Citations

OBJECTIVE The authors hypothesized that the proximity of deep brain stimulator contacts to the anterior thalamic nucleus–mammillothalamic tract (ANT-MMT) junction determines responsiveness to treatment with ANT deep brain stimulation (DBS) in drug-resistant epilepsy and conducted this study to test that hypothesis. METHODS This retrospective study evaluated patients who had undergone ANT DBS electrode implantation and whose devices were programmed to stimulate nearest the ANT-MMT junction based on direct MRI visualization. The proximity of the active electrode to the ANT and the ANT-MMT junction was compared between responders (≥ 50% reduction in seizure frequency) and nonresponders. Linear regression was performed to assess the percentage of seizure reduction and distance to both the ANT and the ANT-MMT junction. RESULTS Four (57.1%) of 7 patients had ≥ 50% reduction in seizures. All 4 responders had at least one contact within 1 mm of the ANT-MMT junction, whereas the 3 patients with < 50% seizure improvement did not have a contact within 1 mm of the ANT-MMT junction. Additionally, the 4 responders demonstrated contact positioning closer to the ANT-MMT junction than the 3 nonresponders (mean distance from MMT: 0.7 mm on the left and 0.6 mm on the right in responders vs 3.0 mm on the left and 2.3 mm on the right in nonresponders). However, proximity of the electrode contact to any point in the ANT nucleus did not correlate with seizure reduction. Greater seizure improvement was correlated with a contact position closer to the ANT-MMT junction (R2 = 0.62, p = 0.04). Seizure improvement was not significantly correlated with proximity of the contact to any ANT border (R2 = 0.24, p = 0.26). CONCLUSIONS Obtained using a combination of direct visualization and targeted programming of the ANT-MMT junction, data in this study support the hypothesis that proximity to the ANT alone does not correlate with seizure reduction in ANT DBS, whereas proximity to the ANT-MMT junction does. These findings support the importance of direct targeting in ANT DBS, as well as imaging-informed programming. Additionally, the authors provide supportive evidence for future prospective trials using ANT-MMT junction for direct surgical targeting.

AbstractVulvar lichen sclerosus (VLS) confers approximately 3% risk of malignant transformation to vulvar squamous cell carcinoma (VSCC). We used unbiased proteomic methods to identify differentially expressed proteins in tissue of patients with VLS who developed VSCC compared to those who did not. We used laser capture microdissection‐ and nanoLC‐tandem mass spectrometry to assess protein expression in individuals in normal vulvar tissue (NVT, n = 4), indolent VLS (no VSCC after at least 5 years follow‐up, n = 5) or transforming VSCC (preceding VSCC, n = 5). Interferon‐γ and antigen‐presenting pathways are overexpressed in indolent and transforming VLS compared to NVT. There was differential expression of malignancy‐related proteins in transforming VLS compared to indolent VLS (CAV1 overexpression, AKAP12 underexpression), particularly in the EIF2 translation pathway, which has been previously implicated in carcinogenesis. Results of this study provide additional molecular evidence supporting the concept that VLS is a risk factor for VSCC and highlights possible future biomarkers and/or therapeutic targets.

Diagnostic devices, methodological approaches, and traditional constructs of clinical pathology practice, cultivated throughout centuries, have transformed radically in the wake of explosive technological growth and other, e.g., environmental, catalysts of change. Ushered into the fray of modern laboratory medicine are digital imaging devices and machine-learning (ML) software fashioned to mitigate challenges, e.g., practitioner shortage while preparing clinicians for emerging interconnectivity of environments and diagnostic information in the era of big data. As computer vision shapes new constructs for the modern world and intertwines with clinical medicine, cultivating clarity of our new terrain through examining the trajectory and current scope of computational pathology and its pertinence to clinical practice is vital. Through review of numerous studies, we find developmental efforts for ML migrating from research to standardized clinical frameworks while overcoming obstacles that have formerly curtailed adoption of these tools, e.g., generalizability, data availability, and user-friendly accessibility. Groundbreaking validatory efforts have facilitated the clinical deployment of ML tools demonstrating the capacity to effectively aid in distinguishing tumor subtype and grade, classify early vs. advanced cancer stages, and assist in quality control and primary diagnosis applications. Case studies have demonstrated the benefits of streamlined, digitized workflows for practitioners alleviated by decreased burdens.

