Citations

Abstract Background Red blood cell (RBC) transfusion may be lifesaving, however transfusion-transmitted infections (TTI) and transfusion-associated graft-versus-host disease (TA-GVHD) still pose a threat despite current donor selection and testing requirements. Amustaline (S-303)/glutathione (GSH) pathogen reduction (PR) is designed to inactivate infectious microbes and leukocytes in RBCs. The RedeS study evaluates the safety and efficacy of amustaline/GSH PR-RBCs compared to conventional RBCs in a broad spectrum of patients requiring acute and/or repeated RBC transfusion support. Methods RedeS is a Phase 3, prospective, multi-center, randomized, double-blind, active-controlled, parallel-design study, with a 6-month extension option to evaluate patients requiring repeated transfusions including red cell exchange (RCE).Eligible subjects will be stratified according to site, baseline bleeding status and participation in the extension period. The study arms include a transfusion period of 28-days for anemia with any bleeding or non-bleeding patients or a 28-day+6-month extension for non-bleeding patients with chronic anemia requiring repeated simple transfusions, or for patients with sickle cell disease (SCD) expected to receive three RCE procedures. The study will seek to enroll 600-800 subjects in the overall safety analysis, including ~140 repeatedly-transfused subjects in the 6-month extension including up to 30 subjects receiving three RCE procedures. The primary safety endpoints are the proportion of patients with any treatment-emergent adverse events (TEAEs) related to study RBC transfusion through 28 days after the last study transfusion, and the proportion of patients with treatment-emergent antibodies with confirmed specificity to PR-RBCs. The primary efficacy endpoint is the hemoglobin (Hb) increment in subjects who are non-bleeding at baseline, adjusted for the grams of Hb transfused and averaged over multiple transfusions. With 352 evaluable transfused non-bleeding subjects (176 per treatment group) from either arm, the study will have 80% power to demonstrate non-inferiority, defined as a Hb increment treatment difference of no more than 15% of the Control group mean, assuming a Control arm coefficient of variation of 50%. Discussion RedeS will characterize the safety of amustaline/GSH PR-RBCs and is designed to demonstrate the non-inferiority of PR-RBCs to conventional RBCs with respect to Hb increment, a common pragmatic clinical assessment of RBC transfusion effectiveness.

ABSTRACT Objectives Odontogenic sinusitis (ODS) refers to purulent sinusitis caused by infectious maxillary dental pathologies, with > 90% occurring unilaterally. While various clinical features suggest ODS, diagnosing some ODS patients can be challenging. This study aimed to determine the value of maxillary sinus papillary edema (MSPE) in predicting ODS. Methods A retrospective cohort study was conducted on patients who underwent at least maxillary antrostomy for unilateral sinus disease (USD). Adequately powered samples of three USD cohorts were generated: ODS, infectious maxillary CRS without nasal polyps (CRSsNP), and noninfectious CRSwNP. Multiple variables were collected, but the primary outcome was MSPE presence via double‐blinded endoscopic image review by three rhinologists. Inter‐rater agreement was calculated, and a predictive model for MSPE was generated. Results Of 41 ODS, 22 infectious CRSsNP, and 13 noninfectious CRSwNP patients, mean age was 57.0 years and 55.3% were female. There was almost perfect agreement between rhinologists when assessing for MSPE on endoscopic images ( κ = 0.927). MSPE was seen in 100% of ODS, 22.7% infectious CRSsNP, and 0% CRSwNP. MSPE was significantly more likely in ODS compared to non‐odontogenic CRS ( p < 0.0001), demonstrating 100% sensitivity and 89.1% specificity for ODS, with 85.7% positive and 100% negative predictive values. Conclusions MSPE is a distinct finding that is reliably identifiable and is significantly more likely in ODS compared to infectious CRSsNP and noninfectious CRSwNP. With 100% sensitivity and NPV, MSPE absence makes ODS very unlikely. With 86% PPV, MSPE is not pathognomonic for ODS, but should arouse suspicion for a possible odontogenic source. Level of Evidence 3.

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.

