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Molecular features of human pathological tau distinguish tauopathy-associated dementias
No full textIn Alzheimer's disease (AD), pathological tau protein shows a progressive accumulation of post-translational modifications (PTMs), reflecting disease severity, progression, and prion-like activity. Although many neurodegenerative diseases with dementia display tau aggregates, the pathological proteoforms of tau protein from each disease type remain unknown. Here, using a quantitative mass spectrometry-based proteomics platform, FLEXITau, deep characterization of pathological tau protein isolated from the brains of 203 human subjects with AD, familial AD (fAD), chronic traumatic encephalopathy (CTE), corticobasal degeneration (CBD), Pick's disease (PiD), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB)-a non-tauopathy symptomatic control-and healthy controls (CTR) is performed. Unsupervised data analyses and supervised machine learning identify distinct molecular features of pathological tau for each disease, enabling molecular disease stratification. This study identifies potential disease-specific biomarkers and therapeutic targets for tauopathies and provides critical quantitative information for pharmacokinetic modeling required for therapeutic and disease mechanism studies
Abstract TP290: Final Infarct Volume as a Surrogate Endpoint in Anterior-Circulation ICAS-LVO Stroke - Secondary Analysis of the RESCUE-ICAS Registry
No full textIntroduction: Final infarct volume (FIV) on 24-hour MRI is a well-established imaging biomarker linked to functional recovery after ischemic stroke,1-3 yet its prognostic value in ICAS-LVO remains poorly explored. The impact of adjunct intracranial stenting on both infarct size and infarct progression also remains unclear in this population. This study aimed to examine the association between FIV and clinical outcome, evaluate the effect of adjunct stenting on FIV and infarct progression, and assess the relationship between infarct progression and functional independence.
Methods: We conducted a secondary analysis of the RESCUE-ICAS registry,4 only patients with anterior circulation LVO with MRI after thrombectomy were included. Final infarct volume (FIV) was measured on diffusion-weighted MRI performed 24-36 hours post thrombectomy. Infarct progression was defined as the difference between baseline CTP infarct volume (CBF <30%) on presentation and 24-36-hour FIV. The primary outcome was 90-day functional independence (mRS 0-2). Secondary outcomes included the effect of adjunct stenting on FIV and infarct progression. Associations were analyzed using multivariable logistic regression and inverse probability of treatment weighting (IPTW).
Results: Of the 417 patients included in the RESCUE-ICAS registry, 203 had anterior circulation ICAS-LVO and underwent MRI 24-36 hours post-thrombectomy. Among these, 80 patients (39%) received adjunct stenting. FIV was independently associated with 90-day functional independence (adjusted OR per 10 mL increase: 0.8; 95% CI: 0.68-0.94; p = 0.007). Adjunct stenting was associated with smaller FIV (IPTW-adjusted mean difference: -25.07 mL; 95% CI: -40.36 to -9.78; p = 0.001). In 108 patients with baseline CTP data and FIV data, infarct progression was not significantly different between stented and non-stented groups (Δ -9.53 mL; 95% CI: -37.9 to 18.8; p = 0.506), but progression <44.5 mL was strongly associated with favorable outcome.
Conclusion: Among ICAS-LVO patients, 24-36-hour FIV is a strong predictor of functional outcome. Adjunct stenting is associated with smaller FIV. Lower infarct progression was also associated with favorable outcome. These findings highlight FIV as a reliable imaging biomarker and potential surrogate endpoint in future trials
Single-Fraction Stereotactic Radiosurgery for Residual, Recurrent, or Metastatic Intracranial Solitary Fibrous Tumors: An IRRF Study Toward Management Guidance
No full textIntracranial solitary fibrous tumors (SFTs) are rare, aggressive neoplasms with high local recurrence. This study evaluates the efficacy and prognostic factors of single-fraction stereotactic radiosurgery (SRS).
This multicenter retrospective study included 107 patients (253 SFTs) treated with single-fraction SRS at 18 centers (1989-2024). We analyzed local control (LC), intracranial tumor control (ITC), overall tumor control (OTC), progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS). Cox regression identified prognostic factors.
Median follow-up was 33 months. LC was 68.4% (5-yr: 56.8% and 10-yr: 38.8%). ITC 54.2% (5-yr: 48.5%) and OTC 50.5% (5-yr: 44.0%). PFS was 56.3% and 30.2% at 5 and 10 years, respectively. DSS remained high at 89.7% (5-yr) and 79.7% (10-yr), while OS was 79.3% (5-yr) and 55.2% (10-yr). Independent predictors of LC included recurrent vs. metastatic SFTs (HR: 1.96, p = 0.028), margin dose ≤16 Gy (HR: 2.35, p = 0.006), larger tumor volume (HR: 1.05, p 70 predicted better outcomes across ITC, OTC, DSS and OS. Radiation-related adverse effects occured in 2.8%.
