Citations

BACKGROUND Differential awakening is a well-known, yet poorly understood phenomenon seen in patients with intracranial pathologies. Because acute postoperative neurological decline has many potentially reversible causes, distinguishing differential awakening from other etiologies is critical. To the authors’ knowledge, differential awakening has not been reported following peripheral nerve procedures. OBSERVATIONS A 40-year-old man presented with a 1.5-year history of painful bilateral cervical and right lumbosacral radiculoplexus neuropathy recently associated with bilateral facial and vestibulocochlear neuropathy. He had not responded to treatment trials. A sciatic nerve lesion in the sciatic notch was identified on imaging and an open biopsy of the posterior femoral cutaneous nerve was pursued. Immediately after emergence from anesthesia, he demonstrated a complete inability to dorsiflex or plantar flex the right foot, despite minimal intraoperative manipulation of the sciatic nerve. Over the ensuing hour, motor function progressively returned to baseline. The transient postoperative motor deficit was attributed to differential awakening of the sciatic nerve. Pathological analysis confirmed high-grade B-cell lymphoma. LESSONS Differential awakening may be an underrecognized cause of transient neurological worsening during emergence from anesthesia following peripheral nerve surgery. Further investigation is needed to clarify the underlying mechanisms and define its incidence and risk factors. https://thejns.org/doi/10.3171/CASE251028

Importance Current risk prediction guidelines for hypertrophic cardiomyopathy predict only sudden cardiac death and are imperfect, leading to avoidable deaths and unnecessary implantable cardioverter defibrillators. Objective To combine prospectively collected clinical history, imaging, genetic, and biomarker data to improve risk prediction of adverse events in hypertrophic cardiomyopathy. Design, Setting, and Participants A total of 2750 patients with hypertrophic cardiomyopathy were prospectively enrolled in the registry-based study from 44 sites in North America and Europe with expertise in hypertrophic cardiomyopathy and cardiac magnetic resonance (CMR) imaging. Participants were enrolled from April 1, 2014, to April 7, 2017. Exposures Patients underwent a health history questionnaire, blood sampling for biomarkers and genotyping, and contrast-enhanced CMR. Patients were followed up yearly by telephone and through records review regarding event documentation. Main Outcomes and Measures The predefined composite adjudicated primary end point was time to first event for hypertrophic cardiomyopathy–related deaths; nonfatal sustained ventricular arrhythmias (VAs) requiring cardioversion or defibrillation; and left ventricular (LV) assist device implant or heart transplant. A secondary end point was a composite of sudden cardiac death and nonfatal VA events. The elastic-net method identified the most important predictors. Cox proportional hazards regression assessed associations with time to the first end point. Results Of the 2750 prospectively enrolled patients, 2698 (98%) had analyzable data after 9 were excluded because they had hypertrophic cardiomyopathy phenocopies and 43 withdrew. Of these remaining patients, 1919 (71%) were male, mean age was 50 years (SD, 11 years), and 423 (16%) were from underrepresented racial and minority groups. The mean follow-up was 6.9 years (SD, 2.1 years). The primary event model in 104 patients included LV scar as a percentage of LV mass by late gadolinium enhancement (LGE%; hazard ratio [HR], 1.86; 95% CI, 1.58-2.20; P < .001), LV mass index (HR, 1.09; 95% CI, 1.01-1.17; P = .03), LV end-systolic volume index (HR, 1.28; 95% CI, 1.12-1.46; P < .001 ), all per 10-unit increase, history of heart failure at study entry (HR, 2.89; 95% CI, 1.75-4.77; P < .001), and log N-terminal pro–B-type natriuretic peptide (NT-proBNP; HR, 1.41; 95% CI, 1.17-1.70; P < .001) level per log unit, (C index for all, 0.77). An LGE percentage of the LV mass of 9% or higher substantially increased the primary composite event rate ( P = .001). The secondary sudden cardiac death and VA risk factor model (in 69 patients) included LGE%, LV mass index, LV ejection fraction, and log(NT-proBNP) (C index, 0.76). Conclusions and Relevance These results provide prospective evidence for incorporating cardiac magnetic resonance and NT-proBNP in the evaluation of patients with hypertrophic cardiomyopathy. Trial Registration ClinicalTrials.gov Identifier: NCT01915615

This secondary analysis of a nonrandomized clinical trial identifies which participant characteristics were associated with selection of centralized or remote trial engagement.

