Citations

Abstract The pulvinar has been proposed as an effective neuromodulation target for patients with posterior quadrant and temporal epilepsies. However, the pulvinar has a large tissue volume, multiple subnuclei, and widespread cortical connections. It remains unknown whether electrical stimulation of distinct pulvinar subregions affects the temporal, occipital, and parietal areas differently. To address this gap, we delivered single-pulse electrical stimulation to the pulvinar and measured the resulting brain stimulation evoked potentials in twelve patients undergoing stereotactic EEG for drug-resistant epilepsy. Brain stimulation evoked potentials were parameterized across the occipital, temporal and parietal cortex. Stimulation of the lateral pulvinar elicited significant brain stimulation evoked potentials in striate and extrastriate areas that diminish as stimulation shifts towards the medial pulvinar. Conversely, stimulation of the ventral aspect of the medial pulvinar produced significant lateral temporal evoked potentials, which diminish with lateral pulvinar stimulation. We also found that stimulation of the dorsomedial pulvinar evoked significant parietal responses with limited striate/extrastriate and lateral temporal responses. These results demonstrate that electrical stimulation of specific pulvinar subregions influences distinct occipital, parietal and lateral temporal areas. Selective targeting of pulvinar subregions to maximize seizure network engagement may be essential for individualized treatment of posterior quadrant and temporal epilepsies.

Abstract The development of targeted therapy for patients with multiple myeloma (MM) is hampered by the low frequency of actionable genetic abnormalities. Gain or amplification of chromosome 1q (1q+) is the most frequent arm-level copy number gain in patients with MM and is associated with higher risk of progression and death despite recent therapeutic advances. Thus, developing targeted therapy for patients with MM with 1q+ stands to benefit a large portion of patients in need of more effective management. Here, we used large-scale dependency screens and drug screens to systematically characterize the therapeutic vulnerabilities of MM with 1q+ and displayed increased sensitivity to myeloid cell leukemia-1 (MCL1) and phosphatidyl inositol 3-kinase (PI3K) inhibitors. Using single-cell RNA sequencing, we compared subclones with and without 1q+ within the same patient tumors and demonstrated that 1q+ is associated with higher levels of MCL1 and the PI3K pathway. Furthermore, by isolating isogenic clones with different copy number profiles for part of the chromosome 1q arm, we observed increased sensitivity to MCL1 and PI3K inhibitors with arm-level gain. Lastly, we demonstrated synergy between MCL1 and PI3K inhibitors and dissected their mechanism of action in MM with 1q+, uncovering a cytostatic effect. In conclusion, this study highlights that MM with 1q+ may present enhanced sensitivity to MCL1 and PI3K inhibitors, enabling their use at lower doses without sacrificing efficacy, and may thus accelerate the development of targeted therapy for patients with MM and 1q+.

AbstractMenopause is associated with vascular dysfunction. During the menopausal transition, endogenous oestradiol concentrations diminish. Oestradiol is vasoprotective because it has direct and indirect effects on the vasculature. The present study aimed to determine the effect of acute exogenous oestradiol on endothelium‐dependent, endothelium independent and β2‐adrenergic receptor‐induced vasodilatation in females. Forearm blood flow (venous occlusion plethysmography) was measured during brachial intraarterial infusions of ACh (endothelium‐dependent agonist), sodium nitroprusside (endothelium independent agonist) and terbutaline (β2‐adrenergic receptor agonist) with and without concurrent infusion of 17β‐oestradiol. Nine young premenopausal (age: 26 ± 4 years) and nine postmenopausal (PM, age: 58 ± 4 years, 8 ± 1 years post‐menopause) females completed the study. Concurrent oestradiol infusion augmented the vasodilatory response to ACh, sodium nitroprusside and terbutaline in young premenopausal (all P < 0.05) but not older postmenopausal (all P > 0.05), females. Local infusion of exogenous 17β‐oestradiol augmented endothelial and smooth muscle microvascular vasodilatation in premenopausal but not postmenopausal, females. imageKey points Menopause is associated with vascular dysfunction. Because oestradiol has vasoprotective effects, the menopause‐associated drop in oestradiol concentrations is hypothesized to contribute to vascular dysfunction during the menopause transition. The present study shows that local infusion of exogenous oestradiol augmented microvascular vasodilatation in premenopausal but not postmenopausal females.

