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ABSTRACT Objective To evaluate the long‐term safety and clinical effect of INO‐3107 immunotherapy in adults with recurrent respiratory papillomatosis (RRP). Methods RRP‐002 was a retrospective, observational extension study that followed patients enrolled in the 52‐week RRP‐001 study. Patients with moderate to severe juvenile or adult‐onset RRP who had undergone ≥ 2 surgical interventions in the year preceding dosing were eligible for enrollment in RRP‐001. Participants underwent surgical debulking within 14 days prior to initial dosing and then received INO‐3107 on Day 0, Weeks 3, 6, and 9. Efficacy assessments during RRP‐002 follow‐up were the frequency of surgical interventions and alternative medication use. The safety evaluation included reported serious adverse events (SAEs). Results Twenty‐eight (28) of 32 participants from the 52‐week RRP‐001 study were enrolled in RRP‐002. The median follow‐up time for RRP‐002 was 1.8 years (range: 1.2–2.4 years) for a total median assessment time of 2.8 years (range: 1.0–3.5 years). There were no SAEs or long‐term safety concerns identified. The mean number of surgeries was reduced from 4.1 in the pre‐treatment period to 1.7 in the first year post‐INO‐3107 treatment (Year 1) to 0.9 in the second year (Year 2). The complete response rate (0 surgeries per year) increased from 28% (9/32) in Year 1 to 50% (14/28) in Year 2. Conclusion INO‐3107 is well tolerated and provides a continued clinical effect against HPV‐6 and 11 RRP that results in further reduction of the surgical burden observed in Year 1. These data support the role of INO‐3107 immunotherapy for adult patients with RRP. Level of Evidence: III.

ABSTRACT Objectives To investigate the value of cytokine, chemokine, and neurofilament light chain (NfL) concentrations in predicting relapse risk, chronic epilepsy, and functional impairment in LGI1 autoimmune encephalitis (AE). Methods Cytokines/chemokines (IL‐1‐beta, IL‐2, IL‐4, IL‐5, IL‐6, IL‐8/CXCL8, IL‐10, IL‐12p70, IL‐13, IL‐17A, GM‐CSF, TNF‐alpha, IFN‐gamma, CXCL9, CXCL10, CXCL13, BAFF) and NfL concentrations were measured in CSF and paired serum from LGI1‐AE patients evaluated at Mayo Clinic (01/2015–02/2024), using a multiplex immunoassay system (ELLA, Bio‐Techne) and correlated with clinical outcomes. A laboratory‐based cohort of LGI1‐IgG‐positive patients and control cohorts, including patients with mixed non‐inflammatory disorders (MNID), Alzheimer's disease (AD), and temporal lobe epilepsy (TLE) were analyzed. Results Forty‐four patients with LGI1‐AE were included; 29 (66%) were male, with a median age of 68.5 years (range, 8–85). Median time from symptom onset to CSF sampling was eight months (IQR, 3–17); 19/42 (45%) experienced a clinical relapse and 27% developed chronic epilepsy. Serum IL‐6, serum and CSF IL‐8/CXCL8, and IL‐17A were higher in LGI1‐IgG positive patients than MNID ( p < 0.05). TLE cytokine/chemokine profiles were similar to LGI1 AE; AD patients had lower serum IL‐6 and CSF IL‐8/CXCL8 ( p = 0.04; p = 0.01), and higher serum IL‐17A and GM‐CSF ( p = 0.004; p = 0.01) than LGI1‐AE. Higher CSF IL‐6 and IL‐8/CXCL8 in LGI1‐AE associated with clinical relapse ( p < 0.05) and higher CSF NfL associated with chronic epilepsy ( p = 0.01). Conclusion Elevations in IL‐6, IL‐8/CXCL8, and IL‐17A were identified in this LGI1‐AE cohort. CSF IL‐6, IL‐8/CXCL8, and NfL levels are potential prognostic biomarkers for risk of relapse and chronic epilepsy in LGI1‐AE.

