Treatment Window Research Articles

What time window do AD trajectories depart from normal? Estimating age‐related trajectories to chart preclinical phase of Alzheimer’s disease and select trial‐ready cohorts

AbstractBackgroundThe preclinical phase of Alzheimer’s disease (AD), where pathology slowly accumulates years before cognitive impairment becomes apparent, could offer a treatment window with the greatest potential to preserve cognitive function before downstream pathological processes gather momentum. Characterizing when biomarker trajectories deviate from normal ageing, and the heterogeneity therein, could facilitate targeted trial recruitment and improved biomarker‐based evidence of disease modification. However, reliably identifying early abnormal changes can be challenging due to various confounds, such as age and vascular factors, as well as disease heterogeneity.MethodData from the following cohorts were analysed: (1) individuals at risk for, or affected by, autosomal dominant AD (ADAD), including the Dominantly Inherited Alzheimer Network; (2) Insight 46, a neuroimaging substudy of the MRC National Survey of Heath and Development; (3) pre‐randomization study data from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4); and (4) the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Linear regression assessed differences between at‐risk groups (biomarker‐ or mutation‐positive) and normal ageing. Longitudinal changepoint models estimated when atrophy rates deviate from normal ageing trajectories. Normative modelling, based on large reference datasets, identified outliers of regional atrophy assessed within‐group heterogeneity at the individual level. Data‐driven disease progression models (DPMs) were used to estimate quantitative signatures of AD, including imaging biomarkers.ResultDPMs reveal that amyloid markers deviate first in ADAD, roughly ten years before neurodegenerative markers. Changepoint models indicate that atrophy rates in ADAD become abnormal 3‐8 years before expected symptom onset, with longitudinal tau PET data suggesting a similar trend. While cross‐sectional volumetric measures showed no evidence of association with amyloid markers, atrophy rates were independently related to both amyloid positivity and markers of cerebrovascular disease, indicating similar, additive effects. Both DPMs and normative modelling found evidence of heterogeneity within imaging biomarkers in ADNI and A4, which explained variability in cognitive decline observed in at‐risk participants.ConclusionBiomarker data from preclinical AD suggests a long temporal gap between amyloidosis and subsequent changes. This represents a treatment opportunity to remove amyloid while minimising irreversible damage. There is evidence of heterogeneity within the biomarker trajectories, which could impact the ability to detect disease modification.

Abstract C087: DHX9 inhibition as a novel therapeutic modality in microsatellite instable colorectal cancer

Abstract Background: DHX9 is a DEAH-box RNA helicase which has been reported to play important roles in replication, transcription, translation and RNA splicing/processing, all of which contribute to DHX9’s role in the maintenance of genomic stability. Functionally, DHX9 unwinds and/or resolves regions of double-stranded DNA and RNA helices but has a greater propensity for secondary structures such as DNA/RNA hybrids (R-loops), circular RNA (circRNA) and DNA/RNA G-quadraplexes. Overexpression of DHX9 is evident in multiple cancer types, including colorectal cancer (CRC) and lung cancer. In particular, microsatellite instable (MSI) tumors exhibiting defective mismatch repair (dMMR) show a strong dependence on DHX9, making this helicase an attractive target for oncology drug discovery. Here, we will demonstrate validation of DHX9 as a novel target for CRC-MSI, and the identification of potent and selective in vitro and in vivo small molecule inhibitors of DHX9. Materials and Methods: DHX9 targeted siRNA or DHX9 small molecule inhibitors were used to assess anti-proliferative activity in multiple different CRC-MSI and CRC-MSS cell lines through either CellTiter-Glo proliferation or colony formation assays. Downstream biological consequences of DHX9 knockdown or inhibition in vitro were determined using immuno-fluorescent imaging, western blot, flow cytometry to measure RNA/DNA secondary structure, cell cycle changes, apoptosis, and qPCR to measure circBRIP1 induction. CRC-MSI and CRC-MSS tumor xenografts were treated with DHX9 inhibitor ATX968 BID orally for 21-28 days. Tumor and plasma samples were collected for pharmacokinetics (PK) and pharmacodynamic (PD) (circBRIP1) measurement. Results: We demonstrate that DHX9 inhibition in CRC-MSI leads to an increase in RNA/DNA secondary structures such as R-loops, G-quadruplexes and Alu mediated circRNA such as circBRIP1, leads to subsequent DNA damage and increased replication stress. Cell lines that exhibit defective DNA repair pathways such as dMMR are unable to resolve this replication stress and demonstrate S-G2 phase cell cycle arrest prior to onset of apoptosis. We confirmed this selective dependency in a panel of cancer cell lines, where anti-proliferative effects mediated by DHX9 inhibition were associated with dMMR status. Furthermore, DHX9 tool compound ATX968 was well tolerated in vivo across a 28-day treatment period with robust and durable tumor regression observed in the MSI CRC tumor xenograft model. Following cessation of treatment, minimal tumor regrowth was observed in a 28-day post treatment window. Tumor and plasma concentrations of ATX968 and changes in PD markers of DHX9 inhibition were measured and resulting PK, PD and efficacy data were highly correlated. Conclusions: Together, these preclinical data validate DHX9 as a tractable new target with potential utility as a novel treatment for patients with CRC-MSI. Conflict of Interests: All authors are current or former employees and shareholders of Accent Therapeutics, Inc. Citation Format: Jennifer Castro, Matthew H Daniels, David Brennan, Brian T Johnston, Rishabh Bansal, Monique Laidlaw, Chuang Lu, Deepali Gotur, Young-Tae Lee, Kevin Knockenhauer, April Case, Jie Wu, Anugraha Raman, Jae Eun Cheong, Julie Liu, Shane M Buker, E. Allen Sickmier, Stephen J Blakemore, P. Ann Boriack-Sjodin, Kenneth W Duncan, Serena J Silver, Scott Ribich, Robert A Copeland. DHX9 inhibition as a novel therapeutic modality in microsatellite instable colorectal cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C087.

