Bidirectional modulation of negative emotional states by parallel genetically-distinct basolateral amygdala pathways to ventral striatum subregions.

Distinct basolateral amygdala (BLA) cell populations influence emotional responses in manners thought important for anxiety and anxiety disorders. The BLA contains numerous cell types which can broadcast information into structures that may elicit changes in emotional states and behaviors. BLA excitatory neurons can be divided into two main classes, one of which expresses Ppp1r1b (encoding protein phosphatase 1 regulatory inhibitor subunit 1B) which is downstream of the genes encoding the D1 and D2 dopamine receptors (drd1 and drd2 respectively). The role of drd1+ or drd2+ BLA neurons in learned and unlearned emotional responses is unknown. Here, we identified that the drd1+ and drd2+ BLA neuron populations form two parallel pathways for communication with the ventral striatum. These neurons arise from the basal nucleus of the BLA, innervate the entire space of the ventral striatum, and are capable of exciting ventral striatum neurons. Further, through three separate behavioral assays, we found that the drd1+ and drd2+ parallel pathways bidirectionally influence both learned and unlearned emotional states when they are activated or suppressed, and do so depending upon where they synapse in the ventral striatum - with unique contributions of drd1+ and drd2+ circuitry on negative emotional states. Overall, these results contribute to a model whereby parallel, genetically-distinct BLA to ventral striatum circuits inform emotional states in a projection-specific manner.

Semantic-to-autobiographical memory priming occurs when stimuli are presented below the threshold of awareness.

A number of studies have now shown that general information processing causes the activation of memories in the autobiographical memory system. These studies have shown that general processing of words, sounds, objects, or pictures primes autobiographical memories on voluntary and involuntary autobiographical memory tasks (the Crovitz cue-word task and the vigilance task). Deemed semantic-to-autobiographical memory priming, our goal in the current study was to demonstrate that this form of priming causes the unconscious activation of autobiographical memories (autobiographical automaticity) at the point of priming. Participants named words under subliminal and supraliminal conditions and then received a test of priming (the vigilance task). The results showed that words that were processed below the threshold of awareness were equally likely as words processed above the threshold of awareness to prime the production of involuntary autobiographical memories on the vigilance task. The results support the idea that autobiographical memory activations in semantic-to-autobiographical priming is both unintentional and unconscious.

Semantic-to-autobiographical memory priming: the role of stimulus processing.

It is now well established that semantic processing can cause the activation of memories in the autobiographical memory system. Studies have shown that semantic processing of words, sounds, objects, or pictures primes autobiographical memories on voluntary and involuntary autobiographical memory tasks (the Crovitz cue-word task and the vigilance task). Known as semantic-to-autobiographical memory priming, our goal in the current study was to demonstrate that this form of priming occurs under different forms of processing (i.e., shallow versus deep), and that some forms of processing (e.g., visual mental imagery) may enhance priming in this domain. In Experiment 1, equivalent semantic-to-autobiographical priming was obtained on the vigilance task following shallow (e-counting) and deep (meaning judgements) word processing. In Experiment 2, word meaning judgements were compared to visual imagery of word meanings, and visual imagery led to more semantic-to-autobiographical priming on the vigilance task than meaning judgements. The results of these experiments support the idea that semantic-to-autobiographical priming occurs under a wide range of processing conditions, supporting a ubiquity claim, with some conditions producing more priming than others, and they further support the idea that this form of may play an important role in the production of involuntary memories in everyday life.

12,13-diHOME Promotes Inflammatory Macrophages and Epigenetically Modifies Their Capacity to Respond to Microbes and Allergens.

Elevated infant fecal concentrations of the bacterial-derived lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) increase the risk for childhood atopy and asthma. However, the mechanisms by which this lipid contributes to disease development are largely unknown. We hypothesized that macrophages, which are key to both antimicrobial and antigen responses, are functionally and epigenetically modified by 12,13-diHOME leading to short- and long-term dysfunction with consequences for both antimicrobial and antigenic responses. Macrophages exposed to 12,13-diHOME are skewed toward inflammatory IL-1ß highCD206low cells, a phenomenon that is further amplified in the presence of common microbial-, aero-, and food-allergens. These IL-1ß highCD206low macrophages also exhibit reduced bacterial phagocytic capacity. In primary immune cell coculture assays involving peanut allergen stimulation, 12,13-diHOME promotes both IL-1ß and IL-6 production, memory B cell expansion, and increased IgE production. Exposure to 12,13-diHOME also induces macrophage chromatin remodeling, specifically diminishing access to interferon-stimulated response elements resulting in reduced interferon-regulated gene expression upon bacterial lipopolysaccharide stimulation. Thus 12,13-diHOME reprograms macrophage effector function, B-cell interactions and promotes epigenetic modifications that exacerbate inflammatory response to allergens and mutes antimicrobial response along the interferon axis. These observations offer plausible mechanisms by which this lipid promotes early-life pathogenic microbiome development and innate immune dysfunction associated with childhood allergic sensitization.

