Citations

Cardiac arrest is a leading cause of global mortality, with low survival rates despite advances in resuscitation science. Reported survival ranges from 8% to 34% for out-of-hospital and in-hospital cardiac arrest. Extracorporeal cardiopulmonary resuscitation (ECPR) has emerged as a rescue therapy for patients unresponsive to conventional CPR, leveraging veno-arterial extracorporeal membrane oxygenation (ECMO) to provide artificial circulation, gas exchange, and maintenance of organ perfusion in the absence of spontaneous native circulation. Successful ECPR depends on minimizing time to ECMO initiation and selecting appropriate patients. While several aspects are consistent across countries, ECPR protocols vary in logistics, team composition, cannulation methods, and monitoring, which may influence patient-important outcomes such as survival and neurological recovery. This narrative review explores current global practices in ECPR, and identifies opportunities for standardization while recognizing elements that should remain context specific.

Background Motor disturbances are common in neurologic and neurodegenerative syndromes. A standard motor speed and dexterity measure is the finger tapping test (FTT). The FTT has traditionally been administered in clinic using a mechanical FTT, limiting accessibility and early motor change quantification. This study assessed the validity of a smartphone app-based FTT, which may expand access and enable more frequent testing. Methods The cohort was diagnostically diverse, including participants with frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal syndrome, primary progressive aphasia, multiple sclerosis, and clinically unimpaired controls. Participants completed a 20-second ALLFTD Mobile App (mApp)-FTT with each hand. Tapping speed metrics were extracted. Participants completed the gold-standard mechanical FTT, a neurologist-administered finger tapping exam, the PSP Rating Scale (PSPRS) and the Unified Parkinson’s Disease Rating Scale (UPDRS). Correlations assessed mApp-FTT and mechanical FTT relationships; regressions evaluated associations with neurologist-rated finger tapping impairment, PSPRS and UPDRS, adjusting for age and sex. Results The mApp-FTT showed moderate-to-strong correlations with the mechanical FTT (dominant: r=0.63, p<0.001; non-dominant: r=0.55, p<0.001). Taps per second were associated with PSPRS motor severity (dominant hand: std. β=-0.59, 95% CI [-0.91, -0.27], p<0.001) and the UPDRS (dominant hand: std. β=-0.41, 95% CI [-0.82, 0.00], p=0.049). Flight time was modestly associated with neurologist-rated finger tapping impairment (dominant hand: std. β=0.15, 95% CI [0.00, 0.29], p=0.044). Conclusion These findings support mApp-FTT validity as a measure of motor function across neurodegenerative conditions. Validation in longitudinal and unsupervised remote settings is warranted to understand scalability and evaluate change over time.

Black race and Hispanic ethnicity are associated with higher mortality in severe combined immunodeficiency (SCID) following hematopoietic cell transplantation (HCT), though mechanisms remain unclear. We evaluated 796 children with SCID who received nonsibling HCT between 1982 and 2020 using data from the Primary Immune Deficiency Treatment Consortium. Overall survival for Black (aHR 2.47, 95%CI 1.64, 3.71) and Asian/Pacific Islander patients (aHR 1.82, 95%CI 1.00, 3.30) was significantly lower compared with non-Hispanic White patients, while Hispanic patients had lower event-free survival (aHR 1.83, 95%CI 1.27, 2.63) compared with non-Hispanic White patients. Even after adjusting for age and infection, Black patients with SCID had more than twofold hazard of death compared with non-Hispanic White patients. NBS was associated with earlier diagnosis, reduced infection at HCT, and elimination of survival disparities between Black and non-Hispanic White patients. These findings suggest that universal, system-level interventions such as NBS can mitigate disparities in outcomes for children with SCID.

