Citations

Abstract Background The incidence of early onset breast cancers (BCs) has increased, paralleling rising trends in delayed childbearing. We hypothesize that a distinct postpartum BC (PPBC) subtype, identifiable by time since last birth (TSLB) and biomarker expression, contributes to this trend. Methods We applied GeoMx Digital Spatial Profiling (DSP) to measure associations between TSLB and 71 proteins in 640 BCs from women aged ≤40 years included in the Young Women’s Breast Cancer Study. We analyzed data using univariable linear regression and multivariable sliced inverse regression to account for higher order interactions among biomarkers. Results In keratin-rich segments, progesterone receptor (PR) (P = 1.00 × 10−4) and PTEN (P = 1.00 × 10−3) were associated with longer TSLB; multivariable analyses revealed positive associations for GZMB (P = 4.00 × 10−4), SMA (P = 1.00 × 10−4), and NF-1 (P = 1.00 × 10−3). In keratin-poor segments, univariable significant positive associations were found for PR (P = 2.00 × 10−4) and PTEN (P = 1.00 × 10−3), whereas CD20 (P = 3.00 × 10−4) and CTLA4 (P = 4.00 × 10−5) were negatively associated; multivariable significant associations were found for fibronectin (P = 3.00 × 10−5) and pan-Akt (P = 1.00 × 10−3). Associations persisted after adjustment for multiple comparisons and BC molecular subtypes. Associations including for PR, PTEN, and CD20 were strongest among women with the shortest TSLB. OPAL multiplex immunofluorescence assays for PR, PTEN, CD20, SMA, and CTLA4 replicated several DSP findings, particularly when stratified by subtype and with compartment matching. In TCGA, RNA species linked to proteins associated with TSLB correlated strongly with a T-cell exhaustion signature previously linked to poor prognosis among premenopausal women. Conclusion These data support PPBC as a biologically coherent phenotype defined by TSLB and biomarker profile, with potential implications for prevention and therapy.

Abstract Introduction Cannabidiol has been shown to exert significant anti-inflammatory effects and has demonstrated efficacy in murine models of autoimmune myocarditis, pericarditis, and heart failure. The ARCHER Study assessed whether a pharmaceutically produced cannabidiol formulation showed beneficial effects on cardiac magnetic resonance (CMR) endpoints known to predict prognosis in this patient population. Methods In a multicentre international double-blind placebo-controlled phase 2 study, we randomly assigned 109 patients within 10 days of CMR confirmed diagnosis of acute myocarditis to 12 weeks of pharmaceutically produced oral cannabidiol (active) or placebo. Dose was titrated up to 10 mg/kg of body weight twice daily. Primary endpoints were the difference in extracellular volume (ECV) and global longitudinal strain (GLS) measured by CMR at week 12. Other CMR endpoints included left-ventricular ejection fraction (LVEF), LV mass, intracellular volume (ICV), LV end-diastolic and end-systolic volumes (LVEDV, LVESV), and left-atrial end-systolic volume (LAESV). Results All randomized patients (56 active/53 placebo) completed the study with no loss to follow-up. Study drug appeared safe and well tolerated. Baseline mean ECV 38.9 ± 10.9 ml, GLS −15.3 ± 3.6%, and LVEF 60.6 ± 9.9% were consistent with mild to moderate myocarditis and predominantly intact LV function. Week 12 mean ECV was 33.6 ml in the active group and 37.3 ml in the placebo group, a difference of −3.7 ml, confidence interval (CI): −7.4 to 0.1; P = .0538; GLS was −16.0% in the active group and −15.9% in the placebo group, difference of −0.1, CI: −1.2 to 1.1; P = .90. Left ventricular mass was significantly reduced in the active group at 121.1 g compared to placebo 130.3 g, a difference of −9.2, CI: −16.4 to −2.1; P = .0117. In terms of remodelling, LAESV was significantly reduced in the active group (−8.1 ml; P = .0376) while the reduction in LVEDV failed to reach significance (−7.4 ml; P = .098). Conclusion In mild-to-moderate acute myocarditis, treatment with pharmaceutically manufactured cannabidiol was not associated with a statistically significant change in myocardial ECV or GLS, although a trend towards reduction in ECV was observed. In addition, improvement in other potential markers of myocardial recovery, including a significant reduction in LV mass, was seen in the active treatment group. Further investigation of the therapeutic potential of this therapy in inflammatory cardiac conditions is warranted.