Background: Patients with D-transposition of the great arteries and atrial switch have a high incidence of atrial arrhythmias. We sought to analyze the arrhythmia substrate, ablation strategies, and outcomes for catheter ablation in this population. Methods: An in-depth analysis of all clinical and procedural data in patients with D-transposition of the great arteries, atrial baffles, and atrial arrhythmia ablation was performed. Results: A cohort of 32 patients (72% male, mean age 38±7 years) underwent ablation for non-AV nodal reentrant tachycardia atrial arrhythmias, and 4 patients underwent AV nodal reentrant tachycardia ablation. Cavotricuspid isthmus flutter (CTI-flutter) was the most common arrhythmia, encountered in 75% of patients, followed by scar-related intraatrial reentrant tachycardia (non-CTI intraatrial reentrant tachycardia, 53%) and focal atrial tachycardia (focal atrial tachycardia, 6%). Among the 32 patients, 26 underwent 31 procedures at our institution. For patients with prior outside intervention, the index ablation at our institution revealed CTI-dependent flutter in 3/5 cases. However, redo ablation after an index ablation with demonstrated bidirectional CTI block revealed different/new arrhythmia substrates (80% non-CTI intraatrial reentrant tachycardia, 40% focal atrial tachycardia). Achieving bidirectional block across the CTI often required ablating on both sides of the baffle (retroaortic access, 81%; using a baffle leak, 11.5%; or transbaffle puncture, 7.7%). Combined approaches were necessary in 19% to reach the critical tissue. Acute procedural success was 81%, and recurrence was documented in 58% of patients. Despite recurrence, clinical arrhythmia burden was significantly reduced post-ablation ( P <0.001), with rare episodes, amenable to antiarrhythmic therapy. Redo ablation was required in 5 (19%) patients and uncovered new arrhythmia substrates. AV nodal reentrant tachycardia ablation also required transbaffle approaches in 3/4 patients. Conclusions: CTI-dependent flutter was the most common arrhythmia in patients with Dextro-Transposition of the Great Arteries and atrial switch. Transbaffle approaches were often necessary, and, provided that bidirectional CTI block was achieved at the index ablation, late recurrence was due to different arrhythmia mechanisms. Despite recurrence, ablation was associated with significant clinical improvement.

Background: Histological changes induced by gluten in the duodenal mucosa of patients with non-coeliac gluten sensitivity (NCGS) are poorly defined. Objectives: To evaluate the structural and inflammatory features of NCGS compared to controls and coeliac disease (CeD) with milder enteropathy (Marsh I-II). Methods: Well-oriented biopsies of 262 control cases with normal gastroscopy and histologic findings, 261 CeD, and 175 NCGS biopsies from 9 contributing countries were examined. Villus height (VH, in μm), crypt depth (CrD, in μm), villus-to-crypt ratios (VCR), IELs (intraepithelial lymphocytes/100 enterocytes), and other relevant histological, serologic, and demographic parameters were quantified. Results: The median VH in NCGS was significantly shorter (600, IQR: 400–705) than controls (900, IQR: 667–1112) (p < 0.001). NCGS patients with Marsh I-II had similar VH and VCR to CeD [465 µm (IQR: 390–620) vs. 427 µm (IQR: 348–569, p = 0·176)]. The VCR in NCGS with Marsh 0 was lower than controls (p < 0.001). The median IEL in NCGS with Marsh 0 was higher than controls (23.0 vs. 13.7, p < 0.001). To distinguish Marsh 0 NCGS from controls, an IEL cut-off of 14 showed 79% sensitivity and 55% specificity. IEL densities in Marsh I-II NCGS and CeD groups were similar. Conclusion: NCGS duodenal mucosa exhibits distinctive changes consistent with an intestinal response to luminal antigens, even at the Marsh 0 stage of villus architecture.

1504 Background: Trial recruitment that requires specific actionable mutations based on next-generation sequencing (NGS) is challenging. Barriers can include competing studies, physician study awareness, site proximity, mutation incidence, among other concerns. Methods: This study (NCT04432454) opened clinical sites using two methods during the COVID-19 pandemic. The “Traditional” approach included site selection, IRB and contract approval, and trial activation prior to a patient being identified for enrollment. The second approach used the Tempus “TIME” Trials network that would only open a site after identifying a patient with a mutation of interest and eligible for the trial. Results: The first patient enrolled was on 10/12/20 and the last patient was on 6/24/21. A total of 16 sites (6 Traditional and 10 TIME) participated. All Traditional sites, and none of the TIME sites, were affiliated with major academic institutions. Duration for full CTA execution for Traditional sites averaged 200.5 days (range 142 to 257) and for TIME sites averaged 7.6 days (range 2 to 14). IRB approval time average for Traditional sites was 27.5 days (range 12 to 71) and TIME sites was 3.0 days (range 1 to 12 days). Days from site selection to activation letter for Traditional sites was on average 250.0 days (range 187 to 281) and for TIME sites was 131.6 days (range 22 to 248). Time from study activation to first consent was 33.3 days (range 18 to 58) for Traditional sites and 8.8 days (range 1 to 35) for TIME sites. The first patient on-study was at a TIME site 115 days prior to a Traditional site and the first 7 patients enrolled were at TIME sites. Traditional sites consented 23 and enrolled 16 patients while the TIME sites consented 16 and enrolled 13. The trial enrolled all 29 patients in 8 months with the anticipated enrollment duration being 12 to 18 months. Conclusions: Although the Traditional and TIME programs had different operational models, they both contributed a significant number of patients and reduced the projected enrollment timeline. TIME sites enrolled the initial patients. These results demonstrate that the “Just-in-Time model,” in conjunction with a Traditional model, can reduce projected overall time to enrollment in biomarker-driven studies. [Table: see text]