Abstract Grey matter network topology is altered in Alzheimer’s disease and these alterations are related to cognitive decline. Understanding the biological underpinnings of loss of brain connectivity may provide insights into mechanisms related to developing Alzheimer’s dementia (i.e. dementia A+). We investigated which biological processes as measured in CSF proteomics were associated with loss of brain connections across the Alzheimer’s disease continuum. We included 347 individuals with abnormal CSF amyloid [mean age ± standard deviation (SD) 66 ± 8; 98 cognitively unimpaired—A+, 88 mild cognitive impairment—A+, 161 dementia A+] and 146 cognitively unimpaired individuals with normal CSF amyloid (mean age ± SD 62 ± 8) and available T1w MRI-scans and CSF proteomic data (3097 proteins using tandem mass tag spectrometry) from the Amsterdam Dementia Cohort. We used an automated pipeline to construct grey matter networks from 3D-T1 sequences and for each network, calculated the small-worldness coefficient, which we previously found to be robustly related to cognitive decline. Linear models were applied to test associations between CSF protein levels and connectivity measures using an interaction term for clinical stage while controlling for connectivity density, age and sex. We validated our results in data from the Alzheimer’s disease Neuroimaging Initiative (ADNI). Pathway enrichment analysis was performed for proteins associated with loss of brain connectivity (P &lt; 0.05) using the Gene Ontology database. Individuals across the Alzheimer’s disease continuum had lower small-worldness coefficients compared with controls (ANOVA P &lt; 0.001). In amyloid positive individuals, higher levels of 222 proteins and lower levels of 482 proteins were associated with lower small-worldness coefficients and were enriched for innate immune system and neuroplasticity pathways, respectively. Stratified for disease stage, most protein associations with lower small-worldness coefficients were found in mild cognitive impairment A+ (n = 527 proteins) and dementia A+ (n = 799 proteins) with considerable overlap (n = 239 proteins). Proteins in these stages were enriched for complement activation and synaptic integrity. In cognitive unimpairment A+, we found proteins enriched for processes involved in apoptosis. We did not find any enriched biological processes in controls. Repeating analyses in ADNI indicated that similar biological processes were associated with altered grey matter network connectivity. Higher CSF levels of proteins involved in immune responses and lower levels of proteins related to neuroplasticity were associated with lower small-worldness coefficients across the Alzheimer’s disease continuum. This suggests that preserving cognitive function in the presence of amyloid and prevention of dementia A+ may require therapies that strengthen synapses and targets the innate immune system in addition to amyloid and tau.

Importance Tofersen is a disease-modifying antisense oligonucleotide therapeutic for people living with SOD1 –amyotrophic lateral sclerosis ( SOD1 -ALS). Autopsy tissue donors have provided the first opportunity to study the distribution of intrathecally administered tofersen in human central nervous system tissues. Objectives To determine the tissue distribution of tofersen and to provide the first estimates of SOD1 reduction in human somatic motor systems tissues. Design, Setting, and Participants This was a cross-sectional autopsy tissue case series conducted between 2018 and 2026. Autopsies were performed at 3 US academic medical institutions. Tissue samples from 8 deceased patients who lived with SOD1 -ALS, participated in tofersen clinical trials (ClinicalTrials.gov Identifiers NCT02623699 [An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)] and NCT03070119 [Long-Term Evaluation of BIIB067 (Tofersen)]) or the Expanded Access Program, and whose families authorized autopsies were eligible for this study. All autopsy tissue donors known at the time of this study were included (none were excluded). Analyses were conducted between August 2020 and January 2026. Exposures Participants received multiple intrathecal 20- to 100-mg tofersen doses. Main Outcomes and Measures Tofersen tissue concentrations were measured using hybridization enzyme-linked immunosorbent assay (ELISA). SOD1 messenger RNA (mRNA) and protein reduction estimates, defined as percentage SOD1 levels in this study’s recently treated autopsy tissue donors compared to a cohort of samples from tofersen-naive SOD1 -ALS autopsy tissue donors, were measured using quantitative reverse transcription polymerase chain reaction (PCR) and ELISA. Histological localization of tofersen and SOD1 transcripts were studied using immunohistochemistry and in situ hybridization assays. Results In 8 tofersen-treated autopsy tissue donors (5 male and 3 female donors; age range, 42-66 years), spinal cord and motor cortical tissue tofersen concentrations strongly correlated with predictions based on individual dosing histories and a preclinical pharmacokinetic model. For 3 recently treated autopsy tissue donors, reductions in lumbar spinal cord tissue SOD1 mRNA and protein levels ranged from 45% to 84% despite not having been administered 1 to 2 scheduled doses before autopsy. Residual somatic motor neurons demonstrated tofersen transduction and low SOD1 mRNA probe hybridization. Misfolded SOD1 protein inclusions were detected in residual motor neurons of tofersen-naive SOD1- ALS tissue donor controls and tofersen-treated tissue donors. Meningeal and perivascular lymphocytic immune responses were observed in 5 recently treated tissue donors but were not apparent in tissue donors with remote final tofersen doses. Conclusions and Relevance This case series presents the first emerging autopsy tissue data confirming the predicted distribution of tofersen and robust SOD1 protein reduction in human somatic motor systems tissues.

Abstract Endocytosis regulates receptor trafficking and signaling, yet its role in colorectal cancer (CRC) remains unclear. We analyzed transcriptomic data from 15,025 CRC tumors to evaluate gene expression in clathrin-mediated endocytosis (CME) and the endosomal sorting complexes required for transport (ESCRT) pathway. Pathway-level signatures were compared across consensus molecular subtypes (CMS) and examined in relation to oncogenic signaling programs, while individual endocytosis-related genes were evaluated for associations with clinical outcomes in an independent randomized trial cohort. Expression of CME and ESCRT pathways varied by CMS, with the highest expression in CMS4 and the lowest in CMS3. Endocytosis signatures correlated with multiple oncogenic signaling pathways, including MAPK, TGF-β, WNT, PI3K, NOTCH, and angiogenesis, suggesting broad links between endocytic activity and tumor biology. In the randomized phase III CALGB/SWOG 80405 trial, low expression of AP2M1 —a core adaptor in the CME complex—was significantly associated with longer overall survival and progression-free survival in patients treated with anti-EGFR agents, but not in those receiving anti-VEGF agents. These findings suggest that endocytic trafficking may be associated with oncogenic signaling and differential therapeutic benefit in patients with metastatic CRC. The endocytosis pathway reflects biologically relevant heterogeneity in CRC and may help guide therapeutic stratification.