SRS offers reasonable tumor control and favorable long-term survival in the adjuvant and salvage setting for patients with residual, recurrent, or metastatic intracranial SFTs. Key prognostic factors included tumor volume, recurrence status, and timing of SRS
Spectrum of DNA Variants Underlying Deafness in an Ecuadorian Cohort
No full textThe genetic etiology of hearing loss (HL) in Ecuador remains largely unexplored. This study investigates the spectrum of genetic variants associated with HL in a cohort of 66 Ecuadorian families using Exome or Genome sequencing (ES/GS). We identified pathogenic and likely pathogenic variants underlying HL in 27 families (41%). While variants were detected in 15 different genes, only GJB2 (in 12 families) and TMC1 (in 3 families) variants were identified in more than one family. The NM_004004.6 (GJB2):c.19 C > T (p.Gln7*) and NM_004004.6 (GJB2):c.35delG (p.Gly12Valfs*2) variants were more common than other alleles in GJB2. In some families, we detected variants of uncertain significance (VUS) in well-established HL genes and classified them as "possibly solved" due to their rarity and equivocal functional predictions. This study provides valuable insights into the genetic basis of HL in Ecuador and lays the groundwork for improved regional genetic diagnostics and management
P-1211. Effectiveness of iMIpenem-Relebactam for multidrug-resistant Pseudomonas AeruGinosa in pnEumonia and bloodstream infections in the United States (MIRAGE)
No full textBackground Imipenem/relebactam (I/R) demonstrates potent in vitro activity against multidrug-resistant (MDR) Pseudomonas aeruginosa. The objective of this study was to evaluate the effectiveness of I/R for treatment of MDR P. aeruginosa infections across the U.S. Methods This was a retrospective, multicenter, observational study of I/R for MDR P. aeruginosa pneumonia and bacteremia. Patients were included if they received I/R for >48h initiated within 7 days of the index MDR P. aeruginosa culture (Table 1). Clinical success was defined as survival, resolution of signs and symptoms of infection, completion of the intended treatment course, and the absence of a recurrent infection due to MDR P. aeruginosa. I/R susceptibility was determined by site-level microbiology labs; non-susceptibility was defined by the Clinical and Laboratory Standards Institute (CLSI) criteria. Results 64 patients from 10 centers were included (Table 2); patients from 6 additional centers were screened and did not meet inclusion criteria. The overall cohort was critically-ill; 80%, 75%, and 48% were in the intensive care unit, receiving mechanical ventilation, and on vasopressors, respectively. The median (interquartile range; IQR) SOFA score was 7 (5 – 12). 53% received treatment with another new β-lactam for MDR P. aeruginosa infections prior to I/R. The median time to I/R initiation was 67 hours. I/R treatment was primarily prescribed based on susceptibility results in 75% of patients, including resistance to other novel β-lactam agents (Table 3). 63% of patients completed the intended I/R treatment course as planned. At day 7 and 30, 80% and 55% met criteria for clinical success, respectively (Table 4). The overall 30- and 90-day mortality rates were 17% and 30%, respectively. Recurrent infections were documented in 38% of patients within 90 days. Conclusion In this critically-ill patient population we found that I/R was often used following treatment with other novel β-lactams. Clinical outcomes were generally comparable to those previously reported in similar real-world studies for other novel β-lactam agents suggesting that I/R plays a role in treatment of MDR P. aeruginosa infections, particularly when other agents are not available or test resistant. Disclosures jason M. Pogue, PharmD, Entasis: Advisor/Consultant|Entasis: Grant/Research Support|GlaxoSmithKline: Advisor/Consultant|Melinta: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support Alexander J. Lepak, MD, FIDSA, BioMerieux: Grant/Research Support William R. Miller, M.D., Merck: Grant/Research Support|UpToDate: Royalties, topic author Jeffrey C. Pearson, PharmD, InflaRx Pharmaceuticals, Inc.: Advisor/Consultant Emre Yucel, PhD, Merck & Co., Ltd: Stocks/Bonds (Public Company
A multicenter, open-label study of RP2 oncolytic immunotherapy expressing anti–CTLA-4 in combination with second-line atezolizumab plus bevacizumab in advanced hepatocellular carcinoma (HCC) or in combination with first-line durvalumab in advanced biliary tract cancer (BTC)
No full textTPS614 Background: Despite recent breakthroughs in first-line treatment of advanced HCC using immune checkpoint inhibitors (ICIs) with or without vascular endothelial growth factor inhibition, second-line options after progression on ICIs remain limited. In BTC, first-line therapy also includes ICIs, but outcomes remain suboptimal. RP2 is an enhanced potency herpes simplex virus type 1 (HSV-1) oncolytic immunotherapy that expresses GM-CSF, a fusogenic glycoprotein (GALV-GP-R − ), and an anti–CTLA-4 antibody. RP2 showed clinical activity as a single agent and when combined with ICIs in a phase 1 study in advanced solid tumors. This study evaluates the safety and efficacy of RP2 combined with atezolizumab (atezo) + bevacizumab (bev) as second-line therapy in patients (pts) with unresectable advanced HCC or RP2 combined with durvalumab (durva) in pts with unresectable advanced BTC after first-line chemotherapy is discontinued. Methods: This is an open-label, multi-cohort, phase 2 trial (NCT05733598; RP2-003). For the HCC cohort (n = 30), pts receive RP2 combined with atezo + bev. Key inclusion criteria include advanced unresectable HCC with ≥1 measurable tumor ≥1 cm (longest diameter), Child-Pugh