Citations

Abstract INTRODUCTION Prospective studies of blood‐based biomarkers reflecting pathogenic processes, other than Alzheimer‐specific pathologies, that contribute to dementia in diverse cohorts are lacking. METHODS We jointly fitted linear mixed‐effect models and proportional hazards models to examine associations of midlife glial fibrillary acidic protein (GFAP), chitinase‐3‐like protein 1 (YKL‐40), soluble cluster of differentiation‐14 (sCD14), neurofilament light chain (NfL), total tau (t‐tau), and ubiquitin C‐terminal hydrolase L1 (UCHL1) levels in serum (collected in 1993 to 1995) with cognitive decline and incident dementia (ascertained over 29 years through 2022) in the community‐based Atherosclerosis Risk in Communities Study. sCD14 and YKL‐40 were measured in 3082 participants and the other four biomarkers in 1766 participants. RESULTS Higher serum GFAP, YKL‐40, sCD14, and NfL were associated with faster cognitive decline and elevated dementia rate (e.g., 1 standard deviation [SD] higher log‐base2 YKL‐40 was associated with −0.11SD faster 25‐year cognitive decline (95% confidence interval [CI]: −0.15,−0.07) and 45% higher dementia hazard (hazard ratio [HR]: 1.45 [95% CI: 1.25, 1.68]). Higher t‐tau and UCHL1 were also associated with faster cognitive decline. DISCUSSION Midlife blood biomarkers reflecting glial and neuronal dysfunction and neuroinflammation are associated with early cognitive impairment.

Abstract Background and aims Interfacility transfers in rural areas are challenging due to limited ambulance and bed availability, image sharing issues, and access disparities. Regional transfers to strategically located primary stroke centers can reduce time to care, decrease helicopter use, support local economies, and conserve comprehensive stroke center (CSC) resources. This study established a primary stroke center as a regional transfer center (rSTC) within a telestroke network. Methods Over one year, stakeholders created regionally appropriate transfer workflows defined as patients without large vessel occlusion, low likelihood for neurosurgical decompression or critical illness within a rSTC and 4 surrounding centers. Continuous education and prospective case logs were maintained by the rSTC stroke coordinator and a retrospective chart review was conducted one year following the intervention period. Results Of 99 patients requiring transfer, 73 (73.7%) went to the rSTC, with an average stay of 2.1 days, no deaths, and no secondary CSC transfers. The remaining 26 (26.3%) were sent to the CSC, with longer stays (10.6 days) and higher mortality (23.1%). Transfers to the rSTC were faster (60 min vs. 188 min). Financial analysis showed significant EMS savings ($455,111) and local health system benefits ($730,000) when compared to the pre-intervention period. Conclusions Establishing an effective regional transfer model is possible with broad stakeholder engagement and regular network maintenance. rSTCs provide the right level of care for the right patient, improving efficient allocation of healthcare resources and avoiding futile transfers with costly admissions far from home while opening beds and reducing transfer times to CSCs. Conflict of interest Nothing to disclose

Study Design. Subanalysis of a prospective, multicenter, observational study at 72 US adult, pediatric, and mixed trauma centers. Objective. We investigated trauma-related risk factors and patient-level factors associated with multiregional spinal column injury, defined as cervical spine injury (CSI) requiring treatment and thoracolumbar injury (TLI). Summary of Background Data. Traumatic spinal injury causes morbidity and mortality in pediatric patients. Injuries to multiple spinal column regions require early identification and thoughtful management. Methods. All children <18 years undergoing cervical spine evaluation after blunt multisystem trauma were prospectively identified and enrolled. Clinically significant CSI was defined by cervical spine surgery or halo placement. TLI incidence and management was recorded. The primary outcome was multiregional spinal column injury (CSI+TLI). Results. Of 19,651 enrolled patients, 1484 children (7.5%) experienced a TLI, 159 (0.81%) had CSI requiring treatment, and 30 (0.15%) had CSI+TLI. Multivariate analysis revealed that the trauma-related factors mechanism of injury ( P <0.001), rib fractures (odds ratio (OR) 2.8 [2.3-3.4]), hemothorax/pneumothorax (OR 2.0 [1.7-2.4]), bowel injury (OR 4.0 [2.9-5.4]), pelvic fracture (OR 1.5 [1.2-1.9]), and clinically significant CSI (OR 1.9 [1.2-2.9]) were independently associated with TLI. Of the 159 children with clinically significant CSI, 30 also experienced TLI (19%). Multivariate analysis identified prehospitalization intubation (OR 3.1 [1.1-8.4]) and rib fractures (OR 3.9 [1.2-12.8]) as independent associations with CSI+TLI. Conclusions. Of children with CSI requiring treatment, 19% experienced TLI. MOI and various trauma-related injuries were independently associated with TLI, whereas prehospitalization intubation and rib fractures were independent risk factors for CSI+TLI. These factors should trigger screening for multiregional spinal column injury in pediatric trauma patients. Furthermore, if there is known TLI, the cervical spine should be evaluated, and if there is significant CSI, then dedicated imaging of the thoracic and lumbar spine is indicated. Level of Evidence. III

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.

