Citations

Background While it is clear that abnormal tau structures contribute to the clinical symptoms of Alzheimer's disease (AD), which of the many structural entities found in the AD brain underlie templated misfolding and progression of disease remains uncertain. However, their identification is crucial to target for more effective diagnostics and therapeutics. Objective To identify the most pathogenic tau species driving Alzheimer's disease progression. Methods We compared the biochemical and templated seeding properties of tau isolated from post-mortem brain tissue of patients with varying rates of clinical progression, categorized as rapid, slow, or typical, based on longitudinal decline in cognitive performance assessed by Clinical Dementia Rating Sum of Boxes scores. Sarkosyl-insoluble filamentous preparations were compared to aqueous-soluble preparations. Focusing on the aqueous-soluble proteins, we further characterized the most efficient seeding species using size-exclusion chromatography and quantifying oligomers using dot blot under both native and denaturing conditions. Results A rapidly progressive course corresponded to enhanced tau seeding behavior, with the strongest correlations observed in the aqueous-soluble fraction. Using size-exclusion chromatography, we demonstrated that the seeding activity of fractions containing oligomers, correlated most strongly with disease aggressiveness. Moreover, quantifying oligomers using dot blot under both native and denaturing conditions, we found that rapid progressors had higher levels of oligomeric tau, which was also more stable. Conclusions Aqueous-soluble oligomeric tau species may be an important driver of AD progression. Substantial heterogeneity was observed even in purified samples, suggesting that variations in tau conformers among patients may contribute to differences in clinical disease progression.

Introduction The safety of operating room extubation (ORE) immediately following cardiac surgery via median sternotomy remains unclear. However, reported outcomes in the setting of parasternal regional analgesia are limited. This study examined the safety of ORE for patients who received postoperative superficial parasternal intercostal plane (SPIP) blocks following median sternotomy for cardiac surgery. Methods Single-center retrospective cohort study from January 2020 to September 2023 compared the outcomes of adult cardiac surgical patients who were either extubated in the operating room immediately after surgery with SPIP blocks (ORE-B), received SPIP blocks and were extubated in the intensive care unit within 6 hours (FTE-B) or did not receive SPIP blocks and were extubated in the intensive care unit within 6 hours (FTE). Assessed outcomes were reintubation, use of non-invasive positive pressure ventilation (NIPPV), intensive care unit (ICU) readmission, return to OR, postoperative transfusion, ICU and hospital length of stay. Results 2294 patients were studied, which included 256 ORE-B patients, 729 FTE-B patients and 1,309 FTE patients. Differences in reintubation rates (1.2% vs 0.7% vs 1.2%, all p≥0.26) and use of NIPPV (4.8% vs 4.8% vs 5.1%, all p≥0.743) did not differ between ORE-B, FTE-B, and FTE groups, respectively. Time to extubation differed between FTE-B and FTE groups (2.5 hours vs 3.8 hours, p=<0.001), respectively. Additionally, hospital length of stay was significantly shorter for groups ORE-B and FTE-B compared with group FTE (5 days vs 5 days vs 6 days), respectively. Conclusions Selective ORE after median sternotomy for cardiac surgery was not associated with an increased risk of reintubation and NIPPV use in the setting of parasternal regional analgesia.

