Citations

Abstract Background Breast cancer chemoprevention is underutilized among high-risk women. We examined whether decision support could increase informed decision making. Methods We conducted a cluster randomized controlled trial to evaluate the effect of a patient-facing decision aid (RealRisks) and provider tool (BNAV) compared with standard education on the number of women with high-risk breast lesions making informed choices. Questionnaires were administered at baseline and 6 and 12 months. The primary outcome was chemoprevention informed choice (defined as adequate knowledge and attitudes congruent with decision) at 6 months. Secondary endpoints included breast cancer risk perceptions, worry, chemoprevention knowledge, decision conflict, and chemoprevention decision. Results Across 31 randomized sites, we enrolled 210 providers, who were primarily breast health specialists. Of these, 24 sites (14 intervention, 10 control) enrolled 412 patients. Among 287 patients evaluable for the primary outcome, there were no statistically significant differences in informed choice between the intervention and control arms at 6 months (35% vs 27%, respectively; P = .20) and 12 months (37% vs 25%, respectively; P = .05). At 6 months, women in the intervention compared with control arm were more likely to have accurate breast cancer risk perceptions (31% vs 21%, respectively; P = .03) and adequate chemoprevention knowledge (33% vs 23%, respectively; P = .04). At 12 months, 52% of women in the control and 50% in the intervention arm self-reported initiating chemoprevention. Conclusion Decision support led to modest improvements in accurate risk perceptions and chemoprevention knowledge but not informed choice. Relatively high chemoprevention uptake was achieved among women with high-risk breast lesions managed mainly by breast health specialists. Trial Registration NCT04496739, https://clinicaltrials.gov/study/NCT04496739?cond=NCT04496739&viewType=Card&rank=1

Abstract Background Acute hypoxemic and hypercapnic respiratory failure are among the most common reasons for ICU admission and need for invasive mechanical ventilation. Noninvasive respiratory support (NIRS) strategies—including high-flow nasal cannula (HFNC), noninvasive ventilation (NIV), and continuous positive airway pressure (CPAP)—may prevent intubation, improve outcomes, and reduce ICU utilization. However, there is uncertainty regarding optimal patient and modality selection, resulting in variable implementation. There are no clinical practice guidelines comprehensively addressing the use of the different noninvasive respiratory support strategies across the spectrum of acute respiratory failure. Objective To update and develop new evidence-based clinical practice recommendations informing noninvasive respiratory support use, including HFNC, NIV and CPAP, in adults with acute respiratory failure. Methods A multidisciplinary panel used the GRADE approach to address four PICO questions related to the use of NIRS for hypoxemic and hypercapnic respiratory failure, preoxygenation for intubation, and post-extubation respiratory support. Recommendations were informed by several systematic reviews and network meta-analyses. Results The panel made a strong recommendation for HFNC and a conditional recommendation for NIV or CPAP for adults with acute hypoxemic respiratory failure with close monitoring for the need for escalation of respiratory support, based primarily on effects on need for intubation. For acute hypercapnic respiratory failure, the panel made a strong recommendation for NIV to reduce mortality and need for invasive mechanical ventilation, and a conditional recommendation for HFNC only in patients with less severe hypercapnia and with mild acidemia (eg, pH > 7.25), provided that close monitoring and prompt escalation to NIV are available. The panel made a strong recommendation for HFNC or NIV for preoxygenation prior to endotracheal intubation to prevent peri-intubation hypoxemia. The panel also issued a risk-based recommendation, suggesting HFNC for low-risk patients and NIV for high-risk patients to reduce the need for re-intubation following extubation after critical illness. Conclusions Noninvasive respiratory support strategies are effective in improving outcomes in a range of clinical scenarios. We provide evidence-based recommendations, which can be further informed by patient risk, institutional capacity, and interface tolerance.