Background: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, disabling, genetic disorder characterized by progressive heterotopic ossification (HO). FOP care pathways are complex, and there are many underrepresented patients globally. Objectives: This scoping review aimed to identify global FOP case reports and investigate real-world management practices. Evidence sources, eligibility criteria, and charting methods: International/local databases and congress proceedings were searched. Publications reporting patient-level data for ⩾1 patient with an FOP primary diagnosis, published January 2000–January 2024, were eligible. Publication details, patient demographics, disease presentation, and care pathway were extracted. Data were charted through categorization of themes and frequency analyses. Results: Of 6064 publications screened, 369 were eligible, reporting on 541 patients with FOP. Most publications (82.4% (304/369)) reported an individual case; the remaining reported 2–25 cases. Cases were from 57 countries, most commonly in the Asia/Pacific region (47.0% (254/541)). Most patients had reportedly seen a single specialist (64.8% (59/91)), and care from multidisciplinary teams was reported for only 5.5% (5/91). HO (84.7% (458/541)) and great toe malformations (66.7% (361/541)) were the most commonly reported signs, though mobility limitations (46.2% (96/208)) and growths/lesions (38.5% (80/208)) were most common before diagnosis. The predominant drug classes reported for FOP treatment were corticosteroids (52.6% (102/194)) and nonsteroidal anti-inflammatory drugs (39.7% (77/194)). Surgeries were reported in 35.1% (190/541) of patients. Where specified, the most common surgery types were malformation correction/bone resection (43.6% (78/179)) and biopsies (34.1% (61/179)). Conclusion: This scoping review synthesized valuable real-world insights from case reports of FOP, potentially supporting outreach initiatives in underserved regions and facilitating shared learnings on diagnosis and treatment. Although the inherent selection bias of case studies toward atypical cases limits definitive conclusions, some global trends in the clinical management practices were revealed.

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.

Abstract INTRODUCTION Brief digital cognitive measures may be a valuable and scalable alternative to traditional tests for improving early detection and disease monitoring in patients with early‐onset Alzheimer's disease (EOAD). METHODS We examined the convergent, diagnostic, and neuroanatomical validity of Tablet‐based Cognitive Assessment Tool (TabCAT) tests in the multisite Longitudinal Early‐Onset Alzheimer's Disease Study. Four hundred seventy‐five participants from 16 sites (83 cognitively unimpaired participants, 146 individuals diagnosed with mild cognitive impairment [MCI], and 246 with mild dementia) underwent TabCAT testing, including two executive/attentional tasks (Match and Flanker) and two visuospatial tasks (Line Length and Line Orientation). RESULTS TabCAT tests showed good convergent validity with traditional pen‐and‐paper tests. Match was the most accurate TabCAT test in differentiating among clinical groups (controls vs. MCI vs. dementia) and predicting amyloid positron emission tomography (PET) positivity in clinically impaired participants. TabCAT tests were associated with regional tau PET patterns. DISCUSSION TabCAT digital measures have promise for frontline identification of patients with EOAD. Highlights Four hundred seventy‐five participants from 16 US sites underwent tablet‐based cognitive assessment. Digital tests assessed executive function and visuospatial abilities. Digital tests correlated with traditional pen‐and‐paper cognitive tests. Match (test of executive function) differentiated clinical groups. Digital tests were associated with amyloid positron emission tomography (PET) status and regional tau PET patterns.

ABSTRACT Chimeric antigen receptor T-cell (CART) and T-cell engager (TCE) therapies targeting B-cell maturation antigen (BCMA) are transforming the treatment landscape for relapsed multiple myeloma (MM). However, despite impressive initial response rates, most patients eventually relapse. To investigate this unmet medical need, we applied whole-genome sequencing (WGS) to MM cells from cohorts of 102 relapsed patients treated with anti-BCMA CART and TCE therapies. Several genomic alterations were associated with clinical outcomes, particularly primary refractoriness, including high genomic complexity and mutations in genes regulating plasma cell identity, which predicted resistance to therapy. Single-cell RNA sequencing further revealed that MM cells from refractory patients exhibited high proliferation signatures and reduced expression of TNFRSF17 (encoding BCMA), while were less enriched for plasma cell–associated transcriptional programs, a phenomenon we term “plasma cell identity escape.” This profile was strongly associated with immune dysregulation of CD8 T cells including increased activation and exhaustion. This evolution of MM toward a more proliferative and lineage-divergent state, refractory to the anti-BCMA T-cell redirecting therapies, was functionally validated in preclinical MM mouse models. Collectively, our results comprehensively define the cellular and molecular mechanisms underlying primary resistance to anti-BCMA therapies.