ECG signal classification based on CNN deep learning

Cardiovascular disease is one of the major health concerns, posing a significant threat to human well-being. Modern diagnostic techniques often rely on electronic devices for assistance. Electrocardiograms (ECG) contain abundant information and serve as a powerful tool in diagnosing cardiovascular diseases. Hence, the vital task of monitoring and categorizing ECG signals is pivotal in averting and identifying cardiovascular ailments. In many hospitals, ECG signal classification often depends on experienced doctors, consuming substantial time and potentially missing the optimal window for disease treatment. This paper presents a methodology utilizing the MIT-BIH arrhythmia database, employing deep neural networks, a 10-layer one-dimensional convolutional neural network, to fulfill the function of ECG signal classification. The model under consideration attains a comprehensive accuracy rate of 99.43% on the test dataset, accompanied by sensitivity (97.86%) and specificity (99.64%). These values surpass other methods mentioned in this paper by 1% to 3%. The experimental findings presented indicate the proposed method holds valuable implications for the future realization of intelligent automated ECG signal classification systems.

A Novel Platform for Evaluating Dose Rate Effects on Oxidative Damage to Peptides: Toward a High-Throughput Method to Characterize the Mechanisms Underlying the FLASH Effect.

High dose rate radiation has gained considerable interest recently as a possible avenue for increasing the therapeutic window in cancer radiation treatment. The sparing of healthy tissue at high dose rates relative to conventional dose rates, while maintaining tumor control, has been termed the FLASH effect. Although the effect has been validated in animal models using multiple radiation sources, it is not yet well understood. Here, we demonstrate a new experimental platform for quantifying oxidative damage to protein sidechains in solution as a function of radiation dose rate and oxygen availability using liquid chromatography mass spectrometry. Using this reductionist approach, we show that for both X-ray and electron sources, isolated peptides in solution are oxidatively modified to different extents as a function of both dose rate and oxygen availability. Our method provides an experimental platform for exploring the parameter space of the dose rate effect on oxidative changes to proteins in solution.

Phase 2 Response-Adapted Study of Ibrutinib with Temozolomide, Etoposide, Liposomal Doxorubicin, Dexamethasone, and Rituximab (TEDDI-R) for Secondary CNS Lymphoma

Background: Secondary CNS lymphomas (SCNSL) are aggressive and there are few treatment options. CNSLs often have underlying chronic active B-cell receptor signaling that responds to BTK inhibitors, but the response duration is short. TEDDI-R achieves durable remissions in primary DLBCL of the CNS (PCNSL), but the molecular profile of SCNSL tumors that are BTK-responsive is unknown. We present results from an ongoing response-adapted study of ibrutinib with TEDD-R in SCNSL [NCT03964090]. Methods: Pts with aggressive B-cell lymphomas with CNS +/- systemic involvement are eligible if age ≥18, PS<3, and adequate organ function. Pts are untreated with CNS involved or relapsed in the CNS after therapy. Prior BTKi is allowed. HIVis excluded. Baseline tests: brain MRI, PET/CT of body, bone marrow (BM), CSF flow cytometry, and fundoscopic exam. Pts receive isavuconazole as fungal prophylaxis throughout therapy. Pts first receive ibrutinib 560mg x 14d in a treatment window to determine ibrutinib-responsiveness. Pts with ≥20% reduction after ibrutinib receive TEDDI-R, and if <20% reduction receive TEDD-R (no ibrutinib). Chemotherapy is 4 cycles x21d as an outpatient and includes intrathecal chemotherapy. There is no maintenance therapy or planned consolidation. Response is assessed after cycles 2 and 4. Complete responses (CR) are confirmed with FDG-PET brain/body, CSF analysis, and BM. Surveillance scans are q3m for 1y, q4m x 1y, q6m x 1y, then annually. The primary endpoint is PFS. Results:50 pts enrolled between June 2019 and March 2023 with median age 63 (range 26-89), and 15 (30%) aged ≥70. 17 pts (34%) were female. 28 (56%) pts had DLBCL: 21 (42%) non-GCB, 5 (10%) GCB, 1 (2%) PMBL, and 1 (2%) unknown. 16 (32%) pts had HGBL: 10 (20%) with MYC/ BCL2-R and 6 (12%) with MYC/ BCL6-R. Two (4%) pts each had MCL and EBV-LPD, and 1 pt each had plasmablastic (2%) and Burkitt (2%). Five (10%) pts were treatment naïve and 45 (90%) were relapsed or refractory. 25 (50%) had synchronous CNS and peripheral disease, and 25 (50%) were isolated to the CNS. All relapsed or refractory pts had prior anthracycline, 29 (58%) prior HD-MTX, and 8 (18%) prior CAR-T. Forty-three pts completed the ibrutinib window and were evaluable for responsiveness; 25 (58%) were ibrutinib-responsive and 18 (42%) were ibrutinib-resistant (Figure 1). The overall response rate (ORR) to TEDDI-R (n=28) was 96%, including a CR rate of 71%. The overall response rate to TEDD-R (n=20) was 35%, with a CR rate of 25%. G3 or G4 neutropenia occurred in 43% and 31% of cycles, respectively, and febrile neutropenia occurred in 11%. G3 or G4 thrombocytopenia occurred in 31% and 12% of cycles, respectively, and G3 anemia occurred in 37%. G3 non-hematologic AEs (% pts) included UTI (20%), hypokalemia (22%), sepsis (14%), diarrhea (16%), hypotension (12%), fatigue (10%), anorexia (10%), adrenal insufficiency (10%), and atrial fibrillation (8%). Few G4 AEs were noted. No opportunistic infections (including Aspergillus) were observed. 14 (28%) pts had hand-foot syndrome. After a median follow-up of 24m, the 1-year PFS and OS of all patients were 37.8% and 59.9%, respectively. Pt deaths were due to disease progression (20 pts, 83%), pneumonia (3 pts, 13%), and a cardiac event (1 pt, 4%). The 1-year PFS and OS for pts with ibrutinib-responsive compared to ibrutinib-resistant tumors were 57.0% vs. 16.7% (p=0.0006) and 73.8% vs. 47.9% (p=0.06) (Figure 2). Most (86%) ibrutinib-responsive DLBCL/HGBL tumors were CD10-negative. CD10-negative DLBCL/HGBL pts had an ORR of 77% and a CR rate of 70%. The 1-year PFS and OS for pts with CD10-negative DLBCL/HGBL were 50.5% and 65.0%, respectively. There was no difference in PFS or OS in pts aged <70 versus ≥70 (p=0.87 and p=0.74, respectively). We performed comprehensive genomic profiling on 27 DLBCL/HGBL tumors according to the LymphGen algorithm. 80% (n=4) MCD, 75% (n=3) BN2, 50% (n=2) EZB, and 50% (n=7) unclassified tumors were responsive to ibrutinib. Conclusions: Pts with ibrutinib-responsive SCNSL achieve a high rate of CR to TEDDI-R, and preliminary data suggest these remissions are durable. Most ibrutinib-responsive tumors are CD10-negative and enriched for MCD and BN2. TEDDI-R can be delivered as an outpatient to pts of all ages.

