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Changes in sleep can impact cognitive and emotional functioning and may contribute to depression. The current longitudinal study included a high-risk sample of adolescents and young adults with depression and/or suicidal thoughts and behaviors who were undergoing intensive outpatient treatment programs. We examined changes in sleep throughout treatment and whether daily changes in sleep impacted next-day depression through altered affective reactivity to interpersonal situations. Participants (N = 198, ages 13-23, 82% White, 76% female sex at birth) were recruited from intensive treatment programs for depression and suicide risk. Participants wore an actigraph and completed daily ratings of depression, sleep, and positive and negative reactivity to interpersonal events throughout treatment (M = 60 days, SD = 22 days). Clinicians rated weekly depression severity. Multilevel models tested changes in sleep and depression throughout treatment and examined daily relationships between total sleep time (TST), next-day depression, and affective reactivity. Multilevel mediation tested whether increased affective reactivity mediated daily relationships between TST and depression. Throughout treatment, self-reported TST increased (b = 0.01; p < .001) and daily self-reported depression severity decreased (b = -0.06; p = .02), although actigraphy-assessed TST did not change (b = 0.01; p = .16). Sleeping less than usual on diaries (b = -0.29; p = .02) but not actigraphy when controlling for covariates (b = -0.19; p = .18) was related to worse next-day depression. Greater clinician-rated depression severity amplified the effects of short TST on next-day depression for both diary (b = -0.22; p = .03) and actigraphy-assessed TST (b = -0.32; p = .01). Increased negative affectivity statistically mediated daily associations between short TST and increased next-day depression (indirect effects: B = 0.03; p < .001). Short sleep may contribute to depression through increased negative affectivity to interpersonal events. Future work should test whether sleep interventions in high-risk samples hastens symptom improvement.

Suicidal ideation (SI) is dynamic and closely tied to social context, yet most work treats these links as static or unidirectional. We tested a transactional account whereby SI and interpersonal appraisals co-evolve over hours and examined personality trait moderators. Young adults receiving behavioral treatment who endorsed SI and/or suicidal behavior in the past four months (N=140) completed 21 days of ecological momentary assessment (7 prompts/day). At each prompt, participants reported current SI and rated interpersonal strain (rejection/criticism/exclusion/stress) and enrichment (enjoyment/connection/meaning/support) from interpersonal interactions. Dynamic structural equation models estimated five features of SI: reactivity, generation, inertia, instability, and intensity. Negative Affectivity, Detachment, and Disinhibition trait domains were tested as moderators. Interpersonal strain was associated with higher subsequent SI (reactivity), and higher SI was associated with higher subsequent strain (generation). Likewise, interpersonal enrichment was associated with lower subsequent SI, and higher SI was associated with lower subsequent enrichment. Detachment uniquely moderated these dynamic processes: higher Detachment was associated with larger SI increases after strain and larger SI decreases after enrichment, as well as higher SI intensity and instability, higher strain, and lower enrichment. Facet models indicated that Anhedonia concentrated Detachment-related risk (higher mean SI, higher strain intensity and instability, lower enrichment, higher SI inertia and instability, and stronger reactivity to strain/enrichment). In contrast, Intimacy Avoidance was associated with lower strain instability and lower enrichment intensity. Negative Affectivity and Disinhibition did not moderate dynamic paths. SI was linked to interpersonal appraisals through short-cycle, bidirectional associations that were moderated by Detachment, especially its Anhedonia facet.

Mary L. Phillips, MD, MD (Cantab), Pittsburgh Foundation-Emmerling Endowed Chair in Psychotic Disorders and Distinguished Professor of Psychiatry, Bioengineering, and Clinical and Translational Science at the University of Pittsburgh, is one of the foremost translational affective neuroscientists of her generation. Elected to the National Academy of Medicine in 2024, recipient of the 2024 Society of Biological Psychiatry Gold Medal Award, the 2014 ACNP Joel Elkes Award for Outstanding Clinical Research, and the 2017 Brain and Behavior Research Foundation Colvin Prize for Outstanding Achievement in Mood Disorders Research; and the author of more than 400 peer-reviewed publications recognized by Clarivate Analytics as Highly Cited Research from 2018 to 2021, she has built a research program that deploys multimodal neuroimaging to map prefrontal-striatal-limbic circuitry abnormalities underlying bipolar disorder, with the overarching goal of converting circuit-level findings into objective biomarkers for earlier diagnosis, risk identification in youth, and targeted neuromodulation and metabolic interventions. In this Genomic Press Interview, Phillips traces a scientific trajectory shaped by intellectual independence and exceptional mentorship, from a pivotal zoology year at Cambridge that introduced her to the Aplysia neural network model, through psychiatry training at the Maudsley Hospital and Institute of Psychiatry in London, to her emergence as a leader in biological psychiatry at the University of Pittsburgh under the mentorship of David Kupfer. She discusses her foundational work demonstrating that abnormal face emotion processing and emotional reactivity serve as behaviorally measurable windows into prefrontal-limbic circuit dysfunction in bipolar disorder, her current work identifying neural circuit biomarkers of mania risk, and her translational agenda examining neurodevelopmental trajectories from infancy through young adulthood to detect risk dimensions before clinical threshold is reached. She also describes the three Phillips Centers she directs: CNCTI-P (Interventional Psychiatry), CENTRIM-BD (Metabolic Psychiatry), and CRTDAN (Translational and Developmental Neuroscience), which together instantiate a comprehensive precision psychiatry infrastructure at the University of Pittsburgh. She has mentored more than 100 trainees across her career, including 15 NIH K awardees, and holds presidential or council roles in major international neuroscience societies. She reflects with candor on gender equity in academic neuroscience, as recognized by the 2023 ACNP Women's Advocacy Award and her inclusion in Research.com's Best Female Scientists in the World for 2023 and 2024, and on her vision for a precision psychiatry grounded in individual-level neural circuit data.