Background/Objectives: Characterizing spinal cord multiple sclerosis (MS) lesions in MRI is critical for diagnosis, monitoring, and treatment evaluation. However, current automated approaches for lesion detection and segmentation are typically designed for specific MRI contrasts or acquisition sites, limiting their generalizability in real-world clinical settings where imaging protocols vary widely. This work proposes a robust multi-site, multi-contrast segmentation framework for spinal cord lesions. Methods: The segmentation model was trained and evaluated on a large-scale dataset comprising 4428 annotated images from 1849 persons with MS across 23 imaging centers, encompassing six MRI contrasts (T1w, T2w, T2*w, PSIR, STIR, and UNIT1) acquired at 1.5 tesla (T), 3 T, and 7 T. Results: Likert-type assessment performed by neuroradiologist ratings demonstrated superior generalization of the model compared to existing contrast-specific pipelines ( p < 0.01). Additional experiments evaluated robustness across spinal levels, acquisition resolutions, binarization thresholds, and quantitative evaluation on external labeled datasets. Conclusions: The proposed model can achieve accurate and reliable spinal cord MS lesion segmentation across heterogeneous MRI data, addressing a key barrier to clinical translation. The model is available in the Spinal Cord Toolbox v7.2 and higher. Code repository: https://github.com/ivadomed/seg-sc-ms-lesion-multicontrast

Summary Longitudinal plasma cell-free DNA profiling from the phase 3 Alliance A031201 trial revealed divergent resistance trajectories in metastatic castration-resistant prostate cancer. Rapid progressors harbored non–androgen receptor (AR) alterations suggesting intrinsic resistance, whereas delayed progressors showed progressive AR amplifications, structural rearrangements, and extrachromosomal DNA–associated evolution. These findings support biomarker-guided strategies targeting AR-dependent and AR-independent disease states. See related article by Valentín López et al., p. 2413

OBJECTIVE: A definition of refractory septic shock is necessary to guide diagnosis, management, prognostication, research, and future guidelines for this most severe form of the disease. We sought to achieve consensus on clinical criteria that would be used to define refractory septic shock. DESIGN: Review of literature, expert panel position statements, and Delphi rounds with an international expert group. SETTING: Consensus was defined as having at least 75% of panellists in agreement or disagreement on the three highest or lowest levels of a 7-point Likert scale or based on responses to single- or multiple-choice questions, respectively. SUBJECTS: A panel of multinational, multiprofessional and multidisciplinary critical care experts assembled by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine (57 invitations and 56 participants). MEASUREMENTS AND MAIN RESULTS: A five-round Delphi process was conducted for consensus and stability. The steering committee proposed 34 statements, and five of them were rejected by panel experts after round 2. Among 29 statements selected from eight domains, consensus was reached for 13. The panel agreed on the need for a comprehensive consensus set of clinical criteria for refractory septic shock. Markers of organ dysfunction (75%, 2 rounds), tissue perfusion (91.1%, 2 rounds) including lactate (94.6%, 2 rounds) and capillary refill time (76.8%, 2 rounds), assessment of fluid-responsiveness after initial resuscitation (92.9%, 5 rounds), and use of vasoactive drugs at norepinephrine equivalents greater than 0.5 µg/kg/min (75.0%, 3 rounds), were selected as clinical criteria of refractory septic shock. The use of critical care ultrasound (CCUS) (92.9%, 3 rounds) was the single diagnostic modality that reached a consensus-based agreement. CONCLUSIONS: A consensus for 13 criteria to frame the definition of refractory septic shock was reached. Refractory septic shock is characterised by persistently elevated lactate concentrations and or prolonged capillary refill time in patients with septic shock who are fluid unresponsive, require a norepinephrine base equivalent dose greater than 0.5 micrograms per kilogram per minute, and undergo CCUS assessment when mixed shock is suspected.

ABSTRACT Purpose To simultaneously measure skeletal muscle energetics and blood flow (BF) before, during, and after dynamic plantar flexion exercise (PFE). Methods Non‐localized pulse‐acquire phosphorus‐31 magnetic resonance spectroscopy ( 31 P MRS) and phase contrast flow magnetic resonance imaging ( 1 H MRI) using golden‐angle rotated spiral readouts were acquired in an interleaved fashion. Data were collected at rest, during PFE to volitional fatigue, and post‐exercise recovery in 10 healthy adults. Interleaved popliteal artery BF was validated against conventional cine phase‐contrast measures at rest and post‐exercise recovery, while calf muscle energetics were validated by comparing to conventional 31 P MRS‐only measures at rest. To minimize motion artifacts during dynamic PFE, flow data were resolved in 3 dimensions (cardiac phase, pedal position, and exercise stage). Results Resting phosphocreatine (PCr) and inorganic phosphate concentrations were similar between both techniques (both p > 0.05). During PFE, PCr declined to 46% ± 10% of rest. PCr recovery time was 43 ± 15 s. Resting BF was 132 ± 43 mL/min and increased up to four‐fold during PFE depending on exercise stage and pedal position. Notably, there was excellent agreement between the interleaved and conventional BF measures ( r 2 = 0.95, slope = 0.977, p < 0.0001) with minimal bias (12.62 mL/min) over a wide range of physiologically relevant BF values (from ∼60 to 600 mL/min). Conclusion The feasibility of simultaneous assessment of skeletal muscle energetics and BF during dynamic exercise by interleaved 31 P MRS/ 1 H flow MRI was demonstrated along with good agreement between interleaved and conventional techniques during rest and recovery. One can now simultaneously quantify critical BF‐metabolism relationships and use this to probe disease‐related adaptations.