Impact of Hypomethylating Agents on Cardiovascular Disease Risk Among Patients with Myelodysplastic Syndromes

Introduction: The association between clonal hematopoiesis (CH) and cardiovascular disease (CVD) risk has drawn attention to cardiovascular outcomes in myelodysplastic syndromes (MDS). CVD accounts for 25% of deaths in MDS, potentially via CH-mediated accelerated atherosclerosis from inflammatory vascular responses. We previously demonstrated that MDS was independently associated with increased risk of CVD in older adults from SEER-Medicare. We subsequently hypothesized that treatment with hypomethylating agents (HMA) could reduce CVD risk by ameliorating CH clones and reducing the inflammation. In this study, we aimed to define the impact of HMA on incident cardiovascular events among older adults with MDS. Methods: We identified subjects ≥66 years diagnosed with MDS from 2007 to 2017 in SEER-Medicare. Exclusion criteria including lacking continuous Medicare parts A, B, and D, enrolled in HMO, or incomplete follow-up. Demographics included age, sex, race, rurality, socioeconomic quintile, marital status, and geographic region. Baseline CVD risk factors, defined from ICD-9/10 codes, included hypertension, hyperlipidemia, diabetes, atrial fibrillation, pre-existing cardiac disease, obesity, and smoking. MDS factors, defined using HCPCS codes, ICD-O-3 codes and prescription records, included MDS subtype and histologic risk stratification, transfusion dependence and treatment with hypomethylating agents (HMA), lenalidomide, or erythropoietin-stimulating agents (ESA) as time-varying variables. Incident CVD was defined as new myocardial infarction (MI) and/or ischemic stroke occurring after MDS diagnosis, using published ICD-9/10 algorithms. We controlled for confounding using 2 complementary analytic approaches. First, we assessed the association between HMA use and CVD using propensity score adjusted cause-specific competing risk Cox hazard models with death as competing risk, Second, we used a case-crossover design with conditional logistic regression, in which subjects with CVD served as their own controls, using a 3-month HMA treatment window and a control period 6 months prior to the incident event. Results: We identified a cohort of 15,227 eligible patients with MDS. Of these, 1,125 patients had an MI and/or ischemic stroke within 1 year before MDS diagnoses and were excluded. We analyzed 14,102 MDS patients, with median age 82 years (IQR 77 - 86), who were predominantly male (53.8%), non-Hispanic white (88.6%), and from urban/suburban areas (86.2%). MDS was of low, intermediate, and high histologic risk in 14.7%, 72.8%, and 12.5%, respectively, and 28.6% were transfusion dependent. Pre-existing CVD risk factors at time of MDS diagnosis were present in 12,538 patients, with baseline cardiovascular risk defined as low, intermediate, and high in 11.1%, 32.3%, and 56.6% of the cohort. The cumulative incidences of MI, ischemic stroke and composite CVD events were 11.3%, 10.6% and 20.4%, respectively. The propensity score (PS) conditional probability for being treated with HMA included demographic variables, CVD risk factors, MDS histology and transfusion dependence. Our PS model adequately predicted HMA treatment propensity (AUC 0.76). Cause-specific regression with death as competing risk, adjusted for PS and other MDS-specific treatments (ESA and lenalidomide), showed no significant effect of HMA on the risk of composite CVD events, MI, or ischemic stroke (Table 1). Conditional logistic regression in the case-crossover analysis of 1,907 patients with composite CVD events showed no significant effect of HMA. Results were similar for analysis of patients with MI and ischemic stroke (Table 2). Conclusions: No study has previously investigated the effect of HMA therapy on cardiovascular outcomes in patients with MDS. We demonstrate that HMA therapy is not associated with a significant risk reduction in cardiovascular events among patients with MDS patients from the SEER-Medicare database. These results show that HMA therapy is unlikely to reduce cardiovascular mortality and underscore the need for alternative therapeutic strategies targeting cardiovascular health patients with MDS.