Importance The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression. Objective To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS. Design, Setting, and Participants Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens. Interventions Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing. Main Outcomes and Measures The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; &amp;lt;1 indicating treatment benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n = 164). Results Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority, 0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified. Conclusions and Relevance In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources. Trial Registration ClinicalTrials.gov Identifier: NCT04297683

Context.— A monthly pathology journal club has met for 24 years. It was established to help members stay apprised of the literature relevant to diagnostic pulmonary pathology. Objective.— To assess whether the journal club met its goal and to report on opportunities identified for improvement. Design.— To determine whether articles chosen for discussion as opposed to notation were more significant, Scopus citation indices for article types reviewed from January 2007 to November 2023 were compared. A survey of current faculty was undertaken to determine if the club was meeting expectations and to identify improvement opportunities. Results.— Articles from January 2007 to November 2023 included 858 discussed and 3385 noted. Mean (SD) citation count was 103.0 (409.80) for discussion and 64.9 (259.77) for notation articles ( P < .001). The citation count was noticeably right skewed, as articles with high citation counts inflated the mean. Members were mostly satisfied with the way the journal club was structured and managed. Members most valued the summary of the articles, followed by the live discussion. Opportunities for improvement included decreasing the number of journals scanned, decreasing detail in summaries, and using generative artificial intelligence (AI) to facilitate summary generation. A pilot using AI anecdotally reduced preparatory time, but the human-edited summary included more specific context, critical commentary, and enhanced take-home messages, providing a more nuanced analysis. Conclusions.— The journal club met its initial goal. Opportunities for improvement have been identified including the use of generative AI to facilitate article summarization.

Objectives To compare postoperative complication rates of patients with metabolic syndrome (MetS) with patients without MetS after holmium laser enucleation of the prostate (HoLEP) for management of benign prostatic hyperplasia (BPH). Patients and Methods We retrospectively reviewed patients aged >40 years who underwent HoLEP at our institution from 2007 to 2022. Criteria for MetS were diagnoses of at least three of the following: diabetes mellitus, hypertension, hyperlipidaemia, or obesity (body mass index ≥30 kg/m 2 ). Uni‐ and multivariable logistic regression were used to compare the likelihood of immediate, 30‐day, and 90‐day complications between groups. Results A total of 1500 patients were included with a median (interquartile range) age of 70 (65–76) years. Patients with MetS were more likely to develop complications at both 30 and 90 days, including urinary incontinence, irritative voiding symptoms, and bleeding ( P < 0.001). After adjusting for potential confounders, patients with MetS had a greater than three times odds of both 30‐ and 90‐day complications compared to patients without MetS (30‐day adjusted odds ratio [aOR] 3.32, 95% confidence interval [CI] 2.21–5.01, P < 0.001; and 90‐day aOR 3.64, 95% CI 2.49–5.31, P < 0.001). Conclusion Metabolic syndrome was associated with a three‐fold likelihood of 30‐ and 90‐day complications after HoLEP. This could be an important factor to consider in preoperative counselling and patient selection.

AbstractSurveillance of individuals at high‐risk of pancreatic cancer using CAPS criteria and other expert consensus guidelines may result in earlier pancreatic cancer detection in some cases; therefore, clinicians are responsible for appropriately identifying and referring these individuals to appropriate high‐risk pancreas cancer screening programs. This study aimed at assessing the perspective, knowledge, and clinical practices of cancer genetic counselors surveyed nationwide towards identification of individuals at high‐risk of pancreatic cancer and utilization of high‐risk pancreatic cancer screening programs. One hundred and eighty‐nine genetic counselors who listed “Cancer” as their specialty on the NSGC website responded to the survey, which consisted of multiple practice‐based, knowledge‐based, and clinical vignette‐based questions. Almost 70% of the genetic counselors surveyed accurately identified when an individual would be considered for high‐risk pancreatic cancer screening, when using 2019 CAPS consensus guidelines as a benchmark. Access to high‐risk pancreatic cancer screening programs and increased provider comfort in counseling individuals at high‐risk of pancreatic cancer were found to be statistically associated in accurate identification of high‐risk individuals in three of the clinical vignettes. Additionally, 60% of genetic counselors reported the majority of high‐risk individuals accept a referral for pancreatic cancer screening, which shows a high uptake of patients accepting referrals from genetic counselors. Genetic counselors have high accuracy in determining who is eligible for high‐risk pancreas screening; thus, they are the ideal providers for initiating referrals to high‐risk pancreatic cancer screening programs. Genetic counseling programs and high‐risk pancreatic cancer screening programs should establish a close working relationship to optimize the identification and subsequent referrals of high‐risk individuals eligible for pancreas cancer screening.

