Citations

BACKGROUND AND OBJECTIVES: Ventriculoperitoneal shunt (VPS) placement is a common treatment for idiopathic normal pressure hydrocephalus (iNPH), but patients may require VPS revision. This study aims to evaluate the effectiveness of a standardized VPS placement protocol by comparing indications and rates of shunt revision compared with a historical institutional cohort. METHODS: All patients treated with VPS for “suspected” iNPH at a tertiary care center between January 2000 and January 2023 were retrospectively reviewed and divided into temporally distinct historical (before 2017) and standardized (after 2017) cohorts. Cumulative incidence and timing of VPS revision were compared using competing risks analyses. RESULTS: A total of 561 patients (median age 75.0 years) were identified with 324 (57.8%) in the historical and 237 (42.2%) in the standardized cohorts. Significant variations in surgical technique and shunt hardware were noted between the cohorts. With a median follow-up of 11.4 months for historical and 12.4 months for standardized cohort, shunt revisions occurred in 19.4% and 8.4% of patients in the historical and standardized cohorts, respectively ( P < .001). Revision indications also varied significantly with lower rates of overdrainage ( P < .001), infection ( P < .001), and proximal malfunction ( P = .042) but higher rate of distal malfunction ( P = .03) in the standardized cohort. Notably, no infections were noted in the standardized cohort. CONCLUSION: Risk of shunt revision among iNPH patients may be associated with modifiable factors related to surgical technique and shunt hardware selection. Importantly, no short-term complications such as hemorrhage, infection, or catheter malposition were observed with the standardized protocol. Development and refinement of standardized shunt protocols for iNPH patients should be commonplace to facilitate tracking, identification, and modification of modifiable technical risk factors.

ABSTRACT Autoantibody internalization has been implicated in autoimmune disease pathogenesis, yet its mechanisms, and generality across different diseases, cell types, and affected tissues remain poorly defined. Using bulk RNA sequencing, we identified reproducible, autoantibody-specific transcriptomic signatures consistent with autoantigen dysfunction in muscle biopsies from patients with anti-Mi2 dermatomyositis and anti-PM/Scl scleromyositis across independent cohorts. Electroporation of purified patient IgG into primary cultures of healthy cells was sufficient to induce the corresponding transcriptomic programs in vitro . Direct immunofluorescence demonstrated immunoglobulin internalization into subcellular compartments matching the localization of the autoantigen in different affected tissues. Spatial transcriptomic analyses revealed that antibody-secreting cells translocated cytoplasmic material (i.e., immunoglobulin RNA) into adjacent affected cells expressing autoantibody-specific transcripts. The disease-specific transcripts were present not only in muscle fibers, but also in other cells, including macrophages, endothelial cells, and fibroblasts. Autoantibody-induced transcriptomic programs were associated with cell damage and autoantibody-specific reactive inflammatory programs, including activation of type I interferon and TGF-ß1 signaling in anti-Mi2 dermatomyositis and activation of type II interferon in anti-PM/Scl scleromyositis. Antibody internalization was also observed in different tissues from patients with other autoimmune diseases, including anti-U1RNP mixed connective tissue disease, anti-Ku overlap syndrome, and anti-Scl70 systemic sclerosis. Together, these findings establish autoantibody internalization as a shared pathogenic mechanism across diverse autoimmune diseases, providing a unifying framework for conditions driven by autoantibodies against intracellular antigens.

Abstract Clinical interventions and neuroimaging in the subcortex require anatomical definitions that exceed the resolution and anatomical detail of currently available deformable brain atlases. Here, we introduce a high-resolution human brain atlas comprising 95 manually segmented grey and white matter structures as well as 82 white matter tracts compiled from a multitude of resources including ex-vivo MRI, histology, fibre dissections, and neuroanatomy textbooks. The atlas is defined at an isotropic resolution of 100 μm and can be precisely deformed to individual subject brain anatomy. By providing precise definitions of both grey and white matter structures within and around the basal ganglia, thalamus, subthalamus, midbrain and cerebellum, the atlas provides a foundational resource for stereotactic surgery and subcortical brain imaging research, as well as for development of next-generation neuromodulation strategies.

