Citations

Background: Premedications used to prevent paclitaxel-associated infusion hypersensitivity reactions (iHSRs) can cause undesirable toxicities, such as sleep disturbance and weight gain. Although phase II data suggest that discontinuing premedications after paclitaxel-associated iHSRs may be safe and feasible in select patients without prior iHSRs, no prospective randomized trials have evaluated this approach. Patients and Methods: This randomized clinical trial enrolled patients with breast cancer receiving paclitaxel chemotherapy. Those who experienced no iHSRs with the first 2 doses of paclitaxel were randomized to either continue standard premedications (control arm) or to discontinue all premedications (investigational arm). Both arms were followed longitudinally for any subsequent iHSRs requiring parenteral rescue medications. Additionally, changes in weight, drug-related side effects, and quality of life were assessed. Results: A total of 98 patients were randomized; 89 were evaluable (46 in the control arm and 43 in the investigational arm). Only 1 (2.3%) patient in the investigational arm experienced an iHSR, which resolved with rescue medications. No iHSRs occurred in the control arm. The estimated proportion of subjects who experienced a hypersensitivity reaction (exact binomial 95% CI) was 2.3% (95% CI, 0.1%–12.3%) in the investigational arm and 0.0% (95% CI, 0.0%–7.7%) in the control arm. Patients in the investigational arm reported significantly less sleep disruption (0.5 vs 1.7; P =.002) and unwanted appetite increases (1.0 vs 2.5; P =.0018). Conclusions: Discontinuation of premedications after 2 uneventful paclitaxel doses was not associated with a high rate of subsequent iHSRs and resulted in fewer steroid-related side effects. This strategy may reduce unnecessary medication exposure, improve patient experience, and streamline clinical workflows. For patients who do not experience iHSRs during the first 2 paclitaxel treatments, discontinuing premedications appears safe and may improve tolerability.

ABSTRACT Supplemental oxygen (hyperoxia), often provided to premature infants, can disrupt lung growth and contribute to development of neonatal and pediatric lung diseases, necessitating understanding of underlying mechanisms. We previously showed that even moderate hyperoxia (< 60% O 2 ) induces detrimental cellular senescence in 18–22 weeks human fetal airway smooth muscle (fASM), a key cell type in airway contractility and remodeling. In this study, we examined the ability of senotherapeutics Fucoidan and Dasatinib (D) + Quercetin (Q) (D + Q) to mitigate adverse effects of hyperoxia and assessed the preventive effect of mitochondrial antioxidants (MitoQ). fASM cells exposed to normoxia (21% O 2 ) or hyperoxia (50% O 2 ) were treated with Fucoidan [100 μg/mL], D + Q [250 nM + 375 nM] or MitoQ [100 nM] and assessed for senescence markers, senescence‐associated secretory profile (SASP), extracellular matrix (ECM) deposition, and cell viability. Our results showed that moderate hyperoxia increases senescence markers and SASP. Fucoidan decreased p21 expression and inhibited SASP release without inducing cell death, while D + Q decreased β‐galactosidase (β‐Gal) activity, p21 and plasminogen activator inhibitor‐1 (PAI‐1) expression, and caused cell death without affecting SASP in hyperoxia‐induced senescent fASM. MitoQ prevented increases in senescence markers and SASP in hyperoxia‐exposed fASM. These findings demonstrate distinct and viable strategies to counter hyperoxia‐induced fASM senescence. Fucoidan (senomorphic), D + Q (senolytic), and MitoQ (prophylactic antioxidant) represent promising, mechanistically different approaches to alleviate detrimental effects of moderate hyperoxia in developing airways towards limiting perinatal lung disease.

