Citations

Abstract Background : Traumatic encephalopathy syndrome (TES) is a clinical research construct used to identify individuals at risk for chronic traumatic encephalopathy (CTE) following exposure to repetitive head impacts (RHI). Adjudication of TES relies on clinical features such as progressive cognitive impairment and neurobehavioral dysregulation. Blood-based biomarkers and structural neuroimaging abnormalities have been associated with TES but are not part of the criteria. This study evaluated whether TES identification was associated with the combined contribution of cognitive performance, blood biomarkers, and structural neuroimaging measures across two well-characterized cohorts. Methods : Participants included 158 professional fighters from the Professional Athletes Brain Health Study and 149 former American football players from The DIAGNOSE CTE Research Project. Three indices were constructed representing complementary domains: a cognitive index reflecting cohort-specific cognitive features, a blood biomarker index including plasma neurofilament light chain, glial fibrillary acidic protein, total tau, tau phosphorylated at amino acid 231, and APOE -ε4 carrier status, and an imaging index comprising volumetric MRI measures of subcortical structures, ventricles, and corpus callosum subregions. Grouped weighted quantile sum regression models were estimated within each cohort to evaluate associations between these indices and TES while adjusting for age, race, competition status, and RHI exposure. Results : Multidomain models demonstrated improved model performance compared with single-domain models in both cohorts (PABHS: AUC=0.91, PPV=0.80; DIAGNOSE CTE: AUC=0.84, PPV=0.85). Biomarker and imaging indices contributed additional information across cohorts, although imaging contributions were more prominent in fighters whereas blood biomarker associations were stronger in football players. Conclusion : TES in RHI-exposed athletes was associated with a convergent clinicobiological profile observed across two independent cohorts with distinct exposure patterns. These findings support multidomain analytic frameworks for evaluating correlated biological signals in RHI-exposed populations and may inform future studies of TES and CTE.

Despite advances in imaging, instrumentation, surgical techniques, and postoperative care, outcomes for certain peripheral nerve procedures remain consistently disappointing. In this article, we describe five surgical scenarios--adult pan-brachial plexus injuries, peroneal nerve injury after knee dislocation, sciatic nerve injury after total hip arthroplasty, radiation-induced brachial plexopathy, and lower trunk injury after cardiac surgery--that, in our experience and review of the literature, frequently lead to limited and consistently poor functional recovery after nerve surgery. These challenging cases reflect not only technical and anatomical complexity but the profound biological limitations of nerve regeneration in specific contexts. By critically analyzing these five procedures, we aim to promote more realistic patient counseling, support timely and individualized decision-making, and foster a more nuanced understanding of when and what type of surgical intervention may or may not be beneficial.

Biparietal osteodystrophy, also known as bilateral parietal calvarium bone thinning, is a rare calvarial condition characterized by loss of diploic bone within the parietal region. Although historically described in anthropologic and radiologic literature, current understanding of its epidemiology, pathogenesis, clinical relevance, and management remains fragmented. This review synthesizes current evidence and highlights emerging studies on biparietal osteodystrophy. Epidemiologic reports indicate that biparietal osteodystrophy affects a broad age range but appears most frequently in older adults, with several series suggesting a slight female predominance. Prevalence is difficult to estimate due to incidental detection, though modern imaging has increased recognition of the condition. Histologically and anatomically, biparietal osteodystrophy is marked by thinning of the outer table and loss of the diploic space, with little osteoblastic or osteoclastic remodeling. Proposed pathogenic mechanisms include chronic degenerative change, impaired vascular supply to the diploë, and other theories, although no single explanation fully accounts for its complete presentation. Clinically, most patients remain asymptomatic, with complications such as calvarial fractures and traumatic brain injury being rare but highlighting the structural vulnerability associated with severe thinning. Management strategies are not standardized, and the use of anti-osteoporotic drugs and cranioplasty has been reported to offer benefit in select cases, although no treatment has been formally validated for biparietal osteodystrophy. As the understanding of biparietal osteodystrophy continues to evolve, future research is needed to clarify its natural history, identify potential etiologic pathways, and establish evidence-based management guidelines.

Abstract Background Isocitrate dehydrogenase (IDH)-mutant gliomas are infiltrative tumors with limited treatment options at recurrence. Early studies suggest IDH inhibition has therapeutic activity. We evaluated clinical outcomes associated with IDH-1 inhibitor ivosidenib in recurrent IDH-1-mutant gliomas and molecular predictors of response. Methods We retrospectively analyzed adults treated with ivosidenib from January 2021 to August 2025 with predominantly recurrent, pretreated CNS WHO grade 2-4 astrocytoma IDH-mutant or grade 2-3 oligodendroglioma, IDH-mutant and 1p/19q codeleted. Prior anticancer treatments, toxicities, enhancement status at ivosidenib initiation, and genomic alterations were collected. The primary endpoint was progression-free survival (PFS); secondary analyses evaluated associations between PFS, genomic complexity, and CDKN2A/B homozygous deletion. Results Ninety-two adults, median age 43, were included: 61 astrocytomas and 31 oligodendrogliomas, mostly grade 2. Before ivosidenib, 69 had surgery, 64 chemotherapy, and 64 radiation. Median time from diagnosis to ivosidenib was 4.8 years, with median of two prior progressions. Median treatment duration was 5.8 months. Median PFS was 15.2, 4.6, and 2.1 months for astrocytoma grades 2-4, 14.0 and 6.9 months for oligodendroglioma grades 2-3. Increasing genomic complexity was associated with shorter PFS in univariate analysis. Patients without CDKN2A/B homozygous deletion had median PFS of 19.2 months. Two patients with homozygous deletion had median PFS of 0.6 months. Conclusions In this retrospective analysis of predominantly recurrent IDH-1-mutant glioma, ivosidenib was associated with longer PFS in lower-grade, non-enhancing tumors that received little or no prior anticancer treatment and less complex genomic profiles. These findings support a context-dependent benefit of IDH inhibition in recurrent disease.