Abstract Glioblastomas exhibit low immunogenicity and a highly immunosuppressive tumor microenvironment (TME) mediated by both tumor cells and tumor associated microglia/macrophages (TAMs). However, biomarkers that allow for specific detection, monitoring and therapy response assessment of the TAM phenotype in glioblastoma are still lacking. To address this gap, we characterized the dynamics of TAM clusters in the TME of experimental SB28 glioblastoma using single-cell RNA sequencing, immunofluorescence, and molecular imaging and identified Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) as a dynamic TAM-specific target. Consequently, we investigated a novel 64 Cu-labeled TREM2 radiotracer with a blood-brain barrier transport vehicle for translational mapping of TAMs in the TME of glioblastoma. We found strong and highly myeloid cell-specific PET signals that followed the trajectory of TREM2 gene expression from early- towards late-stage tumors. Transient myeloid cell depletion via CSF1R inhibition showed a reduction of TREM2 PET signals compared to placebo and prolonged survival in SB28 glioblastoma mice, while TREM2 stimulation led to increased TREM2 PET signals. Translation into a pilot cohort of patients with glioblastoma revealed strong TREM2 PET signals predominantly at lesion edges and high heterogeneity across individuals, matching with immunohistochemistry. In summary, TREM2 PET imaging has strong potential as an immune cell-specific biomarker for personalized assessment of the TAM phenotype in the TME of patients with glioblastoma.

Abstract Background/Introduction Optimal mean arterial pressure (MAP) in patients with acute myocardial infarction related out-of-hospital cardiac arrest (AMI-OHCA) and cardiogenic shock (AMI-CS) remains unclear. Randomized controlled trials (RCTs) comparing MAP targets have been performed in OHCA patients with presumed cardiac cause, but did not provide answers to the important question what MAP target would be optimal for the AMI-OHCA population. To our knowledge, no RCTs comparing MAP targets in AMI-CS patients have been performed. Purpose This comprehensive systematic review and meta-analysis aimed to evaluate the effect of low- and high-MAP levels on short-term mortality in AMI-OHCA and AMI-CS patients. Methods We conducted a systematic search of MEDLINE (OVID), EMBASE (OVID), CINAHL (Ebsco) and Cochrane CENTRAL databases. Eligible studies reported outcomes for AMI-OHCA or AMI-CS patients for at least two groups of different average MAP levels. Both RCTs and observational studies were eligible to ensure comprehensive data collection. Authors were proactively contacted for supplementary AMI data. Random-effects models were used to pool data. Results Of 7,728 screened studies, 57 were assessed for eligibility, and 11 were included in the final analysis (4 RCTs and 7 observational studies), encompassing 3,846 patients. The primary analysis included 1,251 AMI-OHCA patients. In the AMI-OHCA patients, no significant difference in short-term mortality was observed between low- and high-MAP groups in RCT (34.9% vs. 39.4%, RR 0.88, 95%-CI 0.70-1.10), observational-, and combined data. As only one of the 11 included studies reported on separate AMI-CS data, no meta-analyses of solely AMI-CS patients could be performed. Conclusions Our meta-analysis showed no significant difference in short-term mortality between low- and high-MAP levels in AMI-OHCA patients. Only one study in selected AMI-CS patients without OHCA patients was available. This highlights the importance of identifying tailored MAP strategies in both AMI-OHCA and AMI-CS patients.Flow chart of the selection of studies Short term mortality – AMI-OHCA patients

Abstract Background The functional significance of the left ventricular (LV) hypercontractile phenotype (HP) in hypertrophic cardiomyopathy (HCM) remains unclear. Purpose To assess the systemic and coronary hemodynamic correlates of HP in HCM. Methods We enrolled 1533 HCM patients (age 51 ± 15 years, 965 males, 63%) with ejection fraction (EF) ≥50%, referred for rest transthoracic echocardiography (TTE) in 27 laboratories from 13 countries. Two-dimensional volumetric TTE assessment included LV outflow tract gradient (LVOTG), end-diastolic volume (EDV), end-systolic volume (ESV), EF, and LV force (systolic blood pressure + LVOTG/ESV, mmHg/mL). Coronary flow velocity in the mid-distal left anterior descending (LAD) coronary artery was assessed in 325 patients. HP was defined as the highest quartile of the force (&gt; 7.32 mmHg/ml). Results Force was moderately related to EF (r = 0.48, p &lt; 0.0001) and weakly to LVOTG (r = 0.36, p &lt; 0.0001). Compared to non-HP patients, HP showed higher heart rate (72 ± 14 vs 67 ± 14 beats per minute, p &lt;0.0001), lower stroke volume (50 ± 22 vs 67 ± 22 ml, p &lt; 0.0001), larger left atrial volume index (44 ± 16 vs 40 ± 16 ml/m2, p = 0.011) and higher coronary flow velocity in the LAD (n = 325, 41 ± 12 vs 37 ± 14 cm/s, p = 0.021), see Figure. Abnormal B-lines (≥ 2) were present in 11 of the 39 HP compared to 39 of the 271 non-HP patients (28% vs 14 %, p = 0.05). E/e’ ratio was higher in HP (n = 59) vs. non-HP (n = 571) patients (11 ± 5.4 vs 9.6 ± 4.2, p = 0.018). Conclusion In patients with HCM, preserved EF, and no history of coronary artery disease, HP identified by resting TTE with supernormal LV force was associated with an unfavorable systemic hemodynamic and coronary flow profile. Compared to non-HP HCM patients, the HP was characterized by reduced stroke volume, impaired diastolic function, and increased resting coronary flow velocity. HP may reflect inefficient myocardial mechanics, with disproportionate energy expenditure mirrored by higher resting coronary flow despite reduced stroke volume generation, ultimately contributing to adverse remodeling and worse prognosisNon-HP vs HP LAVI and coronary LAD flow