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 Background Frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominant atrophy is an emerging area of interest. Recent findings by the International Working Group (IWG) have identified this subtype as having a distinct clinical profile within the FTD spectrum (Ulugut et al., 2024, A&D). However, its genetic and pathological underpinnings remain unexplored in large, multicultural cohorts. Methods Retrospective analyses encompassing clinical, genetic, pathological, and neuroimaging data from 23 IWG sites across 13 countries in Asia, Middle East, Europe, North and South America were conducted. The study included 444 patients with FTD exhibiting predominant RATL atrophy. Results Genetic screening was performed on 51% ( n = 225) of the cohort for at least the major frontotemporal lobar degeneration (FTLD) mutations including microtubule‐associated protein tau ( MAPT ), progranulin ( GRN ), and chromosome 9 open reading frame 72 ( C9orf72 ), or dementia panels encompassing extended sets of genes. Of these, 81% were sporadic, showing negative results for the screened genes and a modified Goldman Score of ≥ 3, indicating a negative family history for dementia. The MAPT mutation was the most common genetic variant, identified in 7% of the screened cases (Figure 1). Pathological confirmation was available for 63 patients. Among the sporadic cases, transactive response DNA‐binding protein 43 type C (TDP‐C) pathology was most prevalent (60%, n = 32), while tau‐MAPT pathology was most common in the genetic cases (38%, n = 16). Fifteen cases did not fit neatly into genetic or sporadic categories, displaying heterogeneous pathologies (Figure 2). At the initial visit, compared to genetic cases, patients with TDP‐C pathology were older, and more frequently exhibited semantic deficits, with less frequent attention difficulties and executive dysfunction. No differences were observed in sex distribution, symptom duration or disease severity between genetic and sporadic TDP‐C cases. However, left handedness was more common in TDP‐C cases (14%) compared to genetic cases (5%). Conclusion While FTD with RATL atrophy primarily appears sporadic, a significant proportion of cases exhibit genetic variants. These sporadic and genetic subtypes display distinct neuropathological features and clinical manifestations. Given the implications for therapeutic strategies, precise clinical and molecular subtyping is critical for enhancing patient management and ensuring appropriate enrollment in clinical trials.

Abstract Background In recent years, blood‐based biomarkers (BBMs) have transformed the diagnostic landscape of Alzheimer’s disease (AD), with some now approaching readiness for clinical implementation. This progress aligns with the growing importance of accurate early diagnostics and availability of anti‐Aβ therapies for the treatment of early symptomatic AD, reinforcing the need for more rapid and early diagnostic capabilities. To address this need, the Alzheimer’s Association convened a multidisciplinary panel of clinical experts, subject‐matter specialists, and guideline methodologists to conduct a systematic review and develop evidence‐based recommendations for the use of BBMs in the diagnostic evaluation of AD. The scope of this guideline is focused on individuals with cognitive impairment ‐ either MCI or dementia ‐ who are undergoing diagnostic assessment in secondary or tertiary care settings. Method The panel conducted a systematic review to assess BBMs' diagnostic test accuracy in detecting amyloid pathology for triaging (≥90% sensitivity, ≥75% specificity) and confirmatory (≥90% sensitivity and specificity) diagnostic workup. The BBMs of interest included plasma p ‐tau and Aβ tests measuring the following analytes: p ‐tau217, % p ‐tau217, p ‐tau181, p ‐tau231, and Aβ42/Aβ40 ratio. The reference standard tests included CSF, amyloid PET, or neuropathology examination. The panel applied the GRADE approach to assess the certainty of the evidence and the GRADE Evidence‐to‐Decision Framework to develop its recommendations. Result Across 49 observational studies meeting eligibility criteria, 31 different BBM tests were evaluated. Using predefined decision thresholds, the panel determined whether each test has 1) sufficient diagnostic test accuracy to be used as a triaging test where a positive test is to be confirmed by PET or CSF, 2) sufficient diagnostic test accuracy as a confirmatory test to replace PET or CSF, or 3) insufficient diagnostic test accuracy to recommend current use in clinical practice. Recommendations will be provided in case any BBMs met a priori DTA thresholds. Conclusion BBMs can improve early AD diagnosis and expand access to disease‐modifying therapies. Evidence‐based guidelines are key to standardizing their use and will be updated as new evidence and applications emerge.

Abstract Background & Aims: Alcohol is a leading global risk factor, over 200 diseases and injuries, but policy adoption varies. We updated the Alcohol Preparedness Index (API) to track global and regional policy trends from 2010–2019. Methods: Using WHO GISAH data for 141 countries, we scored five domains (policy frameworks; production/pricing/taxation; marketing/availability; drink-driving; monitoring/surveillance). The primary endpoint was % change in API. Trends were summarized by WHO region and correlates tested in adjusted regression. Results: In 2019, <25% of countries had a strong national alcohol plan and 40% had none. Production/pricing/taxation increased most (27%→78%); monitoring/surveillance reached strong levels in 47.5%. Median API increased from 57.0 [39.0–82.0] (2010) to 74.8 [58.3–83.5] (2016) and stayed above baseline in 2019 (67.8 [51.2–83.8]). Larger population predicted less API gain (β=−19.1, p<0.05); HDI and per-capita consumption did not. Conclusions: Global alcohol policy preparedness increased from 2010–2019.

Hearing loss is a highly prevalent disease state affecting almost 1 in 5 individuals globally. Growing research shows that untreated or undertreated hearing loss carries significant long-term sequelae, including increased risk of social isolation, depression, and cognitive decline, among other ramifications. Limited awareness and common misperceptions among the general US adult population and primary care providers contribute to low rates of referral to hearing specialty clinics and underutilization of hearing aids, cochlear implants, and other rehabilitative devices. Comprised of diverse membership, the Hearing Health Collaborative (HHC) was formed in May 2021 to identify and overcome challenges impacting good health care practices and public policy on hearing care in connection with healthy aging. This editorial documents a recent outcome of the HHC derived from a structured A3 process. Specifically, initiative 2, a proposal to develop a simple, clinically anchored staging system primarily for use by frontline providers and patients, is presented. Unlike other common disorders that harbor long-term health sequelae, a corresponding pragmatic clinical staging system—leveraging precedent disease staging convention, based on clinically meaningful outcomes and prognosis for acquired hearing loss—does not exist. The development of this staging system will potentially allow for improved communication across providers and patients, facilitate referral pathways, and ultimately enable patient access to timely and appropriate care.