The novel norcantharidin derivative DCZ5417 suppresses multiple myeloma progression by targeting the TRIP13–MAPK–YWHAE signaling pathway

BackgroundMultiple myeloma (MM), an incurable disease owing to drug resistance, requires safe and effective therapies. Norcantharidin (NCTD), an active ingredient in traditional Chinese medicines, possesses activity against different cancers. However, its toxicity and narrow treatment window limit its clinical application. In this study, we synthesized a series of derivatives of NCTD to address this. Among these compounds, DCZ5417 demonstrated the greatest anti-MM effect and fewest side effects. Its anti-myeloma effects and the mechanism were further tested.MethodsMolecular docking, pull-down, surface plasmon resonance-binding, cellular thermal shift, and ATPase assays were used to study the targets of DCZ5417. Bioinformatic, genetic, and pharmacological approaches were used to elucidate the mechanisms associated with DCZ5417 activity.ResultsWe confirmed a highly potent interaction between DCZ5417 and TRIP13. DCZ5417 inhibited the ATPase activity of TRIP13, and its anti-MM activity was found to depend on TRIP13. A mechanistic study verified that DCZ5417 suppressed cell proliferation by targeting TRIP13, disturbing the TRIP13/YWHAE complex and inhibiting the ERK/MAPK signaling axis. DCZ5417 also showed a combined lethal effect with traditional anti-MM drugs. Furthermore, the tumor growth-inhibitory effect of DCZ5417 was demonstrated using in vivo tumor xenograft models.ConclusionsDCZ5417 suppresses MM progression in vitro, in vivo, and in primary cells from drug-resistant patients, affecting cell proliferation by targeting TRIP13, destroying the TRIP13/YWHAE complex, and inhibiting ERK/MAPK signaling. These results imply a new and effective therapeutic strategy for MM treatment.

Progress of nanomaterials in the treatment of thrombus.

Thrombus has long been the major contributor of death and disability because it can cause adverse effects to varying degrees on the body, resulting in vascular blockage, embolism, heart valve deformation, widespread bleeding, etc. However, clinically, conventional thrombolytic drug treatments have hemorrhagic complication risks and easy to miss the best time of treatment window. Thus, it is an urgent need to investigate newly alternative treatment strategies that can reduce adverse effects and improve treatment effectiveness. Drugs based on nanomaterials act as a new biomedical strategy and promising tools, and have already been investigated for both diagnostic and therapeutic purposes in thrombus therapy. Recent studies have some encouraging progress. In the present review, we primarily concern with the latest developments in the areas of nanomedicines targeting thrombosis therapy. We present the thrombus' formation, characteristics, and biomarkers for diagnosis, overview recent emerging nanomedicine strategies for thrombus therapy, and focus on the future design directions, challenges, and prospects in the nanomedicine application in thrombus therapy.

Non-compliance with medical recommendations results in delayed hospitalization and poorer prognosis in patients with cerebral ischemic stroke in Poland: Non-compliance effects on post-ischemic stroke prognosis

ObjectivesThis study aimed to reveal and analyze the causes of delays in reaching the hospital of patients with cerebral ischemic stroke and to assess their clinical picture. Material and methodsThe study group included 161 patients with stroke, who reported to the hospital beyond the thrombolytic treatment therapeutic window. The control group consisted of 85 patients recruited consecutively with stroke who received thrombolytic treatment per eligibility criteria. Laboratory and medical imaging tests essential for neurological condition assessment were conducted in the study group. Control group research was based on retrospective analysis of medical records. ResultsThe rate of deaths during hospitalization was lower in the control group (4.7%) compared to the study group (14.9%). In the study group, more patients (16.8%) admitted to non-compliance with medical recommendations than in the control group (5.9%). There were no statistically significant differences in nicotinism and alcohol dependence syndrome frequency between both groups. ConclusionsBased on each group inclusion criteria, a lower mortality rate in the control group indicates a crucial role of the therapeutic window in cerebral stroke treatment. Analysis of reasons for delay points out that efficient prophylaxis is the education of patients with stroke risk factors and their families.

