Citations

ABSTRACT Background Cytomegalovirus (CMV) infection is among the most common infections after solid organ transplantation and leads to high rates of morbidity and mortality. With the proliferation of large, claims‐based datasets, there is a need to assess the validity of ICD‐10‐CM codes in identifying CMV infection. Methods We conducted a retrospective cohort study of solid organ transplant recipients (SOTRs) from a regional health system who underwent first transplantation between January 1, 2016, and June 30, 2025, had at least 30 days of post‐transplant follow‐up, and had known donor/recipient CMV serostatus. We performed cross‐sectional and time‐to‐event analyses comparing the test performance of B25 ICD‐10‐CM codes in identifying CMV infection, clinically significant CMV infection (csCMVi), CMV disease, and CMV DNA reaching various thresholds. Results Of 8169 SOTRs, 3084 (37.8%) had B25 coded during follow‐up. In addition, 4287 (52.5%) developed CMV infection, 2356 (28.8%) csCMVi, 297 (3.6%) CMV disease, and 1669 (20.4%) CMV DNA ≥ 1000 IU/mL. B25 codes were most specific to any CMV infection (88.5%), most sensitive to CMV DNA ≥ 100 000 IU/mL (98.2%), and csCMVi had the highest Youden's Index (0.651; sensitivity 84.1%, specificity 81.0%). Multivariable Cox regression provided similar results but with variations in effect measure between ICD‐10‐CM codes and clinical CMV definitions. Conclusions ICD‐10‐CM codes showed modest performance in identifying CMV infection, most closely resembling csCMVi. ICD‐10‐CM codes poorly reflect CMV severity, however, and may overestimate CMV infection by some clinical definitions. These limitations should be considered when using CMV diagnosis codes for claims‐based studies of SOTRs.

Abstract Objective Low back pain (LBP) is a leading cause of pain and disability worldwide. Recent studies demonstrate a vertebrogenic model involving the basivertebral nerve (BVN) as a cause of chronic LBP. Vertebral endplates are highly innervated by the BVN, and literature shows type 1 and 2 Modic changes at vertebral endplates are a source of vertebrogenic low back pain (VBP). As a result, intraosseous radiofrequency ablation of the BVN is a minimally invasive outpatient procedure used to treat VBP. We conducted a retrospective review of 1,145 patients that have undergone BVN ablation to assess for safety and complication management. Methods Chart reviews were conducted to obtain demographic and pre-procedural information regarding patient gender, age at the time of BVN ablation, duration of LBP, and BMI. Post-procedure information derived from chart notes included vertebral levels ablated and post-BVN ablation complications, which were categorized as increased LBP > 7 days, increased radicular pain > 7 days, lower extremity weakness, infection, vertebral compression fracture, superficial bleeding, spinal or epidural hematoma, serious neurological injury, visit to the ER, and deep vein thrombosis/clot. Results 1,145 patient charts were reviewed showing an overall complication rate of 3.2% (37 complications). Increased radicular pain was the most common complication at 2.2% (25 complications) and resolved completely in all but one patient. The overall complication rate fell to 1.1% (13 complications) when the 24 cases of transient radicular pain were not counted as adverse events. Conclusions In this multicenter retrospective review, the overall rate of complications related to BVN ablation was low (3.2%). The most common complication was temporary radicular pain that resolved with conservative care. These findings suggest that BVN ablation is a safe treatment for VBP in real-world clinical settings.

Introduction Krackow Type II valgus deformity is defined by attenuation of the medial collateral ligament (MCL). However, little quantitative information exists about associated intra-operative MCL laxity. Furthermore, a corollary may exist in varus deformity with associated lateral ligament laxity but is poorly described. Robotic-assisted total knee arthroplasty (raTKA) includes quantitative assessment of intraoperative ligament function. This study evaluated whether increased preoperative medial or lateral radiographic joint space width (JSW) in valgus or varus knees, was associated with increased intraoperative soft tissue laxity of the respective compartment. Methodology Intraoperative data from 348 consecutive raTKAs with 270 varus knees (hip-knee-ankle angle [HKA]<-2°), and 78 valgus knees, (HKA>2°) were retrospectively reviewed. For varus knees, lateral JSW was measured on preoperative, standing anteroposterior radiographs to determine lateral widening (threshold 8.0mm). For valgus knees, medial JSW was evaluated to determine medial widening (threshold 7.0mm). Intraoperative medial and lateral gaps at 0° and 90° had been recorded during manual stress testing. Linear regression was performed to determine associations between intra-operative gaps, radiographic JSW, and HKA. Results 51 varus knees demonstrated lateral widening and 15 valgus knees had medial widening. In varus knees, lateral JSW was positively associated with the lateral extension (β=0.76, P <0.001) and flexion (β=0.74, P <0.001) gaps. Similarly, for valgus knees, medial JSW was positively associated with the medial extension (β=0.75, P <0.001) and flexion (β=0.77, P <0.001) gaps. Conclusion Increased preoperative radiographic JSW of the medial and lateral compartment in valgus and varus knees, predicted increased intraoperative gaps of that compartment, consistent with ligament attenuation.

