, or D) (50%), and excessive patellar tilt (41%). The median number of risk factors was 3 (range 0-6), and 17 patients (53%) had three or more risk factors. At final follow-up (24.1 ± 14.5 months), no patients experienced recurrent patellofemoral instability or graft failure. Postoperative IKDC (p < 0.001) and SF-12 PCS (p < 0.001) scores improved significantly compared with preoperatively. In conclusion, the majority of patients presenting for revision MPFL reconstruction had three or more risk factors for recurrent dislocation.IV, Case Series.

This dataset provides a comprehensive collection and classification of publicly available online questions and linked websites related to matrix-induced autologous chondrocyte implantation (MACI), an implant that can be utilized by orthopaedic surgeons for patients requiring knee cartilage restoration. Eight MACI-related search terms were entered individually into a history-cleared Google Chrome browser in incognito mode to minimize personalization bias. For each term, the "People Also Ask" feature was expanded to retrieve approximately 200 question-website pairs, yielding a total of 1620 entries that were compiled and screened for relevance. The final dataset includes 1107 unique, relevant question-website pairs organized in a spreadsheet containing variables for search term, question text, linked website, website source type, Rothwell classification (Fact, Policy, or Value) and subcategories, JAMA Benchmark Criteria component scores, total JAMA credibility score, and thematic grouping based on question content and author consensus. Each entry was rated independently by two reviewers, with discrepancies resolved by the primary author using an Excel-based verification process. Descriptive statistics and logistic regression were performed in Python (statsmodels, SciPy). The dataset is accompanied by materials outlining classification frameworks, frequently repeated questions, and commonly linked websites. By documenting how patients search for and encounter information on a popular cartilage restoration option, this dataset provides a model for evaluating digital health resources and developing accurate, accessible educational content for patients and clinicians across medical disciplines.

RTEL1 R1264H is a founder variant with a carrier frequency of 0.3%-1.0% in the Ashkenazi Jewish population. While biallelic RTEL1 R1264H causes a severe form of telomere biology disorder (TBD) presenting in childhood, the clinical significance of monoallelic carrier status has remained uncertain, limiting effective counseling and management. Here, we describe the clinical features, telomere lengths, and tumor somatic profiles of cancer patients found to be heterozygous for RTEL1 R1264H to evaluate for evidence of subclinical TBD in this population. Among 39,337 individuals who underwent RTEL1 germline analysis via MSK-IMPACT, 32 (0.08%) were incidentally found to be heterozygous for RTEL1 R1264H. Three individuals (9%) met diagnostic criteria for TBD based on compatible clinical features and telomere shortening, and two additional individuals (6%) had histories suspicious for TBD but did not have telomere length data available. Notably, 7 individuals (22%) experienced severe or fatal therapy-related toxicities, despite many lacking other clinical features of a TBD. These findings support that RTEL1 R1264H can act in an autosomal dominant fashion and confer TBD disease risk, albeit with low penetrance, and may increase susceptibility to treatment-related complications.

BACKGROUND:The recommendation for patients with Lynch syndrome (LS) to undergo extended colectomy at colorectal cancer (CRC) diagnosis is increasingly controversial due to associated long-term morbidity, no benefit in overall survival, and recent advances in immunotherapy. STUDY DESIGN/METHODS:A prospective institutional database was queried for patients with LS diagnosed with CRC between 1969 and 2024, and rates of metachronous CRC and 10-year overall survival were analyzed. RESULTS:Metachronous CRC, with a median of 13 (interquartile range 5 to 20) years between diagnoses, occurred in 88 of 450 patients (20%): 83 of 350 patients (24%) who underwent segmental resection, 2 of 40 patients (5%) who underwent extended resection, and 3 of 60 patients (5%) who did not undergo surgery. Metachronous CRC was more common in patients with variants in high-risk ( MLH1 , MSH2 ) vs low-risk ( MSH6 , PMS2 ) genes: 80 of 326 patients (25%) vs 8 of 124 patients (6%) (p < 0.001). Extended resection was associated with a lower rate of metachronous CRC compared with segmental resection in patients with high-risk variants (2 [6%] of 34 vs 75 [30%] of 252; p = 0.006) but not in patients with low-risk variants (0 of 6 vs 8 [8%] of 98; p = 1.00). Ten-year overall survival was 90% (95% CI 86% to 93%) for the full cohort (median follow-up, 7.0 years), 89% (95% CI 85% to 93%) after segmental resection, and 96% (95% CI 88% to 100%) after extended resection. CONCLUSIONS:For CRC patients with variants in high-risk LS genes, extended resection can significantly reduce the risk of metachronous CRC but does not lengthen overall survival. Segmental resection with close endoscopic surveillance can be a reasonable alternative, given the opportunity for repeat surgery or immune checkpoint blockade.