Abstract The link between regional tau load and clinical manifestation of Alzheimer’s disease (AD) highlights the importance of characterizing spatial tau distribution across disease variants. In typical (memory-predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicentres. However, given the limited spatial heterogeneity of tau in typical AD, atypical (non-amnestic-predominant) AD variants with distinct tau patterns provide a key opportunity to investigate the universality of connectivity as a scaffold for tau progression. In this large-scale, multicentre study across 14 international sites, we included cross-sectional tau-PET data from 320 individuals with atypical AD (n = 139 posterior cortical atrophy/PCA-AD; n = 103 logopenic variant primary progressive aphasia/lvPPA-AD; n = 35 behavioural variant AD/bvAD; n = 43 corticobasal syndrome/CBS-AD), with a subset of individuals (n = 78) having longitudinal tau-PET data. Additionally, as an independent sample, we included regional post-mortem tau stainings from 93 atypical AD patients from two sites (n = 19 PCA-AD, n = 32 lvPPA-AD, n = 23 bvAD, n = 19 CBS-AD). Gaussian mixture modelling was used to harmonize different tau-PET tracers by transforming tau-PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether brain regions with stronger resting-state functional MRI-based functional connectivity, derived from healthy elderly controls in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), showed greater covariance in cross-sectional and longitudinal tau-PET and post-mortem tau pathology. Furthermore, we examined whether functional connectivity of tau-PET epicentres (i.e. the top 5% of regions with the highest baseline tau load) and tau-PET accumulation epicentres (i.e. the top 5% of regions with the highest tau accumulation rates) was associated with cross-sectional and longitudinal tau patterns. Our findings show that tau-PET epicentres aligned with clinical variants, e.g. a visual network predominant pattern in PCA-AD (‘visual AD’) and left-hemispheric temporal predominance, particularly within the language network, in lvPPA-AD (‘language AD’). Moreover, more strongly functionally connected regions showed correlated concurrent tau-PET levels (confirmed with post-mortem data) and tau-PET accumulation rates. The functional connectivity profile of tau-PET epicentres and accumulation epicentres corresponded to tau-PET progression patterns, with higher tau-PET levels and accumulation rates in functionally close regions, and lower tau-PET levels and accumulation rates in functionally distant regions. Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicentres, across all AD clinical variants. Since tau proteinopathy is a major driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant-specific end points in clinical trials.

ABSTRACT Background Geriatric screening and multidisciplinary assessment of older adults in the Emergency Department (ED) decrease hospitalizations and ED revisits. The impact on patient‐reported outcomes of health‐related quality of life (HRQoL) and functional status is not known. Methods A hybrid type II implementation/effectiveness prospective cohort study was conducted in an academic ED. The intervention bundle was geriatric screening for delirium, fall risk, and transition of care needs, and multidisciplinary assessment. All older adults (≥ 65 years) placed in the ED observation unit were eligible. HRQoL and functional status were obtained at the ED visit, 30, and 90 days, and were compared between the pre‐ and post‐intervention implementation cohorts. Secondary outcomes included ED revisits, falls, mortality, and intervention adoption measures. Results From 2019 to 2023, 368 adults participated in the study: Most were community‐dwelling (97%) and had multiple comorbidities. The pre ( n = 138) and post ( n = 230) cohorts did not differ in baseline functional status or HRQoL. The rate of geriatric screening improved from 12.3% in the pre‐implementation cohort to 91.3% in the post‐implementation cohort ( p < 0.01). Multispecialty consultation also increased (68.1%–91.3%, p < 0.01). The proportion who had a post‐ED visit decline in functional status did not differ between cohorts. Physical HRQoL declined similarly in both cohorts (−0.73 vs. −0.33, p = 0.61) at 90 days. Mental HRQoL improved in both cohorts; improvement was greater in the pre‐cohort (2.35 vs. 0.32, p = 0.02). ED revisits and re‐hospitalizations were unchanged (30 days: 23.0% vs. 17.2%, p = 0.18, and 90 days: 37.8% vs. 34.8%, p = 0.57). The intervention decreased falls at 30 and 90 days (30 days: 9.7% vs. 3.2%, p = 0.04; 90 days: 22.1% vs. 7.9%, p < 0.01). Conclusions Geriatric screening in the ED increased identification of geriatric syndromes and multidisciplinary consultation. The intervention was associated with decreased falls but did not affect HRQoL or reduce functional decline post ED visit. Trial Registration clinicaltrials.gov : NCT04068311