Abstract BRCA1 -deficient cancers experience persistent replication stress and structural genome instability yet retain the capacity for sustained proliferation, implying reliance on compensatory genome-maintenance mechanisms. Here, we establish BRCA1–FANCM synthetic lethality in human BRCA1 -deficient breast cancer and exploit temporally controlled FANCM depletion to capture genome evolution over successive cell divisions before declining cellular fitness becomes limiting. We show that FANCM restrains genome-wide structural variation in BRCA1 -deficient breast cancer cells under endogenous replication stress. FANCM loss amplifies the characteristic BRCA1 -associated short tandem duplication (TD) phenotype while permitting larger, including megabase-scale, TDs and diverse rearrangements to emerge. Newly emerged TDs preferentially associate with Pol II-occupied regions, and FANCM depletion increases proximity between the replication machinery and elongating RNAPII in BRCA1 -mutant breast cancer cells, linking FANCM-mediated genome protection to transcription–replication encounters. BRCA1 -altered human tumors with low FANCM expression recapitulate key features of this phenotype, while genome–transcriptome integration links newly emerged SVs to configuration-dependent local transcriptional changes. Together, these findings establish FANCM as a replication-stress safeguard coupling survival to restraint of structural genome evolution.

Abstract Identification of gene expression changes in post-mortem brain tissue of Alzheimer’s disease donors compared to controls have implicated numerous biological pathways for Alzheimer’s disease pathophysiology. Nonetheless, there is still limited understanding of how gene expression dysregulation underpins specific proteinopathies core to Alzheimer’s disease. Here we investigate brain transcriptomic changes in a well characterized cohort of Alzheimer’s disease donors to identify genes and networks that associate with Alzheimer’s disease endophenotypes including neuropathology measures (Braak stage, Thal phase and cerebral amyloid angiopathy score) and Alzheimer’s disease-related brain protein levels (Apolipoprotein E, Amyloid-β 40, Amyloid-β 42, tau, and phospho-Tau). Bulk transcriptome measures were collected from the temporal cortex tissue of 477 Alzheimer’s disease donors. Following quality control, transcriptome-wide association studies were performed for each endophenotype. We used weighted gene co-expression network analysis to build co-expression networks and integrated transcriptome with epigenetic and genetic data from the same donors. We detected a total of 5,740 Bonferroni significant temporal cortex gene associations with Alzheimer’s disease endophenotypes, most of which were with brain tau levels. We discovered tau-associated co-expression modules enriched in known and novel Alzheimer’s disease pathways. We found that a beneficial (or neutral) brain biochemical state of higher total tau and lower phospho-Tau are associated with increased levels of synaptic, DNA damage/repair, nucleic acid metabolism and myelin processes. In contrast, in a detrimental state of lower total and higher phospho-Tau, there is upregulation of vascular and immune, and downregulation of mitochondrial and myelin pathways. There are brain gene expression perturbations that are associated with Alzheimer’s disease endophenotypes. While some of these associations are common across multiple endophenotypes, many are distinct for different Alzheimer’s disease-related proteins. Based on these findings, we propose a hypothetical model of dynamic brain gene expression changes that track with progressive Alzheimer’s disease proteostasis. These expression changes hold potential to serve as dynamic, precision biomarkers of brain Alzheimer’s disease progression. This study demonstrates the potential of integrative multiomics and deep Alzheimer’s disease endophenotype analyses in well-characterized brain tissues to uncover with precision the complex biology of Alzheimer’s disease.

Abstract Objective Surgery is an effective, yet underutilized treatment for children with drug‐resistant epilepsy. Although predictors of surgical outcomes are well described, the decision to recommend surgery varies by institution. We aim to evaluate the rates of not recommending surgery, identify associated patient characteristics, and quantify variability across centers. Methods We queried the Pediatric Epilepsy Research Consortium Surgery database, a prospective multicenter cohort of children (0–18 years) undergoing initial evaluation for epilepsy surgery. Patients with documented surgical decisions were included. Demographic, clinical, and presurgical evaluation variables were compared by surgical recommendation status. Logistic regression identified factors associated with not recommending surgery. Mixed‐effects models quantified between‐center variability. Results Among 2480 patients across 29 centers, 532 (21%) were not recommended epilepsy surgery (median center rate 17%, interquartile range [IQR] 10%–28%). After accounting for patient characteristics associated with surgical candidacy, substantial variation in decision‐making remained across centers, with a median twofold difference in the odds of not recommending surgery between otherwise similar patients evaluated at different institutions (Median Odds Ratio = 2.25; Intraclass Correlation Coefficient = .18). The clinical characteristics most strongly associated with not recommending surgery included monthly or less frequent seizures (odds ratio [OR] 2.17, 95% confidence interval [CI] 1.75–2.69), non‐structural etiology (OR 2.02, 95% CI 1.56–2.61), and taking ≤2 anti‐seizure medications (ASMs) (OR 1.67, 95% CI 1.34–2.08, all p 's < .01). These characteristics showed minimal clustering across centers (ICCs < .05). Significance One in five children evaluated for epilepsy surgery are not recommended to pursue surgical treatment. Although clinical factors influence decision‐making, they do not explain the substantial variation in recommendations across pediatric epilepsy centers. Similar children evaluated at different institutions had significant differences in the odds of not being recommended surgery, suggesting that institutional decision‐making contributes importantly to surgical candidacy.