PALB2 plays a crucial role in DNA repair by interacting with BRCA1 and BRCA2. To clarify the clinicopathological impact of somatic PALB2 variants, we analyzed tumor DNA extracted from formalin-fixed, paraffin-embedded (FFPE) breast cancer specimens from 81 patients. Targeted next-generation sequencing identified 1 514 variants, including 84 pathogenic or likely pathogenic variants and 9 genes with high mutation frequency; 2 deleterious somatic PALB2 variants were detected in 33% of samples. To explore transcriptional effects, we analyzed publicly available METABRIC mRNA expression data and found that elevated PALB2 mRNA levels were significantly associated with ER-/PR- tumors and poorer survival outcomes. High PALB2 expression remained an independent predictor of shorter overall survival and relapse-free survival. These findings highlight the clinical importance of somatic PALB2 mutations and the prognostic value of PALB2 expression in breast cancer.

Introduction: Endothelial dysfunction contributes to the pathogenesis of acute kidney injury (AKI) and multi-organ dysfunction in critical illness. We previously identified higher angiopoietin-2 (Angpt2), a marker of endothelial activation, as a risk factor for adverse outcomes in septic patients. We aimed to validate these findings in an independent ARDS cohort. Methods: We analyzed data from the EDEN trial, which randomized 1000 ARDS patients to trophic or full enteral feeding. Baseline plasma Angpt2 was available for 889 patients. Associations between higher Angpt2 and persistent severe AKI were assessed by multivariable regression adjusted for age, gender, and APACHE III. Secondary outcomes included any AKI, stage 2/3 AKI, acute kidney disease (AKD), hepatic dysfunction (bilirubin >2.0 mg/dL), thrombocytopenia (platelets < 100 x10^9/L), 28-day organ failure-free days, ARDS severity, and mortality. Analyses were stratified by sepsis status. Results: In all ARDS patients, higher plasma Angpt2 levels were independently associated with the development persistent severe AKI (OR 2.2, 95% CI 1.4–3.5, p=0.001), development of any AKI in patients enrolled within 24 hours of admission (OR 4.7, 1.5–15.7, p=0.009), stage 2/3 AKI in the first 3 days of randomization (OR 2.7, 95% CI 1.8–3.9, p< 0.001), AKD (OR 2.95, 1.9–4.8, p< 0.001), and fewer 28-day organ failure–free days (IRR 0.86, 0.82–0.90, p< 0.001). For extra-renal organ dysfunction, elevated Angpt2 was associated with hepatic dysfunction (OR 1.8, 1.2–2.8, p=0.003) and thrombocytopenia (OR 1.8, 1.3–2.5, p< 0.001) specifically in patients with sepsis-associated ARDS, but these associations were not observed in non-septic ARDS. Angpt2 was not significantly associated with ARDS severity or mortality. Conclusions: Elevated Angpt2 at enrollment was associated with persistent severe AKI, AKD, and fewer organ failure-free days in all patients with ARDS. The association between Angpt2 and hepatic dysfunction or thrombocytopenia was specific to patients with sepsis-associated ARDS. These findings reinforce the central role of endothelial dysfunction in sepsis-related multi-organ dysfunction and suggest Angpt2 as a promising biomarker and potential therapeutic target in critically ill patients.

While primary invasive lobular carcinoma (ILC) is well characterized, metastatic ILC remains understudied. Within the post-mortem tissue donation programs, UPTIDER (Belgium) and Hope for Others (USA), we first aimed to explore intra-patient heterogeneity of key prognostic and predictive markers (stromal tumor-infiltrating lymphocytes (sTIL), estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and KI67). Secondly, we compared detection of the metastases by pathology on autopsy samples versus pre-mortem imaging. In total, 306 metastases from 12 patients were collected at autopsy (median: 27 per patient). Both primary tumors (n = 15) and metastases (n = 232) had low sTIL levels, with a median of 2% (range: 0.67-6.67%) and 0.67% (range: 0-13.33%), respectively. Regression models showed lower ER- and PR-expression in metastases (respectively, n = 265 and n = 64) compared to primary tumors (both p < 0.01). KI67 was significantly higher in metastases (n = 262, p = 0.02). HER2-low metastases were found in all but one patient although in varying proportion of metastases (range: 7.5-100%). Central radiology and pathology review had a median concordance of 78% at organ level (range: 33.33-100%) and 71% at patient level (range: 55.88-85.29%). Our findings suggest that a single metastatic biopsy has great limitations to guide treatment and that more adequate methods are needed to detect and monitor ILC metastases.