Abstract Transcriptional condensates (TCs) are dynamic, membrane-less assemblies of proteins and nucleic acids that form at specific genomic loci to control gene expression. The primary drivers of TC formation and function are long stretches of polypeptide chains that lack well-defined tertiary structure, known as the intrinsically disordered regions (IDRs) of Transcription Factors (TFs). However, the role of well-structured domains such as the DNA-binding domain (DBD) in condensate formation and downstream regulation remains poorly understood. Here, we investigated whether the DBD of the Progesterone Receptor (PR), a model TF regulated by hormone binding, contributes to the formation of PR TCs. By combining Single Particle Tracking (SPT) with deep-learning-based single-trajectory analysis, we demonstrated that both the IDR and the DBD are required for the formation of PR condensates. Furthermore, transcriptomic analysis showed that mutations of either of the two domains result in the expression of a distinct set of genes, with functional assays corroborating these findings and linking domain-specific transcription to differential effects on cell proliferation and migration. Together, our results show that domains beyond IDRs also play a role in TC formation and function and uncover domain-specific regulation of transcriptional and oncogenic programs.

BACKGROUND AND OBJECTIVES: Intraneural ganglion cysts (IGCs) can arise in different nerves but are uncommon in the tibial nerve (TN) and its branches near the ankle. According to the unified articular theory, a joint connection is always present in IGCs. This study aimed to identify joint connections of tibial-region IGCs and characterize their clinical, radiological, and propagation patterns. METHODS: A prospectively collected international database of >1100 IGCs was reviewed to identify tibial and medial plantar nerve (MPN) and lateral plantar nerve (LPN) IGCs around the ankle. RESULTS: Sixty-two ankle region IGCs were identified: 29 involving the TN (46.8%), 25 the MPN (40.3%), and 4 the LPN (6.4%); in 4 cases, the parent nerve was indeterminate. Thirty-one (50%) cases demonstrated joint connections. Of these, all TN at/distal to the tarsal tunnel (n = 4/4, 100%), MPN (n = 16/16, 100%) and LPN IGCs (n = 2/2, 100%) had a connection to the subtalar (ST) joint. A tibial IGC just proximal to the tarsal tunnel was connected to the tibiotalar (TT) joint in 75% of cases (n = 3/4) and the ST joint in 25% of cases (n = 1/4). Surgical ligation/disconnection of the articular branch was associated with markedly lower recurrence (0/13, 0%) compared with incision or resection of cyst without ligation (8/29, 27.6%; P = .04). CONCLUSION: Our findings support the unified articular theory. All IGCs in the ankle primarily ascend. Two distinct propagation patterns emerged: (1) those that ascend and enter the parent nerve proximal to the tarsal tunnel continue to ascend in the leg, without affecting the plantar nerves, and (2) those that ascend and enter the parent nerve at/distal to the tarsal tunnel have the potential to undergo crossover at the TN bifurcation and subsequently descend down the plantar nerves seen only in ST-origin cysts. Recognizing these pathways enhances diagnostic accuracy, directs identification of the joint of origin, and guides articular branch disconnection to reduce recurrence.

ABSTRACT IDH-mutant astrocytomas maintain telomeres through the alternative lengthening of telomeres (ALT) pathway, producing extreme inter-arm telomere length heterogeneity, yet how this heterogeneity shapes structural genome evolution remains unknown. Using Oxford Nanopore long-read sequencing of 20 IDH-mutant astrocytomas, we profiled structural variants (SVs), copy number variants, extrachromosomal DNA (ecDNA) and measured allele-specific telomere lengths from individual long reads. We identified pervasive complex rearrangements, including chromothripsis and foldback events consistent with breakage-fusion-bridge cycles, and widespread ecDNAs. SV breakpoints were enriched at telomeric and centromeric regions regardless of local telomere length, revealing constitutive structural fragility. Arm-level telomere length analysis uncovered a dual-mode model: arms with short telomeres preferentially harbored breakage-associated events, while arms with long ALT-maintained telomeres were enriched for ecDNA and amplification-associated events. These findings identify chromosome-arm-specific telomere length as a determinant of structural genome evolution in ALT-driven tumors.

Abstract Pancreatic cancer disproportionately affects Black individuals in the United States, but they have limited representation in genetic studies of pancreatic ductal adenocarcinoma (PDAC). To address this gap, we performed admixture mapping and genome-wide association analysis (GWAS) in genetically inferred African ancestry individuals (1,030 cases and 889 controls). Admixture mapping identified three regions with a significantly higher proportion of African ancestry in cases compared to controls (5q33.3, 10p1, 22q12.3). GWAS identified a genome-wide significant association at 5p15.33 ( CLPTM1L , rs383009:T>C, T Allele Frequency=0.51, OR:1.45, P value=1.24×10 -8 ), a locus previously associated with PDAC. Known loci at 5p15.33, 7q32.3, 8q24.21 and 7q25.1 also replicated (P value <0.01). Multi-ancestral fine-mapping identified two potential causal SNPs (rs3830069 and rs2735940) at 5p15.33. Collectively these findings identified novel PDAC risk loci and expanded our understanding of this deadly cancer in underrepresented populations, emphasizing the multifactorial nature of PDAC risk including inherited genetic and non-genetic factors. Statement of Significance To understand how genetic variation contributes to PDAC risk in Black people in North American, we studied individuals of genetically-inferred African ancestry. We identified novel risk loci and differences in the contribution of known loci. This demonstrates that ancestry-informed genetic analyses improve our understanding of PDAC risk and enhances discovery.