PURPOSE/OBJECTIVE:Early-onset endometrial cancer (eoEC) is increasing, and germline drivers may be enriched in younger patients. We sought to define germline pathogenic variants (gPVs) in those with EC by age. METHODS:We identified patients with EC who underwent clinical tumor-normal sequencing from December 2014 to June 2021 and collected clinical variables. Logistic regression models evaluated associations between age at EC diagnosis and presence of gPV, biallelic inactivation, and Lynch Syndrome (LS). Age categories were defined as early-onset (eoEC, EC < 50 years) and late-onset (EC ≥ 70 years) and were compared with those diagnosed ages 50-69 years. RESULTS:= .016). LS was enriched in eoEC, with 6.5% of patients diagnosed age <50 years having LS. In multivariable models compared with those with EC diagnosed age 50-69 years, eoEC was more likely to exhibit biallelic inactivation (odds ratio, 3.34 [95% CI, 1.44 to 7.35]) and be associated with LS (hazard ratio [HR], 3.49 [95% CI, 1.63 to 7.01]). Among early-onset EC, 14 (50%) of 28 gPV were high penetrance and 14 (50%) of 28 exhibited biallelic inactivation. However, heterogeneity was observed, and rates of gPV were 8.9% and 19%, biallelic inactivation was 0% and 11%, and LS was 2.2% and 8% in those diagnosed age <40 years and 40-49 years, respectively. CONCLUSION/CONCLUSIONS:Rates of gPV, biallelic inactivation, and LS differ across age groups for EC, with high-penetrant genes driving tumorigenesis enriched in younger patients. However, very-early-onset EC may have different drivers and necessitates more research.

PURPOSE: BAP1-tumor predisposition syndrome (BAP1-TPDS) is associated with four main cancers: uveal melanoma, cutaneous melanoma, malignant mesothelioma, and renal cell carcinoma. However, additional cancers are found more rarely in BAP1-TPDS patients. The aim of this study was to investigate the association, clinical, and pathologic characteristics of meningioma in BAP1-TPDS. METHODS: We conducted a retrospective chart review of meningiomas in two independent cohorts of patients with germline BAP1 pathogenic or likely pathogenic (P/LP) variants at The Ohio State University Wexner Medical Center and at the Memorial Sloan Kettering Cancer Center from October 1st, 2010 date to April 21st, 2025. Additionally, we conducted a literature review of meningioma case studies for individuals with germline BAP1 (P/LP) variants. RESULTS: In a cohort of 237 subjects with BAP1-TPDS, we identified 6.8% (16/237) with a history of meningiomas. The average age of diagnosis was 44.5 years (17–71). For patients with available pathology, 61.5% (8/13) of the tumors were grade 2/3. Patients with available tumor tissue 83.3% (5/6) showed evidence of BAP1 biallelic inactivation. Family history of meningioma was reported in 18.8% (3/16) of patients. Four cases of meningioma were identified during meningioma surveillance imaging, and five cases had recurrences after treatment. Published cases were consistent with the early age of onset, high-grade tumors, and clinical phenotype of tumors. CONCLUSION: This study provides additional evidence that high-grade brain and spinal meningiomas are part of the clinical spectrum of BAP1-TPDS. Craniospinal imaging surveillance in the BAP1-TPDS population should be considered starting around puberty, enabling early detection and management for individuals with BAP1-TPDS.