Abstract Triple-Negative Breast Cancer (TNBC) presents a significant clinical challenge due to its heterogeneity and lack of targeted treatment options, with chemotherapy and immunotherapy combinations currently serving as the main therapeutic strategy. Efforts to address TNBC heterogeneity have largely focused on classifying intrinsic cancer subtypes based on differential tumor mRNA expression, a strategy that has proven effective in hormone receptor-positive breast cancers but has yet to yield a clinically useful predictor of survival or treatment response in TNBC. We hypothesize that both the intrinsic characteristics of TNBC and the surrounding immune microenvironment influence treatment outcomes and that immune cell infiltration affects TNBC subtype classification and response variability. To explore this hypothesis, we compared the predictive and prognostic capabilities of cancer subtype-based (TNBC-type) gene signatures and immune cell deconvolution methods (CIBERSORT) within the same TNBC datasets. We found that immune cell abundance outperformed TNBC subtype-signatures and multicellular immune cell aggregates showed the highest performance of all. More specifically, aggregate immune cells associated with tertiary lymphoid structures and tumor associated macrophages/monocytes demonstrated statistically significant predictive value. These findings were confirmed in an independent cohort of 67 TNBC patients treated with neoadjuvant chemotherapy. Further, single-cell RNA sequencing analysis revealed that the predictive power of cancer-subtype could be partially explained by immune- and stromal features. Examination of single-cell resolution spatial transcriptomic data confirmed presence of TLS-like, TAM- and cancer-stromal niches within TNBC biopsy samples that were associated with treatment response. Overall, our results highlight that immune cell aggregates, which capture the spatial organization of the TME, outperform cell-type specific gene signatures in predicting TNBC outcomes. Our novel approach provides a robust framework for interpreting spatial relationships in bulk RNA-seq data, offering a pathway for reconciling past data with current advancements in spatial profiling technologies. This work paves the way for future studies to leverage the multi-cellular complexity of TNBC, enhancing diagnostic precision and facilitating the development of therapies that strategically modulate the tumor microenvironment for improved anti-cancer responses.

Abstract BACKGROUND [177Lu]Lu-PSMA-617 improves survival and quality of life in men with metastatic castration-resistant prostate cancer but requires substantial healthcare involvement. Our analysis evaluated the time toxicity associated with [177Lu]Lu-PSMA-617, representing the first dedicated radioligand time toxicity assessment. MATERIALS AND METHODS We conducted a multi-institutional retrospective study of patients initiating [177Lu]Lu-PSMA-617 between April 2022 and March 2023. Patients were followed from first [177Lu]Lu-PSMA-617 administration until 3 months after the final cycle, initiation of new systemic therapy, or death. Time toxicity was quantified as healthcare contact days during the at-risk interval. Associations with baseline characteristics were evaluated using negative binomial regression models. Univariate and multivariable models were performed. RESULTS Among 135 patients, median age was 69 years and median prior systemic therapies was 4. Patients completed a median of 5 [177Lu]Lu-PSMA-617 cycles over 7.6 months. Median healthcare contact days were 20 (IQR, 15–28), representing 9.5% (IQR, 6.4–13.9) of at-risk days. Fifteen patients (11%) experienced high time toxicity (&gt;1 contact day per 5 days), while 42 (31%) had low time toxicity (≤1 contact day per 14 days). Among the 57 patients who received both cycle 1 and cycle 6, mean per cycle healthcare contact days were 4 and 3.6, respectively (paired Wilcoxon signed-rank test, p = 0.04). Routine oncology visits comprised 32.7% of contact days, compared with 8.8% from hospitalizations. Lower baseline hemoglobin was independently associated with greater time toxicity (RR = 0.87; 95% CI, 0.79–0.96; p = 0.004). CONCLUSION In heavily pretreated patients, [177Lu]Lu-PSMA-617 demonstrated relatively low time toxicity, supporting it as a time-efficient therapy.