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Abstract Background The Aging and Cognitive Health Evaluation in Elders (ACHIEVE) randomized trial ( n = 977;ClinicalTrials.gov:NCT03243422) demonstrated that hearing intervention slowed 3‐year cognitive decline by 48% among a subgroup of participants. To further investigate differences by treatment with respect to cognitive benefit, we tested the hypothesis that hearing intervention is associated with improved neurodegeneration blood biomarkers 3‐years post‐randomization and assessed whether combining biomarkers and cognitive results improved power in the trial design. Method The ACHIEVE study is a multicenter, parallel‐arm, randomized trial (hearing intervention vs health education control) on 3‐year cognitive decline among adults 70–84years with untreated hearing loss and without substantial cognitive impairment. Participants were recruited from two populations: (1) a long‐standing cardiovascular health observational study (Atherosclerosis Risk in Communities [ARIC]), and (2) de novo community volunteers. Plasma was collected in year 3 in a subsample ( n = 540) while ARIC participants ( n = 164) also had baseline plasma. Glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) neurodegenerative biomarkers were derived using the Alamar CNS protein panel. Regression models estimated the association of treatment with 3‐year biomarkers and global cognitive differences in the combined sample and by recruitment source and annualized change from baseline in the ARIC sample. We included a simple composite score of the standardized outcomes (Table 2). Result Among the subsample, baseline characteristics were balanced by treatment. There were no significant differences on 3‐year neurodegeneration biomarker levels by treatment in the combined (Table 1) or de novo groups (Table 2). Among ARIC participants, intervention resulted in lower 3‐year GFAP (mean:‐0.415;95%CI:‐0.712,‐0.118) and NfL (mean:‐0.349;95%CI:‐0.652,‐0.046) (Table 2). Annualized change from baseline analyses among ARIC participants (Table 3) revealed intervention was associated with a slower rate of cognitive decline (difference‐in‐means:0.059;95%CI:0.018,0.100) and a slower rate of increase in GFAP (difference‐in‐means: ‐0.060;95%CI:‐0.112,‐0.009). Differences in estimates suggest combined score, relative to cognition alone, may increase power in clinical trials that show a positive effect (ARIC subgroup: p = 0.02vs. 0.08[Table 2] and p = 0.0009vs.0.048[Table 3]). Conclusion Hearing intervention was associated with positive 3‐year effects on neurodegeneration blood biomarkers in ARIC participants which parallels cognitive decline results. Results provides objective evidence of brain changes following hearing intervention and potential signal of a more powerful combined outcome approach for future brain health clinical trials.

Abstract The Atherosclerosis Risk in Communities (ARIC) study started in 1987‐1989 (visit 1), when participants from four U.S. communities were 45‐64yo. Participants have been seen at up to 10 additional in‐person visits with annual/semi‐annual telephone calls to ascertain clinical events, hospitalizations, and other health outcomes. In 2011‐2013, at ARIC visit 5, the ARIC Neurocognitive Study (ARIC‐NCS) was initiated for surviving participants, incorporating neuropsychological assessments at multiple in‐person visits and informant interviews to support cognitive adjudication. A subset of participants have undergone brain MRI with measurement of brain volumes, cortical thickness, arterial disease and vascular lesions, with a smaller subset having brain florbetapir PET. Blood‐based Alzheimer's disease (AD) biomarkers are available at multiple visits along with extensive measurement of vascular risk factors, vascular markers, and ‐omic (e.g.genomic and proteomic) data. This presentation will focus on the available data in ARIC, the methods underlying its collection and subsequent analysis, and some of the primary contributions of this study to the field. With 37 years of follow‐up, a great strength of ARIC is the ability to evaluate risk factors in midlife; ARIC studies have supported an association of midlife hypertension, diabetes, physical inactivity, and other vascular risk factors with reduced dementia risk, even among those with increased genetic risk for dementia. ARIC studies have demonstrated associations between stroke and dementia, and have linked vascular risk factors with blood‐based and imaging biomarkers of AD‐related dementias. ARIC has demonstrated the importance of hearing loss in dementia risk, and a subset of ARIC participants were recruited into (and were those who most benefited from the intervention of) the ACHIEVE study of hearing aid use for reduction of dementia. Proteomic studies have identified markers of dementia risk when evaluated in midlife. Recently, ARIC data informed updated estimates on lifetime risk of dementia, where it was estimated that among individuals surviving beyond age 55, 42% would develop dementia over their lifetime through age 95. ARIC studies continue to focus on risk factors for dementia, particularly now in the oldest old, and on contributors to cognitive reserve and resilience. ARIC follows a model of data sharing and broad collaboration.