Abstract This work presents a first-of-its-kind artificial intelligence (AI-)integrated MR pulse sequence that detects out-of-voxel (OOV) artifacts in real-time (within-TR) and responds prospectively by updating the crusher gradient scheme. Per Excitation Real-time Execution & Guided Responses with Integrated Neural-network Evaluation (PEREGRINE), allows for deployment of deep learning models and pulse sequence updates. In this study, PEREGRINE operated a time-domain (TD) and frequency-domain (FD) convolutional autoencoder that detect OOV artifacts. Scans without (AI-off) and with (AI-on) updates were collected from the medial prefrontal cortex of healthy volunteers using a MEGA-edited MRS experiment. The degree of OOV contamination (OOV Score) was quantified per transient based upon the prevalence of OOV signals in the TD and FD data. OOV Scores above a user-defined threshold triggered an update of the crusher gradient scheme, iterating through 48 permutations (6 axis transpositions × 8 polarity flips). Within each 2-second TR, PEREGRINE successfully provided single-transient OOV Scores and updated gradients accordingly. No difference was observed between the OOV Scores from the full (“Full” condition) AI-on and AI-off sessions due to the AI-on scan cycling over better and worse gradient permutations relative to the AI-off scan. However, the AI-on scan had significantly lower OOV Scores than the AI-off scan when selecting the transients where PEREGRINE persisted (“Dwell” condition) on a given gradient permutation. Ultimately, Fit Quality Number (FQN) from linear combination modeling improved significantly for the AI-on compared to the AI-off scan. PEREGRINE enabled an adaptive and AI-integrated sequence allowing for real-time evaluation and response to OOV artifacts, identifying gradient modifications that produced less OOV contamination. Graphical Abstract Graphical Abstract Summary PEREGRINE, Per Excitation Real-time Execution & Guided Responses with Integrated Neural-network Evaluation, allows for pulse sequence updates using on-scanner deployed neural networks. To demonstrate the utility, PEREGRINE was used to operate two neural networks (time/frequency domain), trained to detect out-of-voxel artifacts, during a MEGA-edited MRS experiment in the prefrontal cortex. When artifacts were detected, PEREGRINE updated the crusher gradients within the same TR. Real-time, adaptive, and AI-driven MR will provide a long-awaited solution for combatting artifacts and poor data quality. Graphical Abstract Figure

Importance Amblyopia is the leading cause of monocular decreased best-corrected vision in children. Early detection and intervention are key for optimal treatment outcomes; however, limited access to pediatric eye specialists may hinder timely care and affect visual outcomes. Given the shortage of specialty-trained eye care professionals in the US, there is need to support comprehensive eye care professionals who are willing to examine and treat children with amblyopia. Objective A panel from the Pediatric Eye Disease Investigator Group synthesized relevant literature and incorporated consensus opinion where direct evidence was lacking to create the Amblyopia Navigator Decision-Support Instrument, a free, web-based amblyopia decision support tool for eye care professionals. Evidence Review The decisions related to optimal diagnostic measures, pass/refer criteria, and management recommendations were informed by 147 publications. In areas where direct evidence was lacking, guidance was supplemented with clinical trial protocols or existing professional guidelines. When data were conflicting or unavailable, recommendations were established through committee consensus. A single reviewer independently performed standardized (though not systematic) literature reviews to avoid missing pertinent recent publications. Findings Presented are the process used, supporting evidence, and recommendations for testing methods, refractive correction, amblyopia treatment options, treatment adjustments, and monitoring schedules. Conclusions and Relevance Because amblyopia is common and typically responds well to treatment, decision support tools that optimize its management could increase access to pediatric eye care by facilitating earlier detection, enabling broader participation of primary eye care professionals, and ultimately improving visual outcomes. Through this work and the development of the forthcoming free, web-based application version, Amblyopia Navigator Decision-Support Instrument, the Pediatric Eye Disease Investigator Group has created decision support tools designed to assist optometrists and ophthalmologists in the care of children aged 3 to 17 years with amblyopia.