BACKGROUND:Patients increasingly turn to online search engines to learn about orthopedic procedures. Matrix-Induced Autologous Chondrocyte Implantation (MACI) is an increasingly popular treatment for cartilage lesions. However, the visibility, range, and credibility of online information about MACI remain unclear. As MACI's clinical use grows, understanding what patients are encountering online is essential to guiding informed discussions. PURPOSE/OBJECTIVE:To (1) identify frequently asked questions about MACI and their thematic categories, and (2) evaluate the types and credibility of linked websites in order to inform a patient-friendly handout with frequently asked questions (FAQs) and high-quality sources. METHODS:We conducted a cross-sectional analysis of 1620 MACI-related entries from Google's "People Also Ask" feature. Questions were categorized using the Rothwell framework, and scored for credibility using JAMA Benchmark Criteria. Kruskal-Wallis tests compared credibility across groups; logistic regression identified predictors of high-credibility content. RESULTS:Most included questions (n = 1107) concerned technical details (n = 285), evaluation of surgery (n = 220), and cost (n = 138). Commercial websites were most common (40.9 %) and, while they often offered patient-friendly content, they had lower average JAMA credibility scores (1.54) compared to government (3.95) and academic (1.97) sources (p < 0.01). CONCLUSION/CONCLUSIONS:Online information about MACI is dominated by commercial websites. While many offer helpful information, key patient concerns, such as pain, are underaddressed in online resources. Surgeon-led efforts, including recommending trusted sources and creating patient-friendly online content (e.g. using keywords, images, structured headings), may improve the visibility and credibility of MACI information, supporting patient understanding and shared decision-making.

BACKGROUND:Patellofemoral instability (PFI) is common in adolescents and may require surgical treatment. Patient-reported outcome scores (PROs) are frequently used to evaluate outcomes after treatment. Commonly used PROs for PFI include disease-specific Banff Patellofemoral Instability Instrument 2.0 (BPII 2.0) and region-specific measures such as the Kujala Anterior Knee Pain Scale (Kujala), Pediatric International Knee Documentation Committee Subjective Knee Form (Pedi-IKDC), and Knee injury and Osteoarthritis Outcome Score (KOOS). HYPOTHESIS/PURPOSE/OBJECTIVE:The study aimed to compare the performance of disease-specific and region-specific PROs in adolescents after PFI surgery, and to evaluate their sensitivity to change. It was hypothesized that disease-specific PROs would perform better than region-specific PROs. STUDY DESIGN/METHODS:Case series; Level of evidence, 4. METHODS:The JUPITER (Justifying Patellar Instability Treatment by Early Results) study database was used to evaluate PROs in 256 adolescents (263 knees) aged ≤18 years who underwent surgical treatment for PFI. Four commonly used PRO scores were analyzed at baseline and at least 1 year postoperatively. Statistical analysis included comparisons between pre- and postoperative scores, calculation of minimal clinically important difference (MCID), correlations among the 4 scores, and evaluation of their sensitivity to change, floor effects, and ceiling effects. RESULTS:The median age was 15 years. Isolated medial patellofemoral ligament reconstruction was the most common procedure. The mean BPII 2.0 scores were lower at baseline and postoperatively, and showed the most substantial change at 1-year follow-up. There was a moderate correlation between the BPII 2.0 and the Kujala, Pedi-IKDC, and KOOS scores, and a strong correlation among the latter 3 scores. All scores were more sensitive to change among those at the lower 50th percentile of baseline scores. The BPII 2.0 was the only PRO that did not exhibit ceiling effects at follow-up. CONCLUSION/CONCLUSIONS:When comparing the performance of disease-specific (BPII 2.0) and region-specific (Kujala, Pedi-IKDC, and KOOS) PROs, the BPII 2.0 was found to be the most sensitive to change after PFI surgery in adolescents, and the only scale that did not have a ceiling effect at baseline and 1-year follow-up. There was a moderate correlation-and thus limited interchangeability-between the BPII 2.0 and the Kujala, Pedi-IKDC, and KOOS scores, both at baseline and at 1-year follow-up, and a strong correlation among the latter 3 knee-specific PROs. The BPII 2.0 should be considered the PRO of choice when evaluating adolescent patients with PFI.