Abstract 14671: Investigating Health Disparities in Arrival From Last Known Well Times in Queens, NY

Background: Stroke is a leading cause of death in the US and the third leading cause of disability worldwide, so timely access to care must be considered as it is a salient predictor of prognosis and outcomes. 1,2 Specifically, because the recommended treatment window for IV tPA (alteplase) is within 4.5hr of last known well (LKW), it is imperative for patients to present to the facility within 3.5hr from symptom onset to receive treatment. 3 There are known health disparities in stroke treatment/outcomes 4 , and this study seeks to explore the population of patients that disproportionately have unknown or LKW >4.5hr to arrival, and the impacts of such. Methods: Stroke patients entered into the Get With The Guidelines™-Stroke excluding patients whose symptoms began after hospital arrival and were discharged from October 2021 to December 2022 from NYC Health + Hospitals/Queens were included. Arrival from LKW time was categorized into ≤0-4.5hr and >4.5hr. Covariates collected and included are age, Hispanic ethnicity, sex, race, final clinical diagnosis of stroke, and history of previous stroke. Logistic regression models were used to analyze data and results are presented as adjusted odds ratios at 0.05 significance. Results: A total of 342 patients were included in this study with 211 patients arriving after 4.5hr. The median time to arrival from LKW was 829min. Notably, patients identifying as Asian were more likely to arrive within 4.5hr of LKW (3.21 adjusted OR, 95% CI 1.30-7.91, p = 0.01) compared to their Black counterparts. White patients were also more likely to arrive within the 4.5hr treatment window compared to Black patients (11.69 adjusted OR, 95% CI 3.39-40.36, p = 0.0001). Increase in age was associated with decrease in timely arrival from LKW (0.98 adjusted OR, 95% CI 0.96-0.99, p = 0.04). Clinically, those that were diagnosed with ischemic stroke were more likely to arrive within 4.5hr of LKW (2.55 adjusted OR, 95% CI 1.37-4.77, p = 0.003) as well as those with a history of previous stroke (2.74 adjusted OR, 95% CI 1.39-5.40, p = 0.004). Conclusion: There are health disparities in stroke treatment because of prolonged patient arrival from or unknown LKW, and these findings will help inform further practices in community education and outreach.

Abstract 211: Comparing Early and Late Window 3mm Trevo Stent Retriever Performance in Medium Vessel Occlusion Thrombectomy

Introduction Endovascular thrombectomy has been shown to be beneficial for select patients with medium vessel occlusion ischemic strokes. Newer mechanical thrombectomy devices have designs to facilitate navigation of the medium and distal cerebrovasculature. In this single‐center study, we aim to compare the performance of 3mm Trevo NXT stent retrievers (Stryker, Kalamazoo, MI) for medium vessel occlusion mechanical thrombectomy for patients treated within either the early (<6 hour) or late (>6 hour) treatment window. Methods A retrospective review was conducted of acute ischemic stroke patients with medium vessel occlusions (i.e., M2‐M4, ACA, and PCA) who underwent thrombectomy over 5 years (2018‐2022) at a single comprehensive stroke center. Classification into early or late window was defined as time from last known well to groin puncture less than 6 hours or greater than 6 hours, respectively. Primary efficacy outcome included successful recanalization (modified thrombolysis in cerebral infarction [mTICI]>=2B) using 3mm Trevo NXT on either first pass or rescue pass (i.e., after initial pass failure with another device). Primary safety outcome is rate of complications associated with the stent retriever. Primary clinical outcome was National Institutes of Health Stroke Scale (NIHSS) shift between admission and discharge. Results Of 81 patients with medium vessel occlusion ischemic strokes, 38 patients (44.7% female, median age of 73.5 years [IQR 66‐82], median initial NIHSS 13 [IQR 8‐23]) underwent thrombectomy with 3mm Trevo NXT. Stent retriever‐assisted aspiration (versus stent retriever only) was performed in 31/38 (81.6%) patients. Successful recanalization with stent retriever was achieved in 28/38 (73.7%) of patients. There was no significant difference in rate of recanalization between early and late window thrombectomy (16/22 [72.7%] early window vs. 12/16 [75%] late window, p=0.8752). The lack of significant difference in recanalization rate was consistent with stent retriever use during first pass (11/14 [78.6%] early window vs. 9/10 [90%] late window, p=0.6146) and as rescue (5/8 [62.5%] early window vs. 3/6 [50%] late window, p=0.6400). There was no significant difference in the rate of stent retriever complications between early and late windows (1/16 [6.3%] early vs. 0/22 [0%] late, p=0.4211). There was no significant difference in median NIHSS shift from admission to discharge ( ‐6 [IQR ‐16 ‐ 9] early window vs. ‐3 [IQR ‐5 ‐ 4] late window, p=0.3666). Conclusion In both early and late window medium vessel occlusion thrombectomy, the 3mm Trevo NXT as first line and rescue intervention performs comparably and adequately. Future multicenter studies will further characterize novel stent retriever performance in medium vessel occlusion thrombectomies.

Stimuli-responsive nanoparticles delivered by a nasal-brain pathway alleviate depression-like behavior through extensively scavenging ROS.