Docosahexaenoic acid (DHA) is an omega-3 fatty acid with important roles in inflammation resolution. We tested the impact of DHA supplementation on monocyte exhaustion, an immune memory state contributing to chronic inflammation and immunosuppression following sepsis. Ex vivo sepsis modeling was performed with C57BL/6 mouse bone marrow monocytes (BMMCs) and peripheral blood mononuclear cells (PBMCs) from septic patients. BMMCs stimulated with lipopolysaccharide (100 ng/mL) for 5 days were supplemented with 60 µM DHA. Septic patient PBMCs were treated for 24 h with 0, 15, 30, 45, or 60 µM DHA. Monocyte exhaustion was assayed by flow cytometry, qRT-PCR, and cytometric arrays. DNA methylation changes linked to exhaustion memory were measured by bisulfite pyrosequencing. Western blots were performed to link DHA treatment to altered cell signaling pathways in septic monocytes. DHA supplementation suppresses the expression major exhaustion regulators CD38 and PD-L1 and dampens inflammatory cytokine transcription. These effects were mechanistically linked to STAT1/3 inhibition and accompanied by altered DNA methylation at immune regulators. DHA treatment also reduced CD157 cell surface levels and CCL2 secretion, both contributors to tissue invasion and injury during sepsis. Our results support the therapeutic application of DHA for the prevention of chronic immune dysfunction in sepsis survivors.

Abstract Background: With myelosuppressive chemotherapy still extensively used and many antibody drug conjugates showing similar cytotoxic properties, complete blood counts (CBCs) continue to be a cornerstone of clinical decision making in cancer therapy. Historically, the need for in-clinic testing has presented logistical challenges for patients, reduced the efficiency of service delivery and delayed identification of complications such as febrile neutropenia, anemia and thrombocytopenia. To address this, the world’s first CBC analyzer has been developed for accessible use by cancer patients in the home (Liberty). The analyzer enables convenient patient self-testing from a single drop of capillary blood (16µL) through use of microfluidic consumables, centrifugation and fluorescent spectroscopy. The results are shared remotely to healthcare professional dashboards directly from the analyzer, providing the opportunity for more convenient and frequent CBC monitoring. Research Population and Methods: A cohort of breast cancer patients receiving systemic anti-cancer therapy (SACT) were selected for a qualitative sub-study from a larger multi-center, multi-indication comparator study evaluating at-home self-testing with Liberty versus standard of care venous blood testing at a health center. The primary endpoint was preference for at-home self-testing with Liberty versus standard of care venous blood testing at a health center. The secondary endpoint was healthcare resource utilisation across both monitoring pathways. Exploratory endpoints included patient experience of training, self-testing, ease of use and recommendation to other patients. Primary and exploratory endpoints were determined via questionnaires issued after at least two tests had been completed. Questionnaires asked participants their preference for self-testing compared to standard testing and to rate on a scale of 1-5, their experience of training, self-testing, acceptability of testing cadence, sense of control, perceived time savings, overall patient experience, likelihood to recommend Liberty to other patients and any additional comments. Results: Patients receiving a range of SACT (paclitaxel, ribociclib, abemaciclib, trastuzumab deruxtecan, sacituzumab govitecan) were recruited over 9 months to this sub-study (n=10). The mean score on participant preference for self-testing with Liberty versus the standard of care was 4.2/5 with 5 representing a strong preference for self-testing with Liberty (median 4.5). Self-testing with Liberty was shown to reduce the need for routine in-clinic blood tests by 96%. Scored out of a maximum of 5, the mean patient score for patient training was 5 (median: 5), experience of self-testing with Liberty 4.9 (median: 5), perceived sense of control 4 (median: 4.5), willingness to keep testing at the defined cadence 4.6 (median: 5), perceived time savings 4.6 (median: 5), overall experience 4.6 (median: 5) and likelihood to recommend Liberty to other patients was 4.9 (median: 5). No adverse events were reported. Conclusions: Liberty was the preferred pathway for blood monitoring and may help to reduce the significant burden faced by patients and healthcare systems for cancer treatment. Subsequent real-world usage of Liberty has demonstrated reductions of up to 91% of routine in-clinic blood tests and shown its utility in avoiding unnecessary emergency room attendance. Citation Format: S. Howell, S. Taylor, D. Ramanujam, T. Basey-Fisher, A. Brufsky. At-home complete blood count monitoring: enhancing care pathways and improving patient experience [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-05-05.