AbstractBackgroundRecent advances in automatic face recognition have increased the risk that de‐identified research imaging data could be re‐identified from face imagery in brain scans.MethodAn ADNI committee of independent imaging experts evaluated 11 published techniques for face‐deidentification (“de‐facing”) and selected four algorithms (FSL‐UK Biobank, HCP/XNAT, mri_reface, and BIC) for formal testing using 183 longitudinal scans of 61 racially and ethnically diverse ADNI participants, evaluated by their facial feature removal on 3D rendered surfaces (confirming sufficient privacy protection) and by comparing measurements from ADNI routine image analyses on unmodified vs. de‐faced images (confirming negligible side effects on analyses).ResultEffects of the de‐facing methods on FreeSurfer at UCSF (Figure 1‐top), ASHS at University of Pennsylvania (Figure 1 bottom‐left), and longitudinal atrophy at Mayo Clinic (Figure 1 bottom‐right) were comparable with each other and sufficiently small vs. unmodified scans to recommend de‐facing in ADNI‐4. The FSL and mri_reface methods were more thorough in removing facial features, partly because these also removed ears (Figure 2‐top). mri_reface was recommended for ADNI‐4 primarily because fewer (zero) images had modified brain (Figure 2‐bottom), and ADNI leadership approved de‐facing with mri_reface. ADNI performed a second validation of its latest version on another diverse sample of 100 ADNI‐3 participants. These analyses included: boundary shift interval at University College London, where average differences in measurements were all <0.05%; cortical white matter hyperintensities at UC Davis, where they found “minimum impact” (R>0.97); and others.ConclusionADNI‐4 de‐faces all indicated image types (Table 1) before subsequent pre‐processing, analyses, and public release. Sites upload images to the central repository (LONI), where they are queued to the MRI Core at Mayo Clinic for de‐facing. Image types requiring de‐facing are de‐faced using mri_reface. Trained analysts inspect de‐faced images to confirm complete removal of the face and complete non‐modification of the brain, and any flagged images are re‐processed manually until issues are resolved. De‐faced images are converted back to DICOM and re‐uploaded for further distribution. Image types not requiring de‐facing are indicated to proceed directly to subsequent steps. In summary, ADNI‐4 has adopted mri_reface because it successfully de‐faces without substantially affecting brain measurements.

AbstractBackgroundRecent advances in automatic face recognition have increased the risk that de‐identified research imaging data could be re‐identified from face imagery in brain scans.MethodAn ADNI committee of independent imaging experts evaluated 11 published techniques for face‐deidentification (“de‐facing”) and selected four algorithms (FSL‐UK Biobank, HCP/XNAT, mri_reface, and BIC) for formal testing using 183 longitudinal scans of 61 racially and ethnically diverse ADNI participants, evaluated by their facial feature removal on 3D rendered surfaces (confirming sufficient privacy protection) and by comparing measurements from ADNI routine image analyses on unmodified vs. de‐faced images (confirming negligible side effects on analyses).ResultEffects of the de‐facing methods on FreeSurfer at UCSF (Figure 1‐top), ASHS at University of Pennsylvania (Figure 1 bottom‐left), and longitudinal atrophy at Mayo Clinic (Figure 1 bottom‐right) were comparable with each other and sufficiently small vs. unmodified scans to recommend de‐facing in ADNI‐4. The FSL and mri_reface methods were more thorough in removing facial features, partly because these also removed ears (Figure 2‐top). mri_reface was recommended for ADNI‐4 primarily because fewer (zero) images had modified brain (Figure 2‐bottom), and ADNI leadership approved de‐facing with mri_reface. ADNI performed a second validation of its latest version on another diverse sample of 100 ADNI‐3 participants. These analyses included: boundary shift interval at University College London, where average differences in measurements were all <0.05%; cortical white matter hyperintensities at UC Davis, where they found “minimum impact” (R>0.97); and others.ConclusionADNI‐4 de‐faces all indicated image types (Table 1) before subsequent pre‐processing, analyses, and public release. Sites upload images to the central repository (LONI), where they are queued to the MRI Core at Mayo Clinic for de‐facing. Image types requiring de‐facing are de‐faced using mri_reface. Trained analysts inspect de‐faced images to confirm complete removal of the face and complete non‐modification of the brain, and any flagged images are re‐processed manually until issues are resolved. De‐faced images are converted back to DICOM and re‐uploaded for further distribution. Image types not requiring de‐facing are indicated to proceed directly to subsequent steps. In summary, ADNI‐4 has adopted mri_reface because it successfully de‐faces without substantially affecting brain measurements.