Depression is one of the most common mental diseases, which seriously affects patients' physical and mental health. Emerging evidence has indicated that oxidative stress (OS) is a major cause of neurodegeneration involved in the pathogenesis of depression. Consequently, targeted reactive oxygen species (ROS) elimination is regarded as a promising strategy for efficient depression therapy. In addition, insufficient brain drug delivery is the main obstacle to depression therapy owing to the presence of the blood-brain barrier (BBB). To achieve the goals of bypassing the BBB and promoting antioxidant therapy for depression, a broad-spectrum ROS scavenging NPs was rationally designed through a nasal-brain pathway developed for combined ROS scavenging and brain drug delivery. A hexa-arginine (R6) modified ROS-responsive dextran (DEX) derivate was synthesized for antidepressant olanzapine (Olz) and H2 donor amino borane (AB) loading to prepare Olz/RDPA nanoparticles (NPs). Subsequently, the NPs were dispersed into a thermoresponsive hydrogel system based on poloxamer. In vitro and in vivo results demonstrated that Olz/RDPA in situ thermoresponsive hydrogel system could effectively deliver NPs to the brain via the nasal-brain pathway and alleviate depression-like behaviors through combined ROS depletion and inhibition of 5-HT dysfunction of the oxidative stress-induced. The proposed ROS-scavenging nanotherapeutic would open a new window for depression treatment. STATEMENT OF SIGNIFICANCE: ROS is an innovative therapeutic target involving the pathology of depression whereas targeted delivery of ROS scavenging has not been achieved yet. In the current study, ROS-responsive nanoparticles (Olz/RDPA NPs) were prepared and dispersed in a thermosensitive hydrogel for delivery through the nasal-brain pathway for the treatment of depression. Sufficient ROS depletion and improvement of delivery capacity by the nasal-brain pathway effectively could reverse oxidative stress and alleviate depressive-like behavior. Collectively, these nanoparticles may represent a promising strategy for the treatment of depression.

8 Perspectives of Self, Stigma, and the Future Following Alzheimer's Disease Biomarker Disclosure in Cognitively Symptomatic Older Adults

AbstractObjective:In the absence of treatments to halt or reverse symptoms of Alzheimer's disease, early detection may extend the window for meaningful treatment, advanced planning, and coping. Positron emission tomography (PET) scans for amyloid and tau are validated biomarkers of AD, yet results are rarely disclosed to participants due to concerns about negative impacts. While prior studies suggest limited anxiety, depression, or suicidality following biomarker disclosure, no study to date has examined broader psychological impacts of PET amyloid/tau disclosure to symptomatic individuals. Therefore, we explored post-disclosure changes in future time perspective (perceptions of limited time or possibilities left in the future), self-efficacy for managing symptoms, and perceived stigma as a function of result received.Participants and Methods:Forty-three older adults (age = 72.0±6.2 years; education = 16.5±2.6; 88.4% White Non-Hispanic; 48.8% female) participated in the study, of whom 62.8% were diagnosed with mild cognitive impairment (MCI) and the remainder with Dementia of the Alzheimer's type. All participants underwent pre-disclosure biomarker education and decisional capacity assessment, followed by baseline measures. Participants demonstration decisional capacity completed an interactive disclosure session during which they received dichotomous results of their research positron emission tomography (PET) scans for amyloid and tau (elevated versus not elevated for each biomarker). Findings were discussed in relation to presence/absence of Alzheimer's disease, the etiology of their cognitive difficulties, and risk for conversion or further decline. At baseline, immediately following disclosure, and at 1-week follow-up, participants completed several questionnaires: the Future Time Perspective (FTP) scale, a measure of how much the participant sees time as limited, the Self Efficacy for Managing Chronic Disease scale (SECD), and the Stigma Scale for Chronic Illness (SSCI-8), all of which were modified to apply to Alzheimer's disease and associated experiences.Results:The main effects of time (F=1.10, p=.334, A?p2=.026), biomarker status (F(1)=3.10, p=.086, Ajp2=.070), and the time by biomarker status interaction (F=0.39, p=.661, Ajp2=.009) on FTP score was not significant. Though neither time (F=0.07, p=.933, A?p2=.002) nor the time by biomarker status interaction (F=2.16, p=.122, Ajp2=.050) effect on SECD was significant, being biomarker positive (A+T-/A+T+) was associated with lower self-efficacy (F(1)=5.641, p=.022, Ajp2=.121). Neither main effect for time (F=0.15, p=.853, Ajp2=.004) or biomarker status (F(1)=0.35, p=.558, A?p2=.009) on SSCI-8 was significant. The time by biomarker status interaction was significant (f=4.27, p=.018, =.096), such that biomarker negative participants experience a transient increase in perceived stigma directly after disclosure that resolves one week later, and biomarker negative participants experience the opposite pattern.Conclusions:Findings suggest that individuals who receive biomarker positive results may feel less competent to manage their symptoms compared to those who are biomarker negative, emphasizing the need for post-disclosure interventions targeting self-efficacy. The effect of disclosure on perceptions of time being limited and on perceived stigma were minimal, even when those results indicate evidence of Alzheimer's disease and risk for clinical progression. These results further support the safety of biomarker disclosure procedures. Future studies should provide longer-term assessment of psychological, behavioral, and clinical outcomes following Alzheimer's disease biomarker disclosure.