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.

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 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cervical Cancer provide diagnostic workup, staging, and various treatment recommendations for cervical cancer based on clinical and surgical staging. This selection from the NCCN Guidelines for cervical cancer specifically focuses on diagnosis and workup, principles of staging and surgery, and primary treatment recommendations for early-stage and advanced disease and provides a detailed overview of systemic therapy recommendations for cervical cancer.

PURPOSE Low-grade serous carcinoma (LGSOC) of the ovary, fallopian tube, or peritoneum is a hormonally driven, relatively chemoresistant malignancy with limited treatment options in the recurrent setting. Given frequent estrogen receptor (ER) expression and dysregulation of the cyclin-dependent kinases 4 and 6 (CDK4/6)–p16–Rb pathway, features shared with hormone receptor–positive breast cancer, dual endocrine, and CDK4/6 inhibition is a biologically rational strategy. This phase II trial evaluated ribociclib plus letrozole in recurrent LGSOC. METHODS This open-label, single-arm, multicenter phase II study enrolled women with measurable, recurrent LGSOC. Patients received ribociclib (600 mg orally, once daily, days 1-21 of a 28-day cycle) and letrozole (2.5 mg orally, once daily). The primary end point was investigator-assessed objective response rate (ORR) per RECIST 1.1. Secondary end points included clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS Of 74 patients screened, 51 were enrolled and 49 treated. The confirmed ORR was 30.6% (90% CI, 19.9 to 43.2), including one complete and 14 partial responses. Among responders, the median duration of response was 21.2 months. The CBR was 84% (90% CI, 72.5 to 91.6). The median PFS was 14.5 months (90% CI, 10.1 to 28.8), and the median OS was 44.5 months (90% CI, 31.8 to not reached). The most common grade ≥3 adverse event (AE) was neutropenia (47%), managed with dose modifications. Three grade 5 events (6%) occurred but were unrelated to treatment. Treatment discontinuation because of AEs occurred in 4%. No dose-limiting toxicities were observed. CONCLUSION Ribociclib plus letrozole met the primary end point, achieving meaningful response rates and durable disease control in recurrent LGSOC. The safety profile was consistent with prior CDK4/6 inhibitor studies. This combination represents a therapeutic option in this rare and genomically distinct subtype.

BACKGROUND Among antiretroviral therapy–suppressed (ART-suppressed) people with HIV (PWH), women have higher levels of some inflammatory markers than men, but the effect of sex on the inflammatory proteome, and whether age modifies these differences, remain unclear. METHODS Plasma inflammatory protein levels were assessed in ART-suppressed PWH from the Center for AIDS Research Network of Integrated Clinical Systems. The relationship between sex and plasma proteins — including 22 interferon-α response pathway proteins — was assessed, adjusting for confounders and assessing interactions by age. RESULTS Of 922 participants, 162 (18%) were female. The median age was 47, above which the majority of women had undetectable plasma anti-Müllerian hormone levels, a biomarker of ovarian reserve. Age modified the influence of sex on the inflammatory proteome. Older age (>47) was associated with greater increases among women than men in 194 proteins. Interferon-α response proteins were higher in men in those ≤ 47 but higher in women in those > 47 (interaction P < 0.001). Among the 131 proteins associated with mortality risk ( q < 0.05), only 5 differed by sex among those ≤ 47, while 79 differed by sex in those > 47, with nearly all being higher in women. Women had decreased mortality than men ≤ 47 ( P < 0.001) but had similar mortality > 47 ( P = 0.84). CONCLUSION The menopausal transition appears to increase systemic type I interferon responses and inflammation in women with HIV, which may contribute to a loss of female advantage in mortality. FUNDING NIH National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke; National Institute of Allergy and Infectious Diseases.