OBJECTIVES: To investigate whether severe hyperoxia predisposes to end-organ complications and whether these complications contribute to in-hospital mortality among cardiogenic shock (CS) patients supported in venoarterial extracorporeal membrane oxygenation (VA-ECMO). DESIGN: Adult patients with CS from the Extracorporeal Life Support Organization Registry between 2010 and 2023 were categorized into normoxia (Pao 2 60–150 mm Hg), mild hyperoxia (Pao 2 151–300 mm Hg), and severe hyperoxia (Pao 2 > 300 mm Hg) based on their Pao 2 at 24 hours. The primary outcome was in-hospital mortality. End-organ complications were analyzed using multivariate logistic regression models, and causal mediation analysis was performed to estimate the direct and indirect effects of hyperoxia on mortality. SETTING: Multicenter, multinational prospective cohort study. PATIENTS: Adults with CS supported on VA-ECMO. INTERVENTIONS: Partial pressure of oxygen at 24 hours after VA-ECMO cannulation. MEASUREMENTS/MAIN RESULTS: A total of 10,541 patients were included (normoxia: 48.4%, mild hyperoxia: 30.0%, severe hyperoxia: 21.5%). There was higher in-hospital mortality in patients with severe hyperoxia (71.7%, adjusted OR [aOR]: 2.17; 95% CI, 1.19–2.50) and mild hyperoxia (63.8%, aOR: 1.34; 95% CI, 1.19–1.50) compared normoxia (52.7%; referent group). Severe hyperoxia was associated with more end-organ complications, which incrementally predicted higher mortality (aOR: 1.42; 95% CI, 1.25–1.61). Mediation analysis demonstrated that hyperoxia primary exerted a direct effect on mortality (86%), with contributions from neurologic (3.1%), hepatic (3.9%), renal (3.5%), and bleeding (2.3%) complications. CONCLUSIONS: Severe hyperoxia in patients with CS receiving VA-ECMO is associated with increased mortality and more end-organ complications. However, most of the effect of severe hyperoxia on mortality occurs via direct effects, independent of end-organ complications. These findings highlight the potential direct toxicity of hyperoxia and underscore the need for strategies to optimize oxygen delivery in this critically ill population.

ABSTRACT Rationale Longer duration of epilepsy before surgery is a predictor of poor outcome. While referral delays of surgical candidates are well documented, factors causing delay during the presurgical evaluation remain unclear and may vary depending on institutional characteristics. By benchmarking the duration of presurgical evaluation across multiple centers and identifying patient and evaluation characteristics contributing to duration, we can ascertain best practices and address modifiable contributors to reduce delays. Methods We queried the Pediatric Epilepsy Research Consortium Surgery Database, a prospective, observational multicenter study enrolling children 0–18 years at 27 US pediatric epilepsy centers, for all patients undergoing initial presurgical evaluation for drug‐resistant epilepsy (DRE). We included patients with completed evaluations and data on duration from initiation of presurgical evaluation to final surgical decision. We compared patient characteristics and evaluation components between those with long duration evaluations (> 75% quartile) and those with short evaluations (< 25% quartile). Akaike information criteria selection identified variables associated with longer duration. From these, we developed a logistic prediction model for evaluation duration, using a random 80/20 training/testing split of the entire cohort. The model was tested among institutions with ≥ 10 patients in the cohort to assess its accuracy in predicting long durations. Linear models for each site assessed each variable's impact on duration. Variables with < 10% of the patient population at each site were excluded. Beta values were compared to identify intra‐ and inter‐institution variability and to delineate institutions with the shortest added duration for each variable. Results Of 2318 patients undergoing surgical evaluation, 1655 (71%) from 23 sites had complete data. Median evaluation duration was 8 weeks (interquartile range 3–22); 453 (27%) were short‐duration evaluations and 414 (25%) were long‐duration evaluations. Multiple patient and evaluation characteristics were associated with duration (Table 1). Table 6 provides the average duration each variable contributes to evaluation by site, highlighting the shortest durations compared with other groups. Conclusions Duration of presurgical evaluation for DRE can be accurately modeled using multiple patient characteristics and testing strategies commonly employed in epilepsy surgery evaluations. This predictive model can not only estimate evaluation duration but also identify opportunities to improve systemic efficiency. Institution‐level modeling identifies specific program strengths, providing an opportunity to learn from successful processes. Subsequent research will focus on institutional process mapping to better understand systemic practices that lead to improved efficiencies, then sharing these processes across the consortium to shorten evaluation durations.