Spinal sarcomas are rare, aggressive tumors requiring wide resection that creates large, challenging defects. Conventional reconstruction using allografts or metallic implants is prone to failure in compromised settings like irradiated or infected tissue. This narrative review synthesizes the literature on biologic reconstruction strategies, focusing on vascularized bone grafts (VBGs) and the ‘spinoplastic’ reconstruction approach, to provide a clinical framework for their application. We performed a narrative literature review using PubMed and Scopus to synthesize clinical studies describing biologic spinal reconstruction in compromised host beds. The main findings show that pedicled VBGs (e.g., rib, iliac crest) and free VBGs (e.g., fibula) function as living structural components. ‘Spinoplastic’ reconstruction leverages these grafts to promote biologic fusion, with clinical series reporting high union rates, even in irradiated or revision settings, offering a durable alternative to avascular constructs. Biologic reconstruction using VBGs is a critical strategy for achieving durable spinal stability in these challenging scenarios, and future directions point toward hybrid strategies combining 3D-printed implants with the biologic power of VBGs.

Background/Objectives: Overall survival in patients with amyotrophic lateral sclerosis (ALS) is linked to the rate of predicted respiratory vital capacity (PVC) loss. The objective of this study was to test whether changes in quantitative PVC measures over time linked to survival would define an immunopathogenic subset of ALS responsive to NP001, a regulator of innate immunity. Methods: In a retrospective study, data from intent-to-treat (ITT) population of two phase 2 trials of NP001 were evaluated for over time changes in PVC, time-to-event (TTE) loss of 15% PVC and PVC change from baseline, as linked to survival outcomes in patients treated with NP001 vs placebo. Results: Treatment with NP001 was associated with a significantly lower risk compared to placebo in the loss of 15% PVC over six months (p = 0.01; HR = 0.60, 95% CI: 0.39, 0.90). Data from the two trials were subsequently divided by a disease progression rate (DPR) value of 0.50 units of ALSFRS-R score lost per month for analysis of slow vs. rapid disease. In ALS patients with slowly progressive disease (DPR < 0.50), TTE PVC changes from baseline were slowed (p < 0.0005) and overall survival extended significantly (18.5 months) in NP001-treated vs. placebo groups. The rapidly progressive ALS patients (DPR ≥ 0.50) treated with NP001 showed no significant difference in PVC change or survival from the placebo group. Conclusions: These hypothesis-generating observations suggest that inflammation might play a significant role in the loss of respiratory function in a major subset of ALS patients.

Background: Inflammatory bowel disease (IBD) is associated with systemic inflammation and potential cardiovascular complications. This meta-analysis evaluates long-term cardiovascular risks in IBD. Methods: Electronic databases were searched for studies examining cardiovascular, cerebrovascular, and thromboembolic risks in IBD. Adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) were pooled using a random-effects model. Results: Fifty-three studies comprising 1,406,773 patients were analyzed. IBD was linked to increased risk of ischemic heart disease (aHR 1.25; p = 0.001) myocardial infarction (aHR 1.25; p = 0.01), acute coronary syndrome (aHR 1.43; p < 0.00001), heart failure (aHR 1.24; p < 0.00001), atrial fibrillation (aHR 1.20; p < 0.00001), and stroke (aHR 1.13; p < 0.00001). Elevated risks were also observed for peripheral arterial disease (aHR 1.41; p < 0.00001), diabetes mellitus (aHR 1.40; p < 0.00001), venous thromboembolism (aHR 1.98; p < 0.00001), deep vein thrombosis (aHR 2.85; p = 0.0004), and pulmonary embolism (aHR 1.98; p = 0.03). Importantly, IBD was associated with increased cardiovascular (aHR 1.14; p = 0.03) and all-cause mortality (aHR 1.53; p < 0.00001). Conclusions: IBD patients face higher risk for adverse cardiovascular outcomes, thromboembolic disease, and mortality, necessitating early cardiovascular risk assessment and targeted interventions in this population.