Abstract When using real-world data to construct an external comparator arm for a single-arm trial, there may be differences in how and when patients are assessed for disease between trial and real-world settings. Such differences can generate outcome measurement error when comparing time-to-event endpoints and lead to biased findings. Recent methods have been developed to mitigate measurement error bias in real-world endpoints; however, they rely on the existence of a validation sample, ie, data on a set of patients where both the “true” trial-like and “mis-measured” real-world measures are collected. We demonstrate how novel statistical methods can be leveraged as quantitative bias analyses (QBA) to contextualize real-world evidence findings when outcome measurement error is of concern, but validation samples are infeasible to collect. Quantitative bias analyses allow researchers to set plausible ranges for the amount of error when not directly measurable. We highlight how to conduct QBA with two recent methods, cumulative incidence curve correction and survival regression calibration, and illustrate how to generate plausible parameter values through simulation. We provide an illustrative QBA example in a cohort of real-world patients with newly diagnosed multiple myeloma and provide practical guidance to apply QBA for outcome measurement error and interpret results.

Abstract Background The presence of the significant left ventricular outflow tract gradient (LVOTG) changes clinical symptoms, prognosis and treatment in hypertrophic cardiomyopathy enabling the classification into its obstructive (HOCM) and non-obstructive form (non-HOCM). However, the more detailed functional characteristics and comparison of these forms remains poorly known. Purpose To compare the demographic, clinical and echocardiographic features between non-HOCM (defined as LVOTG &lt; 30 mmHg) and HOCM patients enrolled into multi-centred study in years 1996-2024 as well as to analyse their long –term prognosis in relation to registered LVOTG. Methods We enrolled 1533 HCM patients (age 51 ± 15 years, 965 males, 63%) with ejection fraction (EF) ≥50%, referred for rest transthoracic echocardiography (TTE) in 27 centers, nevertheless quantitative assessment of LVOTG was available in 1252 patients. Survival analysis was performed in a subset of 1200 patients with follow-up information. Beyond standard TTE, the number of B-lines, the maximal diastolic velocity of coronary flow in left anterior descending artery (LAD) as well as left ventricular force defined as the ratio of systolic blood pressure plus LVOTG divided by left ventricular end-systolic volume was assessed with specification of hypercontractile phenotype (HP) as the highest force quartile. Additionally age and sex matched control group was included. Results Compared to non-HOCM patients, HOCM showed a bit higher body mass index (27 ± 4 vs 26 ± 4 kg/m2, p = 0.001), were often burdened with diabetes and hypertension, presented more advanced NYHA class and higher risk of SCD, see Table. In the echocardiographic assessment HOCM presented lower end-systolic left ventricular volume (LV ESV: 27 ± 14 vs 29 ± 13 ml, p = 0.014) although maintained equal stroke volume and even higher ejection fraction (EF: 69 ± 8% vs 67 ± 7%, p &lt; 0.001), cardiac output (CO: 4.3 ± 1.7 vs 4.0 ± 1.4 l/min, p &lt; 0.001) and force in comparison to counterparts without LVOTG. This high-contractility performance was however sustained at the cost of larger left atrium volume index (LAVI: 49 ± 19 vs 40 ± 15 ml/m2, p &lt; 0.001), higher coronary flow velocity (43 ± 12 vs 27 ± 13 cm/s, p &lt; 0.001) as well as more frequent B-lines in the lung assessment. During a median follow-up of 87 months (interquartile range 45 – 143 months), 131 all-cause deaths occurred and not only patients with HOCM but also those with HP showed the worse long-term survival, see Figure. Conclusion HOCM remains the form of HCM burdened with more overt clinical symptoms, signs and prognosis. On the other hand LVOTG seems to be important but not always necessary element of this presentation, which seems to be related even more tightly to general hypercontractility phenotype reflected by higher force and resting coronary flow.Table.Non-HOCM vs HOCM comparison Figure.Force and LVOTG prognostic value