Abstract INTRODUCTION Clinicopathological studies offer crucial interpretations of 18 F‐flortaucipir (FTP) tau positron emission tomography (PET) signal but are limited by methods. We leveraged whole‐brain, quantitative immunohistochemical (IHC) Alzheimer's Disease (AD) tau density maps to comprehensively evaluate the FTP tracer. METHODS We generated IHC maps for three AD‐tau antibodies—AT8, AT100, and MC1—using two human brains histologically staged at Braak IV and VI. FTP‐PET scans were acquired 6 and 10 weeks prior to death. Using region‐wise and voxelwise methods, we correlated FTP‐PET with IHC signals. RESULTS Only AT8 (p‐tau Ser202/Thr205; neuronal and neuritic tau pathology) showed a notable correlation with FTP standardized uptake value ratios (SUVRs) in the Braak VI case (Spearman's rank correlation coefficient [r s ] = 0.461, p < 0.001). FTP SUVRs failed to capture medial temporal lobe (MTL) tau burden, whereas neocortical regions showed lower IHC burden but more variability in FTP uptake. DISCUSSION Although FTP signals correlate well with AT8‐positive tau in the more advanced case, they underestimate the severity of MTL burden, potentially confounding assessments of tau‐targeted therapies.

OBJECTIVE Adamantinomatous craniopharyngioma (ACP) is a rare type of brain tumor that affects a wide age range, from children to older adults. Due to the rarity of the disease, existing studies are predominantly limited to single-center or single-surgeon experiences, often lacking statistical power and generalizability. The aim of this study was to address this gap by providing a comprehensive analysis of ACP outcomes based on a large multicenter cohort from the Registry of Adenomas of the Pituitary and Related Disorders (RAPID). METHODS This multicenter retrospective cohort study was conducted via the RAPID consortium and assessed patients with histologically confirmed ACP treated surgically between August 2000 and November 2024 at high-volume pituitary centers across the United States. RESULTS Among the 359 patients (206 male, median age at primary surgery of 47 years) included in the analysis, 76% underwent endoscopic transsphenoidal surgery and 22% underwent craniotomy. Gross-total resection was achieved in 45% and subtotal resection in 47%. Notably, 120 of 311 patients (39%) presented with preoperative hypothalamic-pituitary axis dysfunction. Following all treatments, permanent hypothyroidism was reported in 40% of patients, adrenal insufficiency in 33%, and arginine vasopressin deficiency in 19%. Of 263 patients who underwent primary surgery, radiation therapy was administered in 84 (32%). Progression-free survival (PFS) declined from 66% at 1 year to 31% at 6 years. In the multivariable analysis, independent predictors of worse PFS included subtotal resection (HR 0.22, 95% CI 0.11–0.42; p = 0.001), partial resection (HR 0.11, 95% CI 0.04–0.28, p = 0.001), larger tumor size (HR 0.77, 95% CI 0.64–0.94; p = 0.009), and tumor extension beyond the sella and suprasellar regions (HR 0.21, 95% CI 0.06–0.74; p = 0.016). Primary surgery and salvage surgery groups showed comparable PFS. CONCLUSIONS In this large multicenter cohort study, gross-total resection was achieved in fewer than half of patients and was independently associated with improved PFS. Approximately one-third of patients underwent radiation therapy after primary surgery. These findings provide robust evidence supporting the prognostic value of extent of resection and inform contemporary treatment algorithms for ACP. The high incidence of postoperative endocrinopathy underscores the need for individualized multidisciplinary long-term care. While the retrospective design is a limitation, the multicenter approach enhances the generalizability of these results.

Abstract Human genomic studies link reduced CUB domain-containing protein 1 (CDCP1) expression with myocardial recovery in heart failure. While CDCP1 regulates cardiac fibroblast proliferation in vitro, it’s in vivo role in cardiac fibrosis remains unclear. Using a Cdcp1 -knockout (KO) angiotensin II/phenylephrine mouse model, we show that Cdcp1 deletion reduces echocardiographic left ventricular mass, histologic cardiac fibrosis, and pro-fibrotic gene expression, along with decreased fibroblast activation and inflammatory markers. Spatial transcriptomics identified a pressure overload–expanded fibroblast subpopulation enriched for growth factor and TGF-β signaling (FB5), which was markedly attenuated in Cdcp1 -KO hearts, alongside reduction of a pro-inflammatory cardiomyocyte subtype (CM4). Complementary studies in human ventricular fibroblasts demonstrate that CDCP1 knockdown reduced extracellular matrix gene expression and collagen I deposition. These findings establish CDCP1 as a regulator of cardiac fibrotic remodeling in vivo and open avenues for its further investigation as a potential therapeutic target.