class A, ECOG performance status of 0–1, and progression on 1 prior systemic treatment (anti–PD-1/PD-L1 as immediate prior therapy). Key exclusion criteria include untreated/incompletely treated esophageal or gastric varices with bleeding or high bleeding risk and macroscopic invasion of the tumor into any major blood vessels or main bile ducts. Pts receive intratumoral (IT) RP2 every 2 weeks (Q2W) until the 4 th dose, then Q3W thereafter. Bev is given IV at 10 mg/kg Q2W with the 1 st dose of RP2, then 15 mg/kg Q3W starting with 4 th dose and thereafter; atezo is given IV at 840 mg Q2W for 2 doses starting with the 2 nd dose of RP2, then 1200 mg Q3W thereafter. For the BTC cohort (n = 30), pts receive IT RP2 Q2W combined with durva 1500 mg Q4W after combination chemotherapy is discontinued. Pts must be on a combination of gemcitabine, platinum-containing chemotherapy, and a checkpoint inhibitor for ≥12 weeks and have documented stable disease or partial response on ≥2 scans. Pts with mismatch repair deficiency/microsatellite instability-high tumors are excluded. For both cohorts, the primary endpoint is overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Secondary endpoints include safety, ORR per RECIST 1.1 modified for use in HCC (HCC cohort only), duration of response, complete response rate, progression-free survival, and overall survival. Clinical trial information: NCT05733598
Unified Protocols for Transdiagnostic Treatment of Emotional Disorders in Children and Adolescents
No full textTreatment for emotional disorders in children and adolescents is increasingly being applied in a transdiagnostic manner to address the need for more broadly applicable yet mechanism-focused psychotherapy. The Unified Protocols for Transdiagnostic Treatment of Emotional Disorders in Children and Adolescents (UP-C/A) are flexible, evidence-based treatment manuals that utilize evidence-based, largely cognitive and behavioral strategies to treat anxiety, mood, and other emotional disorders. In this chapter, we describe the rationale and empirical support for the use of the UP-C/A, provide a pragmatic overview of its contents, and briefly discuss application of core intervention components
Using digital phenotyping to index 12-month treatment effects of xanomeline and trospium chloride on physical activity in outpatients with schizophrenia
No full textPoint-of-Care Molecular Diagnostics in a Post-Pandemic Era
No full textThe field of molecular diagnostics has normally been confined to laboratories. This centralization enables a concentration of technology and technical training to identify a wide variety of diseases. This system is sufficient in many places; however, many regions in the world do not have adequate access to pathology laboratories. The lack of routine diagnostic tests results in poorer health outcomes in low-resource regions. This disparity was highlighted during the COVID-19 pandemic with developed countries able to create sufficient testing capacity for their populations while many low-resource countries’ disease prevalence was chronically under counted. Developing affordable rapid diagnostic tests can narrow this health disparity and enable healthcare providers to limit the spread of infectious diseases within their communities. The focus of this dissertation is the development of effective point-of-care diagnostic platforms which can be applied to a variety of infectious diseases.The first approach was the rapid point-of-care detection of SARS-Cov-2. The platform consisted of reverse transcription recombinase polymerase amplification (RT-RPA) combined with paper-based lateral flow tests. This diagnostic platform was applied and refined for the pipette-less, rapid detection of Human Papillomavirus for cervical cancer screening. Finally, we simplified loop-mediated isothermal amplification (LAMP) using modified self-annealing primers to develop stem-loop amplification (SLA) coupled with colorimetric G-quadruplex DNAzyme probes for detection. The work presented demonstrates that the simplification of molecular diagnostics is possible for the development of the next generation of point-of-care tests. The robust platforms developed in this work can be applied and utilized in field settings, enabling accurate and timely screening for low-resource regions. Ultimately, improved access to diagnostic capacity is a key component to reducing preventable diseases in the most vulnerable communities. </p
The Effect of Institution Crisis Management on Undergraduate Students’ Continuation
No full textThis study explored the relationship between crisis management strategies used in higher education—resources and funding, caring and compassion, communications and response, and leadership—and their impact on undergraduate students’ intent to return to campus after a crisis. Additionally, the study investigated how this relationship varies by student background variables. Findings indicated that student motivation to return after a crisis was significantly decreased when response and communication was used as crisis management strategy. However, no difference in student outcome was found when other crisis management strategies were used. Student background variables such as career aspirations, GPA scores, campus environment perception, and personal involvement play a crucial role in influencing the desire to remain in the same institution. Despite study limitations and the influence of COVID-19, the current study underscores the importance of the appropriate use of crisis management to bolster student retention. The study concludes by proposing avenues for future research, including realistic scenario experiments, qualitative inquiries, and case studies on specific institutions. </p