CNN and Rf based Early Detection of Brain Stroke Using Bio-Electrical Signals

The brain is a vital component of the body that is in control of involuntary and voluntary movements such as walking, memory, and vision. Nowadays, some of the most prevalent brain disorders include Alzheimer's disease, brain tumors, and epilepsy (paralysis or stroke). As a result, stroke has become a significant global health concern, with high rates of mortality and disability. Importantly, approximately two-thirds of all strokes occur in developing countries, highlighting the significant burden of this condition in these regions. Therefore, emphasizing the timely detection and appropriate treatment of brain tumors is crucial. Given the high potential for mortality or severe disability associated with stroke disease, prioritizing active primary prevention and early identification of prognostic symptoms is of paramount importance. Ischemic stroke and hemorrhagic stroke are the two primary classifications for stroke diseases. Each type calls for specific emergency treatments, such as the administration of thrombolytics or coagulants, tailored to their respective underlying mechanisms. However, to effectively manage stroke, it is crucial to promptly identify the precursor symptoms in real-time, as they can vary among individuals. Timely professional treatment within the appropriate treatment window is essential and should be provided by a medical institution. In contrast, prior research has primarily centered around the formulation of acute treatment strategies or clinical guidelines subsequent to the occurrence of a stroke, rather than giving sufficient attention to the early identification of prognostic symptoms. Specifically, recent research has extensively utilized image analysis techniques, such as computed tomography (CT) or magnetic resonance imaging (MRI), as a primary approach for detecting and predicting prognostic symptoms in stroke patients.
 Traditional methodologies not only encounter difficulties in achieving early real-time diagnosis but also exhibit limitations in terms of prolonged testing duration and high testing costs. In this study, we introduce a novel system that employs machine learning techniques to predict and semantically interpret prognostic symptoms of stroke. Our approach utilizes real-time measurement of multi-modal bio-signals, namely electrocardiogram (ECG) and photoplethysmography (PPG), with a specific focus on the elderly population.
 To facilitate real-time prediction of stroke disease during walking, we have developed a stroke disease prediction system that incorporates a hybrid ensemble architecture. This architecture synergistically combines Convolutional Neural Network (CNN) and Random Forest (RF) models, enabling accurate and timely prognostication of stroke disease. The suggested method prioritises the convenience of use of bio-signal sensors for the elderly by collecting bio-signals from three electrodes placed on the index finger. These signals include ECG and PPG, and they are obtained while the participants walk. The CNN-RF model delivers satisfactory prediction accuracy when using raw ECG and PPG data. F1-Score, Sensitivity, Specificity, and Accuracy were the performance parameters used to evaluated the model's performance.

Antiplatelets Are Enough for Nondisabling Strokes

This Viewpoint argues, in keeping with current stroke management guidelines, that patients with mild, nondisabling strokes should not receive thrombolysis, even when presenting within the time window for treatment.

Early Resveratrol Treatment Mitigates Joint Degeneration and Dampens Pain in a Mouse Model of Pseudoachondroplasia (PSACH).

Pseudoachondroplasia (PSACH), a severe dwarfing condition associated with early-onset joint degeneration and lifelong joint pain, is caused by mutations in cartilage oligomeric matrix protein (COMP). The mechanisms underlying the mutant-COMP pathology have been defined using the MT-COMP mouse model of PSACH that has the common D469del mutation. Mutant-COMP protein does not fold properly, and it is retained in the rough endoplasmic reticulum (rER) of chondrocytes rather than being exported to the extracellular matrix (ECM), driving ER stress that stimulates oxidative stress and inflammation, driving a self-perpetuating cycle. CHOP (ER stress signaling protein) and TNFα inflammation drive high levels of mTORC1 signaling, shutting down autophagy and blocking ER clearance, resulting in premature loss of chondrocytes that negatively impacts linear growth and causes early joint degeneration in MT-COMP mice and PSACH. Previously, we have shown that resveratrol treatment from birth to 20 weeks prevents joint degeneration and decreases the pathological processes in articular chondrocytes. Resveratrol's therapeutic mechanism of action in the mutant-COMP pathology was shown to act by primarily stimulating autophagy and reducing inflammation. Importantly, we demonstrated that MT-COMP mice experience pain consistent with PSACH joint pain. Here, we show, in the MT-COMP mouse, that resveratrol treatment must begin within 4 weeks to preserve joint health and reduce pain. Resveratrol treatment started at 6 or 8 weeks (to 20 weeks) was not effective in preventing joint degeneration. Collectively, our findings in MT-COMP mice show that there is a postnatal resveratrol treatment window wherein the inevitable mutant-COMP joint degeneration and pain can be prevented.

Control of physical properties in BiFeO3nanoparticles via Sm3+and Co2+ion doping.

Highly crystalline BiFeO3(BFO), Bi0.97Sm0.03FeO3(Sm-BFO) and BiFe0.97Co0.03O3(Co-BFO) nanoparticles (NPs) were utilized as potential magnetic hyperthermia agents at two different frequencies in the radiofrequency (RF) range, and the effect of Sm3+and Co2+ion doping on the physical properties of the material was examined. The thermal behaviour of the as-prepared powders disclosed that the crystallization temperature of the powders is affected by the incorporation of the dopants into the BFO lattice and the Curie transition temperature is decreased upon doping. Vibrational analysis confirmed the formation of the R3c phase in all compounds through the characteristic FT-IR absorbance bands assigned to O-Fe-O bending vibration and Fe-O stretching of the octahedral FeO6group in the perovskite, as well as through Raman spectroscopy. The shift of the Raman-active phonon modes in Sm-BFO and Co-BFO NPs indicated structural distortion of the BFO lattice, which resulted in increased local polarization and enhanced visible light absorption. The aqueous dispersion of Co-BFO NPs showed the highest magnetic hyperthermia performance at 30 mT/765 kHz, entering the therapeutic temperature window for cancer treatment, whereas the heating efficiency of all samples was increased with increasing frequency from 375 to 765 kHz, making our doped nanoparticles to be suitable candidates for potential biomedical applications.