Background: In younger patients (<60 years) with cryptogenic stroke presumed to be patent foramen ovale (PFO)-related, the standard approach involves transcatheter PFO closure combined with antithrombotic therapy (ATA). However, due to their exclusion from randomized clinical trials, no formal recommendations exist for patients ≥60 years. This study investigates whether PFO closure benefits patients ≥60 years with prior cryptogenic stroke or if ATA remains the preferred option. Methods: We searched the PubMed, Embase, Web of Science, and ScienceDirect databases to obtain articles in all languages from January 2004 until July 2025. The primary outcome was a risk of recurrent stroke during follow-up and secondary outcomes were risk of new-onset atrial fibrillation (AF), all-cause mortality and in-hospital complications. PROSPERO registration ID: CRD420250652870. Results: One post hoc evaluation of the DEFENSE-PFO trial and eleven observational studies were included. Compared to ATA, PFO closure was associated with a reduced risk of recurrent stroke (HR=0.60; 95% CI: 0.45 to 0.80, p<.001) and mortality (HR=0.41; 95% CI: 0.19 to 0.90, p=.02; I2 = 43.8%) with no difference in risk of new-onset AF (HR=1.13, 95%CI: 0.53 to 2.44, p=.74). When compared with patients <60 years, individuals ≥60 years had a higher risk of recurrent stroke (HR = 2.68; 95% CI 1.40–5.13; p=.002), new-onset AF (HR = 4.12; 95% CI 1.90–8.95; p<0.001) and mortality during follow-up (HR = 8.24; 95% CI 3.49–19.46; p<.0001). In-hospital complications after PFO closure were comparable between two age groups. Conclusion: While PFO closure may reduce ischemic stroke risk in older patients with cryptogenic stroke, this benefit is offset by higher absolute risks for recurrent stroke, new-onset AF, and mortality. Therefore, highly individualized patient selection and age-specific risk tools are crucial. Further long-term randomized trials are essential to optimize PFO closure in this population.

TPS611 Background: GPC3 is an oncofetal protein expressed in up to 75% of hepatocellular carcinomas (HCCs) and associated with poor prognosis. Its selective expression in tumor and not in normal tissue makes it a promising target for radiopharmaceutical imaging and therapy (theranostics). The GPC3-selective diagnostic RYZ811 ([ 68 Ga]Ga-RAYZ-8009) and therapeutic α particle-emitting RYZ801 ([ 225 Ac]Ac-RAYZ-8009) are a theranostic pair. Previous studies show high uptake of RYZ811 in intrahepatic and extrahepatic HCCs, with low normal liver background uptake. In GPC3+ HCC mouse models, single administrations of RYZ801 significantly inhibited tumor growth. Methods: RYZ801-101 is a single-arm, open-label, phase 1/1b study of RYZ811 and RYZ801 in previously treated patients with GPC3+ unresectable HCC. The study has two parts: dose escalation (part 1) and dose expansion (part 2). Each part consists of two stages: RYZ811 imaging and RYZ801 treatment. The aim of imaging is to determine if RYZ811 safely and adequately identifies patients with GPC3+ tumors. The aim of treatment is to determine the safety, pharmacokinetics (PK), recommended phase 2 dose (RP2D; part 1), and preliminary antitumor activity (part 2) of RYZ801. Key eligibility criteria are: confirmed HCC; Barcelona Clinic Liver Cancer stage B or C; Child-Pugh A; ≥1 RECIST v1.1-measurable lesion (treatment stage); and disease progression after ≥1 systemic therapy in part 1 and 1 prior line in part 2. In part 1, approximately 60 patients will receive RYZ811 (185 MBq) in the imaging stage; up to 30 of these will receive escalating doses of RYZ801 (2.6–5.5 MBq × 4 doses) in the treatment stage. In part 2, approximately 80 patients will receive RYZ811 (185 MBq) in the imaging stage; up to 40 of these will receive RYZ801 at the RP2D in the treatment stage. Primary RYZ811 objectives are to assess the safety/tolerability and biodistribution of RYZ811. Secondary objectives are to determine absorbed doses (ADs) to organs and tissues and any association between RYZ811 uptake and RYZ801 efficacy. Primary RYZ801 objectives are to identify the RP2D and safety/tolerability of RYZ801. Secondary objectives are to assess PK, ADs to critical organs and tumors, and preliminary antitumor activity. Enrollment for Part 1 is ongoing in the USA. Clinical trial information: NCT06726161 .