Objective Positive α‐synuclein seed amplification assay (SAA) is a biomarker found in most people with Parkinson's disease (PD). We explored if free‐water (FW) imaging detects microstructural differences in the brains of patients with early PD with SAA+ or SAA– status. Methods We studied patients with PD with baseline diffusion imaging and α‐synuclein SAA data from the Parkinson's Progression Markers Initiative (PPMI). We compared FW, FW corrected fractional anisotropy (FA T ), and clinical characteristics between SAA+ and SAA– groups. We also applied the Automated Imaging Differentiation for Parkinsonism (AIDP) at baseline to classify PD versus atypical parkinsonism, stratified by SAA status. Results Among 462 participants (41 SAA– and 421 SAA+), individuals with SAA+ had hyposmia and shorter motor symptom duration before baseline magnetic resonance imaging (MRI). AIDP identified PD in 92.4% (n = 427, 91.6% had SAA+) and classified 7.6% as atypical parkinsonism (n = 35, 85.7% had SAA+). At baseline, SAA+ individuals had lower FW in the superior cerebellar peduncle, compared to SAA– (pFDR < 0.05). No significant differences in FA T were found between groups. Interpretation Positive α‐synuclein SAA was associated with focal microstructural differences but did not distinguish broader diffusion MRI (dMRI) changes across FW and FA T metrics. These findings indicate that molecular confirmation of synuclein aggregation (via SAA) provides limited stratification of neurodegeneration detected by FW imaging in early PD. ANN NEUROL 2026;100:295–304

ABSTRACT Background Opioids are indicated for pain that occurs with cancer and other disorders that become more prevalent with aging. The most prevalent and persistent adverse effect of opioid therapy is opioid‐induced constipation (OIC). OIC impairs patient quality of life (QoL) and leads to suboptimal pain management due to medication non‐adherence. Unlike other adverse effects, OIC persists and is not associated with pharmacological tolerance, necessitating long‐term management. Objectives The objective of this study is to evaluate current clinical strategies for OIC by comparing recommendations from American, European, and Japanese clinical guidelines. We reviewed the clinical evidence for the peripherally acting μ‐opioid receptor antagonist (PAMORA) naldemedine (the only PAMORA approved in Japan) and the rationale for early intervention in OIC. Methods The clinical guidelines and recent clinical trial data, including the COMPOSE program (phase III clinical trials of naldemedine for OIC in patients with chronic non‐cancer pain), were reviewed to establish an evidence‐based framework for the management of chronic cancer and non‐cancer pain. Results Conventional laxatives frequently provide inadequate relief as they address secondary symptoms rather than the underlying receptor‐mediated cause. PAMORAs (including naldemedine, methyl naltrexone, and naloxegol) antagonize gastrointestinal opioid receptors without compromising central analgesia. Early initiation of PAMORAs stabilizes bowel function and reduces the incidence of treatment‐related diarrhea that occurs when using conventional laxatives to treat OIC. Conclusion The 2023 Japanese guidelines advocate the proactive use of the PAMORA naldemedine as a primary treatment option. This mechanism‐based early intervention model offers a promising framework for optimizing QoL and implementing effective analgesia in an aging global population.

Abstract INTRODUCTION Prospective studies of blood‐based biomarkers reflecting pathogenic processes, other than Alzheimer‐specific pathologies, that contribute to dementia in diverse cohorts are lacking. METHODS We jointly fitted linear mixed‐effect models and proportional hazards models to examine associations of midlife glial fibrillary acidic protein (GFAP), chitinase‐3‐like protein 1 (YKL‐40), soluble cluster of differentiation‐14 (sCD14), neurofilament light chain (NfL), total tau (t‐tau), and ubiquitin C‐terminal hydrolase L1 (UCHL1) levels in serum (collected in 1993 to 1995) with cognitive decline and incident dementia (ascertained over 29 years through 2022) in the community‐based Atherosclerosis Risk in Communities Study. sCD14 and YKL‐40 were measured in 3082 participants and the other four biomarkers in 1766 participants. RESULTS Higher serum GFAP, YKL‐40, sCD14, and NfL were associated with faster cognitive decline and elevated dementia rate (e.g., 1 standard deviation [SD] higher log‐base2 YKL‐40 was associated with −0.11SD faster 25‐year cognitive decline (95% confidence interval [CI]: −0.15,−0.07) and 45% higher dementia hazard (hazard ratio [HR]: 1.45 [95% CI: 1.25, 1.68]). Higher t‐tau and UCHL1 were also associated with faster cognitive decline. DISCUSSION Midlife blood biomarkers reflecting glial and neuronal dysfunction and neuroinflammation are associated with early cognitive impairment.