The experiences of parents of children diagnosed with cerebral adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is a rare X-linked neurodegenerative disease, affecting the brain, spinal cord and adrenal cortex. Childhood cerebral ALD (CCALD) is the most severe form of disease, involving rapidly progressive neurological deterioration. The treatment option for CCALD is allogenic haemopoietic stem cell transplant, which is only successful for early-stage disease. Parents' experiences of CCALD can inform healthcare delivery. To detail the experiences of parents of children diagnosed with cerebral ALD. A descriptive qualitative study. Parents were recruited via a UK-based community support organisation. Data collection involved single semi-structured interviews structured around a topic guide and conducted remotely. Data were analysed using the thematic analysis approach. Twelve parents from 11 families with a total of 16 children with ALD contributed to the study. Their 16 children with ALD followed one of three disease pathways, determined by the extent of neurological damage at diagnosis. Three themes, and their respective sub themes, describe the pathways and what they meant for parents. 'No possibility of treatment' concerns situations when CCALD was diagnosed at an advanced stage, the landslide of deterioration parents witnessed and their efforts to maintain normality. 'Close to the treatment threshold' describes situations where a small treatment window required parents to make agonising treatment decisions. 'Watching and waiting' explains the challenges for parents when disease was detected early enabling children to benefit from timely treatment. Parents' experiences were largely defined by the extent of cerebral damage at diagnosis, which determined the availability and success of treatment. There were specific challenges related to the three situations, indicating areas where support from health and care services may help parents deal with this devastating diagnosis. This study indicates support needs of parents across the spectrum of CCALD diagnoses and highlights the critical importance of early diagnosis.

Perfusion Computed Tomography as a Screening Tool for Pending Delayed Cerebral Ischemia in Comatose Patients After Aneurysmal Subarachnoid Hemorrhage: A Retrospective Cohort Study

BackgroundAneurysmal subarachnoid hemorrhage (aSAH) is frequently complicated by delayed cerebral ischemia (DCI), leading to poor outcomes. Early diagnosis of DCI is crucial for improving survival and outcomes but remains challenging in comatose patients. In this study, we aimed to evaluate computed tomography with angiography and perfusion (P-CT) as a screening modality on postictal days four and eight for impending DCI after aSAH in comatose patients using vasospasm with hypoperfusion (hVS) as a surrogate and DCI-related infarction as an outcome measure. Two objectives were set: (1) to evaluate the screening’s ability to accurately risk stratify patients and (2) to assess the validity of P-CT screening.MethodsWe conducted a retrospective review of the records of comatose patients with aSAH from January 2019 to December 2021 who were monitored with P-CT scans on days four and eight. The event rates of DCI-related infarction, hVS, and endovascular rescue therapy (ERT) were analyzed, and the sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) for DCI were calculated. DCI-related infarction was defined as new secondary cerebral infarction > 48 h < 6 weeks post aSAH not attributable to other causes, and hVS was defined as arterial narrowing with corresponding hypoperfusion on P-CT.ResultsFifty-six comatose patients were included, and 98 P-CT scans were performed. The incidence of DCI-related infarction was 40%. Screening P-CT on days four and eight found vasospasm in 23% of all patients, including 11% with hVS. A positive hVS on day four or eight revealed a relative risk of 2.4 [95% confidence interval (CI) 1.13–5.11, p = 0.03], sensitivity of 23% (95% CI 8–45, p = 0.03), specificity of 95% (95% CI 36–100, p = 0.03), PPV of 0.83 (95% CI 0.36–1.00, p = 0.03), and NPV of 0.65 (95% CI 0.50–0.78). Six positive P-CT scans led to digital subtraction angiography in five patients, three of whom received ERT. All ERT-intervened patients developed DCI-related infarction.ConclusionsP-CT resulted in few interventions and often resulted in late detection of DCI at an irreversible stage. Although a positive P-CT result accurately predicts impending DCI-related infarction, screening on days four and eight alone in comatose patients with aSAH often fails to timely detect impending DCI. Based on our analysis, we cannot recommend P-CT as a screening modality. P-CT is likely best used as a confirmatory test prior to invasive interventions when guided by continuous multimodal monitoring; however, prospective studies with comparison groups are warranted. The need for a reliable continuous screening modality is evident because of the high rate of deterioration and narrow treatment window.

Investigating Paracetamol's Role as a Potential Treatment for Parkinson's Disease: Ab Initio Analysis of Dopamine, l-DOPA, Paracetamol, and NAPQI Interactions with Enzymes Involved in Dopamine Metabolism.

Recently, it was found that paracetamol can extend the therapeutic window of l-DOPA treatment for Parkinson's disease [Golding (2019) BJPharm, 4(2), Article 619]. It has been posited that the effect could be due to paracetamol and its metabolite, NAPQI, inhibiting pain signals in the spinal column. In this work, we examine the possibility that the therapeutic effect of the paracetamol for the Parkinson's disease patient may be due to an inhibition of the enzymes that metabolize dopamine and/or l-DOPA, thus effectively extending the lifetime of the l-DOPA treatment. In this work, we use the M062X/6-311+G* level of theory to calculate the electronic binding energies (including explicit desolvation) of several ligands (paracetamol, NAPQI, dopamine, and l-DOPA) with a series of enzymes important to the production and metabolism of dopamine and compare them to calculated binding energy values for the natural substrates for those enzymes in order to predict possible inhibition. Benchmark interaction energies for a subset of the systems studied are calculated using the more accurate second-order Møller-Plesset perturbation (MP2) method in order to calibrate the accuracy of the M062X method. If we assume that the interaction energies calculated here can serve as a proxy for in vivo inhibition, then we can predict that paracetamol and NAPQI should not inhibit the natural production of dopamine and may in fact inhibit the metabolism of l-DOPA and dopamine, thus extending the length of l-DOPA treatments.