This practice guideline addresses perioperative pain management using local and regional anesthesia for cardiothoracic, mastectomy, and abdominal surgery in adults and children. For adults, the American Society of Anesthesiologists (Schaumburg, Illinois) Task Force on Perioperative Pain Management strongly recommends fascial plane blocks to reduce pain and/or opioid requirements in the first 24 h postoperatively for open cardiothoracic, abdominal, retroperitoneal, and pelvic surgeries and mastectomy. Fascial plane blocks are also recommended in adults to reduce pain and/or opioid requirements after minimally invasive abdominal procedures. The Task Force conditionally recommends use of fascial plane blocks for minimally invasive cardiothoracic surgeries and open hernia repair to reduce pain in the first 24 h postoperatively. For children, the Task Force strongly recommends use of fascial plane blocks to reduce pain/and or opioid use after open cardiac or thoracic surgeries. Fascial plane blocks are conditionally recommended to reduce pain the first 24 h in children undergoing open hernia repair. Overall, data analysis for this practice guideline was limited by low methodologic quality, inconsistencies in outcome measurements, and small sample sizes from individual centers. Future research in regional anesthesia and analgesia needs to address these pervasive limitations.

Abstract Immune checkpoint inhibitor–associated immune thrombocytopenia (ICI-ITP) has been described in case reports and small case series, but comprehensive data on its incidence, risk factors, clinical features, treatment, and outcomes are lacking. We reviewed medical records of all adults initiating ICI therapy between 2016 and 2023 at 29 US hospitals across 7 major cancer centers to identify patients with ICI-ITP. Multivariable logistic regression was used to identify risk factors, and Cox modeling was performed to assess the association between ICI-ITP, its severity, and mortality. Among 86 467 patients, ICI-ITP occurred in 214 (0.25%). Independent risk factors included lower baseline platelet count, combination ICI therapy, stage IV cancer, and additional immune-related adverse events. ICI-ITP occurred at a median of 8 weeks (interquartile range [IQR], 4-18) after ICI initiation, with a median nadir platelet count of 41 × 109/L (IQR, 17 × 109/L to 64 × 109/L). Patients were treated with glucocorticoids (n = 106 [49.5%]), immune globulin (n = 39 [18.2%]), and thrombopoietin receptor agonists (n = 29 [13.6%]). Recovery occurred in 161 patients (75.2%) at a median of 2.3 weeks (IQR, 1.0-5.3). Of 76 patients rechallenged with ICIs, 23 (30.3%) developed recurrent ICI-ITP. ICI-ITP and its severity were associated with higher all-cause mortality, with a nearly threefold increase in risk among patients with severe ICI-ITP than those without ICI-ITP (adjusted hazard ratio, 2.96 [95% confidence interval, 2.14-4.08]). These findings establish ICI-ITP as a rare but clinically significant complication of ICI therapy, provide, to our knowledge, the first large-scale description of its risk factors and clinical course, and underscore the importance of timely recognition and management.

Abstract Wiskott-Aldrich syndrome (WAS), an X-linked disorder characterized by immunodeficiency, thrombocytopenia, autoimmunity, and malignancy, can be effectively treated with allogeneic hematopoietic cell transplantation (HCT). Older age at HCT and mismatched donors are known to affect overall survival (OS). However, the influence of specific clinical manifestations or WAS variant class on OS and factors associated with event-free survival (EFS) remain incompletely defined. We analyzed outcomes of 308 patients with WAS who underwent HCT at 37 institutions of the Primary Immune Deficiency Treatment Consortium from 1990 to 2018. With a median follow-up of 5.3 years, the 5-year OS and EFS were 87.2% and 79.7%, respectively. Age ≥5 years, donor type, and a pre-HCT history of severe infection had a negative impact on OS and EFS, whereas pre-HCT autoimmunity had no impact. Reduced-intensity regimens were associated with lower T-cell and myeloid donor chimerism, particularly when non–busulfan-based regimens were used. Low myeloid donor chimerism was associated with lower platelet counts. Mixed chimerism was not consistently associated with post-HCT autoimmunity. Patients with class I (exon 1-2 missense and intron 5 hot spot variants) and class II variants (all others) had similar pre-HCT clinical symptom severity and no difference in OS, EFS, or platelet recovery post-HCT. In conclusion, our study showed excellent long-term OS and EFS after HCT for WAS, highlighting the importance of early HCT, before the development of severe infections. We confirmed that HCT using busulfan-based conditioning was associated with improved donor chimerism and platelet recovery. This trial was registered at www.clinicaltrials.gov as NCT02064933.