Study Design. Post hoc analysis of prospectively-collected data. Objective. To identify factors predicting the most (and least) satisfaction following surgery for cervical spondylotic myelopathy (CSM). Summary of Background Data. Patient satisfaction affects long-term outcomes after surgery but the preoperative factors that influence postoperative satisfaction have not been well studied in patients with CSM. Methods. We conducted a post hoc analysis of prospectively-collected data from the Quality Outcomes Database (QOD) CSM registry cohort. Baseline and surgical characteristics were compared for patients with CSM reporting the most [North American Spine Society Satisfaction Score (NASS) 1] and least (NASS 4) satisfaction 24 months postoperatively. A multivariable logistic regression model was constructed using backward stepwise elimination to determine significant predictors of most versus least satisfaction. Twenty-four-month patient-reported outcomes (PROs) were compared. Results. Overall, 1141 patients were prospectively enrolled with 948 (83.1%) reaching 24-month follow-up. Of these, 699 met prespecified inclusion criteria: 610 (87.3%) were most satisfied and 89 (12.7%) were least satisfied. Though there were mean improvements in all 24-month PROs for the most satisfied cohort ( P <0.001), there were no significant improvements in 24-month PROs for the least satisfied cohort ( P >0.05). Using multivariable logistic regression modeling, a preoperative symptom of upper extremity weakness (OR=2.5, P =0.003), subjective myelopathy (OR=2.0, P =0.04), absence of numbness complaints (OR=2.2, P =0.003), symptom duration under 12 months (OR=1.6, P =0.047), Caucasian race (OR=2.3, P =0.001), participation in activities outside of the home (OR=2.0, P =0.04), anterior approach (OR=2.3, P <0.001), and higher baseline quality of life (OR=4.0, P =0.01) were predictive of the most satisfaction. Conclusion. Compared with the least satisfied, those most satisfied following surgery for CSM more often had a preoperative symptom of arm weakness, subjective myelopathy, the absence of numbness complaints, symptom duration under 12 months, higher baseline quality of life, and participation in activities outside of the home. Compared with a posterior approach, an anterior approach was associated with the most satisfaction. Taken together, early surgical treatment--before myelopathic symptoms significantly impact one's quality of life--may be considered to optimize patient satisfaction following CSM surgery.

Background: Integrating machine learning (ML) with population pharmacokinetic (PPK) modeling may improve therapeutic drug monitoring predictions. Methods: Tacrolimus trough concentrations from lung transplant patients were split into a training data set (1151 concentrations in 80 patients) and a testing data set (224 concentrations in 20 patients). A PPK model was developed using NONMEM, followed by the development of 10 ML models to fit individual pharmacokinetic parameters from the PPK model with Bayesian forecasting. The best performing ML model was selected as the final model. Both the final PPK and ML models were compared for prediction performance. A web-based dashboard was established with R-shiny to recommend dosing regimens based on patient data. Results: In the PPK model, postoperative days, hematocrit, aspartate aminotransferase, tacrolimus daily dose, coadministered voriconazole or posaconazole, and the CYP3A5*3 genotype were identified significant covariates on the clearance. The Cubist ML model outperformed the PPK model, showing lower root mean squared error for tacrolimus concentrations in the testing data set. An online web-based precision dosing dashboard was created, accessible at (https://tac-dose-ml.shinyapps.io/shiny/). Conclusions: Integrating ML with PPK modeling could yield superior tacrolimus concentration predictions for lung transplant patients, offering an efficient alternative to Bayesian forecasting. The online dashboard provides rapid, individualized dosing recommendations.

Abstract Unvetted scientific claims about vaccines can spread rapidly and undermine decades of progress in immunization and public trust. A recent non-peer-reviewed analysis, promoted at political hearings, in the documentary “An Inconvenient Study,” and on social media, has been used to suggest that vaccinated children experience higher rates of chronic illness than unvaccinated peers. Despite standard regression models, critical flaws - uncontrolled confounding, exposure misclassification, unequal follow-up, and outcome multiplicity, invalidate causal inference. An independent group of international experts critically appraises this analysis and contrast its claims with the consistent evidence confirming vaccine safety and effectiveness. We also show how poorly designed studies can distort public discourse, amplify misinformation, and fuel vaccine hesitancy. We outline actions to strengthen research integrity, such as transparent data sharing, labeling of non-peer-reviewed content, and evidence-based communication. Safeguarding public health demands that vaccine evidence be methodologically sound, reviewed, and interpreted by qualified experts.