BACKGROUND Patients with severe aortic stenosis (AS) exhibit heterogeneous flow-gradient hemodynamics and ventricular remodeling, which may influence symptomatic, functional, and structural responses to transcatheter aortic valve implantation (TAVI). Thus, we evaluated differences in functional recovery and reverse remodeling after transfemoral TAVI across flow-gradient phenotypes. METHODS In this sub-study of the COMPARE-TAVI 1 trial, 975 patients undergoing transfemoral TAVI were classified as classical low-flow low-gradient (cLFLG, 9.1%), paradoxical low-flow low-gradient (pLFLG, 7.7%), low-flow high-gradient (24.7%), normal-flow low-gradient (NFLG, 13.0%), and normal-flow high-gradient (45.4%). The primary functional outcome was longitudinal change in six-minute walk test distance (6MWTD) from baseline to 1 year follow-up. Secondary endpoints included changes in NYHA functional class and reverse remodeling from baseline to 1 year follow-up along with the incidence and risk of all-cause death and a composite MACE-endpoint. RESULTS Mean 6MWTD increased by 59±4 meters at 1-month (p=0.000) with no additional improvement at 1-year, but with heterogeneity between groups (p=0.000). Improvements among NFLG, cLFLG and low-flow high-gradient AS were comparable with normal-flow high-gradient AS, while pLFLG AS exhibited significantly increments at 1-year (−28±15 meters, p=0.007). Patients with NFLG, cLFLG and pLFLG were more symptomatic at baseline (NYHA ≥III: 40.5%, 57.3% and 50.6%, respectively, p=0.000). NYHA improved in all groups at 1-year follow-up (p=0.000), although persistent symptoms at 1-year were most frequent in pLFLG (NYHA ≥II; 38.7%, p=0.012). Reverse remodeling was also comparable between normal-flow high-gradient AS and NFLG, cLFLG, and low-flow high-gradient AS, respectively, but attenuated in pLFLG AS in both unadjusted and adjusted analyses. No differences were observed in the incidence and risk of all-cause death or the composite MACE-endpoint. CONCLUSION TAVI associates with functional recovery across all flow-gradient phenotypes, although with heterogeneous responses. Patients with NFLG showed comparable functional recovery and reverse remodeling at 1-year follow-up compared with normal-flow high-gradient AS, whereas pLFLG demonstrated attenuated benefits across all parameters.

Abstract The genetic contributions of the X chromosome to Alzheimer’s disease (AD) remain poorly understood yet are expected to importantly shape sex differences in AD. We therefore performed large-scale X-chromosome-wide association studies (N=1,240,451), evaluating differential risk due to sex, APOE *4, and escape from X-chromosome inactivation, finding most X-linked loci appear relevant to female-biased AD etiology. In evaluating genetic pleiotropy with hormonal, lipid, and brain imaging traits, we discovered X-linked AD loci converged on white matter traits, particularly in the anterior corona radiata and splenium of the corpus callosum. Through brain-centric functional genomics analyses, we then nominated candidate causal genes, including 5 that appeared highly robust. Notably, we found the escape gene RBBP7 decreases AD risk in APOE *4 carriers likely through higher expression in excitatory neurons to counter tau-related neurodegeneration. Altogether, we provide an atlas of sex and APOE *4-informed candidate X-linked AD risk loci, genes, and mechanisms that will guide future studies.