Importance Molecular analyses of biospecimens collected from study participants are essential for identifying biomarkers that can tailor treatments to specific subsets of patients who are most likely to benefit. Sharing of data and biospecimens from clinical trials enables personalized, patient-centric use of cancer therapies and accelerates the development of new treatments. Objective To describe obstacles to sharing data and biospecimens and to propose strategies to enhance access and collaboration. Evidence Review This is a Special Communication authored by 53 academic investigators and patient representatives from the breast cancer community with extensive experience in conducting clinical and translational research. The article also evaluates the impact of biomarker research on specifying responsive subpopulations in the 29 registrational clinical trials that have led to approval of a new drug for treatment of breast cancer between 2017 and 2024. Findings Clinical trial participants are increasingly asked to provide tissue and/or body fluid biospecimens for biomarker research that is typically controlled by the sponsoring pharmaceutical company, but published biomarker studies are rare. Among 29 breast cancer registrational studies reported in the past 8 years, none resulted in biomarker research that restricted a drug’s approved indication. Herein, strategies to maximize the value of clinical data and biospecimens contributed by participants are proposed, thereby supporting the shared goals of the pharmaceutical industry and academia to improve patient care. These strategies include (1) establishing coleadership structures involving academia and patients in clinical trial design and conduct, (2) ensuring that informed consent forms state that data and biospecimens will be shared with academia for future research, (3) requiring the sharing of clinical data as a condition for regulatory approval, and (4) enabling access to biospecimens and translational research data for independent studies on biomarkers that may indicate drug efficacy and toxicity. Conclusions and Relevance Data and biospecimen sharing from registrational trials has been suboptimal. Improving clinical data, biospecimens, and biospecimens’ related data sharing requires concrete actions and a multidimensional stakeholder approach to accelerate the impact of clinical cancer research on the quality of patient care.

Abstract The cortical asymmetry index evaluates the cortical thickness asymmetry between hemispheres. We investigated cortical asymmetry index in asymptomatic and symptomatic mutation carriers of autosomal dominant Alzheimer’s disease to explore the brain asymmetry within the Alzheimer’s disease continuum. Sixty baseline T1-weighted MRI scans were obtained from the Clinic Barcelona cohort. Baseline and longitudinal MRI data from 564 participants within the dominantly inherited Alzheimer network observational study were used as an independent, confirmatory cohort. Cerebrospinal fluid and plasma neurofilament light chain levels were included when available. Cortical thickness was calculated using Freesurfer and cortical asymmetry index was calculated via an open-source pipeline. Cross-sectional analyses examined cortical asymmetry index differences based on clinical classification and APOE ε4 status, adjusting for age, sex and estimated years from onset, while correlations were assessed with age, estimated years from onset, mini-mental state examination scores, and neurofilament light. Longitudinal cortical asymmetry index evolution was modelled using generalized additive models in the dominantly inherited Alzheimer network observational study cohort, incorporating age, sex, and the interaction between group and estimated years from onset. The cortical asymmetry index successfully distinguished asymptomatic mutation carrier and symptomatic mutation carriers from healthy controls in the Clinic Barcelona cohort and symptomatic mutation carriers from controls in dominantly inherited Alzheimer network observational study. Higher cortical asymmetry index in mutation carriers (asymptomatic mutation carrier and symptomatic mutation carriers combined) and in symptomatic mutation carriers were associated with higher plasma neurofilament light levels, a closer proximity to symptom onset, and lower mini-mental state examination in the Clinic Barcelona cohort. In the dominantly inherited Alzheimer network observational study cohort, mutation carriers exhibited increased cortical asymmetry index compared to controls and correlated with elevated neurofilament light (plasma and Cerebrospinal fluid), lower mini-mental state examination, and a closer proximity to symptom onset. APOE3/3 carriers showed greater asymmetry than other APOE genotypes and significant cortical asymmetry index differences between asymptomatic mutation carrier and symptomatic mutation carriers. Longitudinally, cortical asymmetry index increased over time significantly in symptomatic mutation carriers. These findings underscore brain asymmetry as a potential biomarker for early Alzheimer’s disease progression in autosomal dominant Alzheimer’s disease, with implications for detection and monitoring tracking disease-related neuroanatomical changes.

Pain management after thoracotomy is particularly complex in lung transplant recipients on extracorporeal membrane oxygenation (ECMO), where anticoagulation significantly limits available treatment options. Coagulopathy constitutes a contraindication to neuraxial and deep peripheral nerve blocks due to hemorrhagic complications. Uncontrolled thoracotomy pain, hypoxia due to increasing opioid use, and hemodynamic instability can delay successful weaning from ECMO. We present the case of a patient on bivalirudin after undergoing a thoracotomy for a right lung transplantation. This case highlights the successful use of a serratus anterior plane block (SAPB) as an alternative approach to neuraxial anesthesia in an anticoagulated patient, optimizing analgesia and facilitating recovery postthoracotomy.