Abstract Background Direct measurement of low-density lipoprotein cholesterol (LDL-C) is widely used and recommended by professional society guidelines despite its potential limitations in patients with hypertriglyceridemia and low LDL-C. This study evaluated the performance of 3 direct LDL-C (LDL-CD) assays, 2 modern LDL-C calculation methods [LDL-C Martin (LDL-CM), LDL-C modified Sampson (LDL-CS)] and the conventional Friedewald (LDL-CF) method against the reference method, beta-quantification (LDL-CBQ). Methods A total of 181 remnant sera from patients with standard lipid panel orders or from patients with LDL-CBQ orders with triglycerides (TG) ≥ 400 mg/dL (4.5 mmol/L), or with TG ≥ 150 mg/dL (1.69 mmol/L) and LDL-C &lt; 70 mg/dL (1.8 mmol/L) were included. LDL-CD and lipid panel data were gathered from Abbott Alinity, Roche Cobas, and Siemens Atellica platforms. Results LDL-CD among the 3 platforms showed a median CV of 11.2%. In patients with TG &lt;400 mg/dL, LDL-CM and LDL-CS demonstrated less bias and less misclassification at the clinical decision LDL-C levels than LDL-CF or LDL-CD. In the 400 to 800 mg/dL (9.0 mmol/L) TG group, LDL-CS was superior to LDL-CD or LDL-CM in accuracy. When TG is ≥ 800 mg/dL, LDL-CD (Roche) showed substantial bias from LDL-CBQ while LDL-CS (Roche) showed smaller but significant bias. Conclusions In summary, LDL-CD or LDL-CF showed little advantage over the 2 modern LDL-C calculation methods. LDL-CS showed the best overall correlation with LDL-CBQ and therefore is recommended to replace LDL-CF and potentially LDL-CD when making clinical decisions in patients with low LDL-C and hypertriglyceridemia.

Tumour-infiltrating lymphocyte (TIL) therapy has emerged as a promising adoptive cell transfer strategy for solid tumours. The recent accelerated approval of lifileucel by the Food and Drug Administration marks a significant milestone in the clinical application of TIL therapy. This review comprehensively examines the historical development, biology, clinical efficacy, safety and limitations of TIL therapy. We explore advancements in TIL manufacturing, including novel culture techniques, genetic modifications and automation, to enhance scalability and effectiveness. Despite promising results, TIL therapy faces challenges such as high-dose interleukin-2 toxicity, complex manufacturing processes and immune evasion mechanisms. Emerging strategies, including checkpoint inhibitor combinations, engineered TIL constructs and metabolic reprogramming, aim to improve TIL therapeutic efficacy. This review provides insights into the evolving landscape of TIL therapy and its potential to enhance current cancer immunotherapy.

Abstract Background Despite advances in diagnosis and management, the interstitial lung disease (ILD) lexicon is plagued by ambiguous and inconsistent terminology that complicates communication and impedes knowledge generation. The objective of this Fleischner Society Consensus Statement was to produce standardized terminology for ILD multidisciplinary diagnoses and major phenotypes. Methods Interviews with 10 experts were used to identify ILD clinical diagnoses and major phenotypes. The preferred terms for each entity and potential alternatives were identified, alongside the rationale for the preferred term. Entities with more than one potential term were the subject of an online modified Delphi survey posed to the 29 committee members, aiming to achieve consensus. Committee members rated their agreement with the initially preferred term—5 (strongly agree), 4 (agree), 3 (neutral/unsure), 2 (disagree), and 1 (strongly disagree)—with the option to provide additional comments. Median score ≥4 and interquartile range ≤1 were considered consensus agreement. Terms not reaching agreement were discussed by video conference, followed by an additional survey that incorporated feedback. Results From the 60 initial terms, there were two root terms that required upfront consensus before survey initiation (ILD and interstitial pneumonia) and another eight terms that had no alternative suggested by the committee or in the literature. Agreement was met by 47/50 terms (94%) in Round 1 of the survey. The three terms (6%) that did not reach agreement met agreement in Round 2. Conclusions This document provides standardized recommended terms for ILD multidisciplinary diagnoses and major phenotypes that will facilitate communication among clinicians, researchers, patients, and other stakeholders.