Abstract Background Age and sex influence the clinical expression of transthyretin (ATTR) amyloidosis, but limited evidence exists on their real-world impact across disease phenotypes. The prospective, multi-national MaesTTRo study, currently enrolling patients from the USA, Canada, the UK, Germany and Spain, provides a uniquely comprehensive opportunity to explore age- and sex-associated differences in routine practice. The aim of this analysis was to quantify the associations between these factors and diagnostic delay and cardiac findings. Methods Baseline data from 230 consecutively enrolled patients were analysed. Cohorts were stratified by age at diagnosis (<60 y, n = 45; ≥60 y, n = 185) and separately by sex (female n = 70; male n = 161). Clinical characteristics, laboratory values, echocardiographic parameters and Kansas City Cardiomyopathy Questionnaire (KCCQ-23) scores were compared descriptively. Additional data will be included in the presentation as enrollment continues. Results Younger patients exclusively expressed a hereditary genotype (100% vs 63%), and experienced a longer mean (+SD) diagnostic delay than older patients (48 ± 61.5 vs 40.9 ± 64.4 months). Cardiac involvement was markedly age-dependent: median NT-proBNP was 91.5 pg ml⁻¹ (IQR 48.5–307) in the <60 yrs group versus 1,393.5 pg ml⁻¹ (457–3,065) in the ≥60 yrs group. Older patients were more likely to experience New York Health Association (NYHA) class II–IV limitation than younger patients (88% vs 44%). Nonetheless, LV ejection fraction remained preserved in both cohorts (51 ± 14.8 vs 55.6 ± 9.3%). Older patients also reported a higher burden of cardiac symptoms (52% vs 33%). Patient-reported KCCQ scores were lower in the ≥60 yrs group vs <60 years (68.4 ± 22.3 vs 73.3 ± 27.4). Females were more often diagnosed with ATTRv (84% vs 63%) after longer delays (51.3 ± 80.9 vs 38.3 ± 54.6 months), despite a stronger family history (61% vs 34%), and had lower biomarkers (NT-proBNP: 589 pg ml⁻¹ [111–2,509] vs 1,220 pg ml⁻¹ [386–2,941]) and wall thickness (LV wall thickness >12 mm: 58% vs 73%), although there was no difference in LV mass index. Males reported better health status (KCCQ: 70.7 ± 22.2 vs 64.7 ± 24.4). Neurologic manifestations were common in both sexes (~70%), while musculoskeletal symptoms were more commonly reported in females (33% vs 23%). Conclusions Age and sex may independently modulate the diagnostic trajectory and cardiac presentation of ATTR amyloidosis. Advanced age and male sex are associated with more pronounced structural biomarker evidence of myocardial damage, whereas younger age and female sex are linked to delayed diagnosis of primarily hereditary ATTR amyloidosis with polyneuropathy and less cardiac involvement, especially when non-indexed echo measurements are used. These results underscore the need for age- and sex-specific approaches to prompt early clinical suspicion and diagnosis in order to enable treatment to mitigate disease progression.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.

Abstract Dermatomyositis is driven by overactivation of type I and II interferons and other proinflammatory cytokines that signal via the JAK-STAT pathway. We conducted a 12-week, open-label study of brepocitinib, an oral TYK2/JAK1 inhibitor, in five adults with severe cutaneous dermatomyositis. Treatment was associated with rapid, clinically meaningful improvement in cutaneous disease activity. Single-cell and spatial transcriptomic profiling of lesional skin showed marked suppression of interferon-responsive pathways and inflammatory cell states by week 4. Together with findings from a Phase 3 randomized trial in DM patients with skin and muscle involvement (VALOR, NCT05437263 ), these data support TYK2/JAK1 inhibition as a promising therapeutic strategy for DM.

Abstract INTRODUCTION Face identification algorithms have increased the risk of study participants being identified through different neuroimaging modalities. De‐facing algorithms can de‐identify neuroimages; however, none are validated in individuals with Down syndrome (DS) – a population at high risk of Alzheimer's disease and the focus of numerous Alzheimer's disease cohort studies. METHODS Overall, 37 adults with DS were parcellated using FreeSurfer before and after de‐facing with mri_reface . A group of neurotypically developed individuals balanced on age, sex, and magnetic resonance imaging scanner manufacturer served as controls. RESULTS De‐facing produced no effect on cortical thickness or volumetrics in adults with DS compared to controls or regional discrimination based on an area under the receiver operating characteristic curve analysis after correcting for multiple comparisons. DISCUSSION FreeSurfer‐derived volumetric and cortical thickness measures changed minimally following de‐facing with mri_reface in adults with DS and are unlikely to influence study outcomes. De‐facing should be considered prior to data sharing in studies of adults with DS.