Abstract Combination therapy incorporating programmed cell death protein 1 (PD-1) blockade results in unprecedented response rates in both frontline and relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL). Previous retrospective studies have suggested benefit for PD-1 blockade before autologous stem cell transplant (ASCT) but included few patients receiving PD-1 blockade with cytotoxic chemotherapy. To explore the impact of anti–PD-1 based salvage on outcomes for patients with R/R cHL, we retrospectively reviewed 1280 patients with R/R cHL who underwent ASCT from 2010 to 2022 at 6 transplant centers, none of whom received PD-1 blockade as part of frontline therapy. Overall, 25% received a PD-1 inhibitor at any point before ASCT (10% in conjunction with chemotherapy), 28% received salvage brentuximab vedotin (BV) without PD-1 blockade, and the rest received salvage chemotherapy alone. Patients who received PD-1 inhibitors at any point before ASCT had a significantly higher 2-year progression-free survival than those who received BV without PD-1 inhibitors or patients receiving chemotherapy alone (88.2%, 70.2%, and 67.4%, respectively; P&lt; .0001). When restricted to patients in complete response before ASCT, the benefit of PD-1 blockade remained significant. PD-1 blockade before ASCT is independently associated with superior post-ASCT outcomes and patients proceeding to ASCT should be treated with PD-1–based salvage.

An ST-segment elevation myocardial infarction is a life-threatening condition within the spectrum of acute coronary syndrome, with well-recognized implications for short-term and long-term health outcomes. Retrospective review of our institutional electronic health records identified patterns of inaccurate acute coronary syndrome diagnostic assignment, including the presence of erroneous ST-segment elevation myocardial infarction diagnoses in discharge records. Such erroneous diagnoses in the durable health record may increase risk to patients through inadequate risk assessment and inappropriate follow-up care. Misapplication of a shortcut in our electronic health record system for rapidly ordering emergent cases was identified as a potential cause of the quality gap. To address this issue, a nurse-led quality improvement project was developed by using the define, measure, analyze, improve, and control framework. The project intervention decreased the percentage of patients with erroneous diagnoses from 24% to 7% and marginally improved nursing staff satisfaction. Our project successfully addressed an institutional quality concern. Our goal of reducing erroneous discharge diagnoses with minimal disruption to our existing practice was achieved, positively affecting our patients. Including both nurse leaders and frontline health care workers ensured the success of our project.

The treatment landscape for soft tissue sarcomas (STS) is evolving constantly. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for STS specific to surgical management and systemic therapy recommendations for various subtypes.

Nutritional supplement use is common among athletes aiming to enhance performance, recovery, and health. However, variable regulatory frameworks and limited safety oversight create risks for inadvertent doping violations. This article provides a global overview of supplement use, relevant authorities, legislation, and safety measures, with a focus on third-party testing (TPT) as a risk-mitigation strategy. Data from six global regions—Africa, Asia, Australia/New Zealand, Europe, Latin America, and North America—were synthesized from peer-reviewed studies, governmental sources, and regional expert contributions. Reported supplement use ranged from 7% to 100% among athletes (variability within regions), with protein powders, vitamins/minerals, creatine, caffeine, and sports drinks being most prevalent. High-risk products (potential anti-doping rule violations), including certain herbal blends, preworkouts, and weight-management supplements, were reported across all regions. While some countries have robust regulatory systems, most lack harmonized or enforceable safety frameworks. TPT programs, which independently verify products for prohibited substances, remain concentrated in the global northwest (Europe, North America, and Australia/New Zealand); awareness and use of TPT certification vary widely, and even in regions with established systems, athlete adherence is inconsistent. Barriers to low-risk supplement use are limited TPT availability, cost, differences in labeling (including language), and cultural factors. Firsthand experiences and perceptions highlight widespread misconceptions about supplement safety and certification. The authors recommend expanded athlete and team-around-the-athlete education, improved global access to TPT low-risk supplements, and policy initiatives to harmonize safety standards. This work emphasizes the need for coordinated international efforts to protect athlete health and integrity while allowing access to evidence-based supplementation.