Background COVID‐19 and other respiratory viral infections can cause cardiovascular complications. SARS‐CoV‐2 virions are found in the blood, and circulating viral RNA levels are associated with death. We hypothesized that viremia can induce thrombotic endotheliopathy that contributes to death and studied this relationship in patients hospitalized for COVID‐19 and enrolled in the ACTIV‐4a (Accelerating COVID‐19 Therapeutic Interventions and Vaccines) randomized trial of antithrombotic therapy. Methods We quantified SARS‐CoV‐2 nucleocapsid RNA and protein in plasma and measured their associations with clinical outcomes and biomarkers of thromboinflammation and endotheliopathy. We used Cox regression and Fine–Gray competing risk models to analyze survival and thrombosis. We conducted causal mediation analysis to explore whether thrombotic endotheliopathy mediates the relationship between viral RNA and death. Results In 93 patients, SARS‐CoV‐2 RNA and N‐antigen were higher in nonsurvivors. Baseline viral RNA levels were associated with increased 90‐day death (hazard ratio [HR], 1.31 [95% CI, 1.17–1.46]) and thrombosis (HR, 1.35 [95% CI, 1.24–1.47]). Viral RNA more effectively predicted survivorship than N‐antigen levels. Soluble thrombomodulin, a biomarker of thrombotic endotheliopathy, positively correlated with viral RNA levels. Mediation analysis revealed that soluble thrombomodulin accounts for 12.2% (95% CI, 0.1%–32.3%; P =0.048) after adjustment for age and sex of the relationship between viral RNA and the 90‐day mortality rate. Conclusions Elevated plasma SARS‐CoV‐2 RNA levels are associated with death in ACTIV‐4a, which is causally mediated in part by soluble thrombomodulin. We propose that lung–blood viral dissemination is a potential mechanism for cardiovascular complications of respiratory viruses. Registration URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT04505774.

Abstract Background and aims Patient foramen ovale (PFO) is a stroke risk factor evaluated using transthoracic echocardiogram (TTE), transesophageal echocardiogram (TEE), transcranial Doppler ultrasound (TCD), and cardiac computed tomography (CCT). TCD is non-invasive, but its diagnostic performance relative to other modalities is unclear. We hypothesized that TCD has high sensitivity but low specificity for PFO detection. Methods We conducted an IRB-approved, single-center retrospective study of patients undergoing TCD for right-to-left shunt (RLS) detection between January 2024 and April 2025. Patients were identified from the Neurosonology Laboratory Quality Database. Records were reviewed for demographics, comorbidities, and TTE, TEE, and CCT findings. Sensitivity, specificity, and positive and negative predictive values were calculated for TCD, TTE, and CCT relative to TEE, the gold standard. The sensitivity and specificity of TCD versus TTE were compared using McNemar test. Results Ninety-two patients were included. Mean age was 52.66 ± 15.78 years, and 51% were female; qualifying events included ischemic stroke or transient ischemic attack. RLS was detected in 53 patients (57.6%) by TCD, 17 (30%) by TTE, 18 (28.5%) by TEE, and 3 (21%) by CCT. TCD demonstrated 94% sensitivity and 53% specificity, (PPV 66%, NPV 89%). TTE showed 50% sensitivity and 82% specificity (PPV: 75%, NPV 61%), while CCT showed 33% sensitivity and 100% specificity (PPV 100%, NPV 33.3%). TCD had significantly higher sensitivity than TTE for RLS detection (p=0.039) with a non-significant difference in specificity (p=0.062), using TEE as the reference. Conclusions TCD has high sensitivity for RLS detection in patients with ischemic stroke or transient ischemic attack. Conflict of interest Rachel Knopp: nothing to disclose; Kelly Flemming: nothing to disclose; Eugene Scharf: nothing to disclose; Zafer Keser: nothing to disclose; Jessica Prink: nothing to disclose; Shari Johnson: nothing to disclose; Guy Reeder: nothing to disclose; Robert Brown: nothing to disclose; William Harmsen: nothing to disclose; Muhib Khan: nothing to disclose Table 1 - belongs to Results

This multicenter, single-arm, phase 1/2 study evaluated the safety and efficacy of CD19-directed allogeneic chimeric-antigen-receptor (CAR) immunotherapy CTX110 in adult patients with relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (NHL). Patients received 1 or 2 treatment courses: standard lymphodepletion, followed by 1 CTX110 infusion at dose levels (DLs) 1-4 (3-60 × 107 CAR T-cells; dose escalation, N=32), or 2 infusions at DL4 on days 1 and 35 (cohort expansion, N=31). Primary endpoints in dose escalation and cohort expansion were incidence of dose-limiting toxicities and objective response rate, respectively. CTX110 was administered to 63 heavily pretreated patients: 59% primary refractory, 43% with ≥3 prior treatment lines. Among 57 patients whose first infusion was DL≥3, rates of objective and complete response (CR) were 65% and 39%, respectively. Among 22 patients achieving CR, 5 (23%) had ongoing CR at data cutoff, with 15-50 (median 34) months follow-up. The 2-infusion regimen appeared to prolong response duration compared to 1 infusion (hazard ratio 0.65). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were reported in 54% and 13% of treated patients, respectively, including 2 grade ≥3 cases each. The most common grade ≥3 adverse events were neutropenia (59%), and anemia and thrombocytopenia (35% each). Serious adverse events occurred in 32% of treated patients, including CRS (14%), ICANS (8%), and febrile neutropenia (6%). In this r/r NHL population, CTX110 was well-tolerated, resulting in clinically meaningful responses at DL≥3, with a second infusion demonstrating evidence of further clinical benefit. This trial (NCT04035434) was registered at www.clinicaltrials.gov.