ABSTRACT Background Most genomic studies of adult-type diffuse gliomas have focused on predominantly European ancestry populations, limiting the generalizability of molecular classifications and precision medicine approaches. We assembled a multi-institutional glioma cohort of diverse patients to investigate how germline ancestry, molecular subtypes, and mutational processes shape tumor biology and clinical outcomes. Methods We analyzed 1,102 adults with WHO 2021–classified diffuse gliomas (IDH-mutant, 1p/19q-codeleted oligodendroglioma; IDH-mutant astrocytoma; IDH-wildtype glioma) from seven U.S. institutions. Whole-exome sequencing (WES) of FFPE tumors identified somatic alterations and COSMIC SBS v3.2 mutational signatures. Genetic ancestry was estimated from WES using 1000 Genomes reference populations. Overall survival was assessed using Kaplan–Meier and multivariable models. Results The cohort included 66.9% European (EUR), 21.1% Admixed American/Hispanic (AMR), 10.3% Admixed African (AFR), and 1.6% Asian (AS) ancestry. Survival followed expected molecular hierarchy (median overall survival: oligodendroglioma 15.7 years, astrocytoma 10.6 years, IDH-wildtype glioma 1.9 years). Within oligodendroglioma, AMR patients showed improved survival versus EUR (HR 0.67, 95% CI 0.48–0.94; p=0.011), with similar trends across subtypes. Somatic profiling confirmed canonical subtype-defining alterations and revealed higher ATRX alterations in AFR and AMR IDH-wildtype tumors compared with EUR. ATRX alterations were associated with improved survival only in AFR (p=0.003). Mutational signature analysis identified subtype-specific signatures, including therapy-associated signatures. Chemotherapy-related signatures were more frequent in EUR and AMR than in AFR. Conclusions This ancestrally diverse glioma cohort confirms established molecular classifications and identifies ancestry-associated differences in survival, somatic alterations, and mutational processes, indicating the critical need for broad representation to inform precision neuro-oncology. Key Points A multi-institutional glioma cohort validates subtype and survival patterns across ancestries. Therapy-associated mutational signatures differ by ancestry, suggesting distinct treatment-related mutational processes. Admixed American patients show improved survival, particularly in oligodendroglioma. Importance of the Study Most genomic studies of adult-type diffuse glioma have focused on populations of predominantly European ancestry which limits the ability to examine variation in tumor biology and clinical outcomes across populations. In this study, we assembled one of the largest ancestrally diverse cohorts of molecularly characterized adult diffuse gliomas, integrating germline ancestry inference with tumor whole-exome sequencing and mutational signature analysis. We confirm that established molecular classifications and survival hierarchies remain robust across ancestry groups. However, we also identified ancestry-associated differences in survival within specific tumor subtypes, higher ATRX alteration frequencies in African American and admixed American patients with IDH-wildtype tumors, and variation in therapy-associated mutational signatures across ancestry groups. These findings highlight the importance of incorporating population differences into genomic studies of glioma and provide a resource for future multi-ancestry investigations of glioma risk, tumor evolution, and treatment response, ultimately supporting more inclusive precision neuro-oncology.

Since its US Food and Drug Administration approval in 2016, magnetic resonance–guided focused ultrasound (MRgFUS) thalamotomy has grown into one of the procedures of choice among patients with essential tremor (ET). Approved applications for the procedure have expanded over time from unilateral thalamotomy to treat ET and Parkinson disease tremor to bilateral staged thalamotomy for ET. As the procedure expands to healthcare environments beyond large academic centers, guidance is required to ensure that the responsible clinicians are appropriately trained to undertake this operative procedure. Although multidisciplinary movement disorder teams are important for the optimal management of patients, MRgFUS lesions are inherently surgical interventions. Neurosurgeons are trained to evaluate these patients, consider surgical alternatives and conduct these operations, particularly after completing a fellowship in the subspecialty of stereotactic and functional neurosurgery. At present, all high-level evidence regarding the safety and efficacy of MRgFUS lesions to treat movement disorders derives from procedures performed by neurosurgeons, so those results may not be generalizable to other physicians. Based on these considerations and potential liability issues, the American Society for Stereotactic and Functional Neurosurgery, which acts as the joint section representing the field of stereotactic and functional neurosurgery on behalf of the Congress of Neurological Surgeons and the American Association of Neurological Surgeons, puts forth this position statement that only neurosurgeons appropriately trained to conduct functional neurosurgery procedures should conduct MRgFUS surgical lesions.

Anesthesiologists are sometimes slow to adopt new technologies despite proven benefits. The authors undertook to understand community anesthesiologists’ perspectives and practices regarding neuromuscular monitoring and reversal. Specifically, they sought to generate evidence for why some guidance-congruent practices— i.e. , quantitative train-of-four monitoring, ulnar nerve stimulation, and evidence-based reversal—remain inconsistently adopted despite robust evidence of patient harm from residual neuromuscular blockade and decades of effort to improve adoption. Thirty-six U.S. community anesthesiologists underwent a detailed qualitative cognitive interview. Analysis revealed four clinician archetypes whose neuromuscular monitoring and reversal practices are shaped by identifiable individual and practice-related biases and device- and system-level barriers. Perceived confidence in sugammadex efficacy was frequently cited as a rationale for omitting quantitative neuromuscular monitoring. The authors propose a research and implementation action agenda to close the evidence-to-practice gap in neuromuscular monitoring and reversal.