Validation of the Interpersonal Relationships in Eating Disorders (IR-ED) Scale in an Eating Disorder Sample.

OBJECTIVE: Interpersonal problems have been identified as a plausible mechanism underlying the onset and maintenance of eating disorders. The Interpersonal Relationships in Eating Disorders (IR-ED) scale is the first eating disorders-specific measure of interpersonal problems, which was developed in a nonclinical sample. The aims of the current study were to (a) confirm the factor structure of the IR-ED within a large clinical sample, (b) investigate measurement invariance of the IR-ED across nonclinical and clinical samples, (c) examine the convergent validity of the IR-ED using a generic measure of interpersonal problems, and (d) investigate the incremental clinical utility of the IR-ED in uniquely predicting eating disorder symptomatology. METHOD: Treatment-seeking individuals (N = 437) completed the IR-ED at their initial assessment appointment at a specialist eating disorder outpatient service. RESULTS: A multiple-group confirmatory factor analysis supported an invariant bifactor structure comprising a general interpersonal problems factor and two group factors-Avoidance of Body Evaluation and Food-Related Interpersonal Tension. Convergent validity was demonstrated by a large, statistically significant correlation with a generic measure of interpersonal problems (r = 0.62, p < 0.001). A series of structural equation models further revealed unique incremental predictive utility of the IR-ED for eating disorder symptomatology. DISCUSSION: The IR-ED has strong psychometric properties and may prove beneficial in the assessment, formulation, and treatment of eating-specific interpersonal problems among patients with eating disorders.

Pembrolizumab-induced vasculitis demonstrated by FDG-PET/CT.

A 76-year-old man with a history of malignant pleural mesothelioma treated with pembrolizumab underwent FDG-PET/CT for restaging. The images demonstrated FDG uptake overlying the right hepatic and splenic artery, which were new from the previous FDG-PET/CT 2.5 years prior before the patient started pembrolizumab, suspicious for vasculitis. A follow-up MRI supported the diagnosis with evidence of celiac, splenic, common hepatic, and right hepatic artery involvement. Pembrolizumab was discontinued and the patient received a short course of oral glucocorticoids. Subsequent FDG-PET/CT performed 14 months after initiation of treatment for vasculitis demonstrated resolution of vasculitis. Immune checkpoint inhibitors can cause vasculitis, which can be recognized on FDG-PET/CT and lead to appropriate treatment.

Dietary supplementation with grape seed extract from Vitus vinifera prevents suppression of GABAergic protein expression in female Sprague Dawley trigeminal ganglion in a model of chronic temporomandibular joint disorder.

OBJECTIVE: To investigate cellular changes in protein expression in the trigeminal ganglion in an established preclinical chronic model of temporomandibular joint disorder (TMD) in response to grape seed extract (GSE) supplementation based on its beneficial use in preclinical chronic orofacial pain models. DESIGN: Three experimental conditions included female Sprague-Dawley rats as naïve controls, and animals subjected to neck muscle inflammation and prolonged jaw opening with and without daily supplementation of GSE in the drinking water prior to inflammation. Changes were evaluated in mechanical sensitivity to von Frey filaments and protein expression in the trigeminal ganglion of animals 14 days post jaw opening. RESULTS: Calcitonin-gene related peptide and protein kinase A, proteins positively associated with peripheral sensitization and enhanced nociception, did not show elevated expression at day 14 in the model compared to naïve or GSE supplemented animals. However, neuronal levels of glutamate decarboxylase (GAD) 65/67, which are enzymes responsible for the synthesis of the inhibitory neurotransmitter GABA that functions to suppress neuronal excitability, were significantly decreased on day 14 post jaw opening. Similarly, a significant decrease in neuronal expression of the GABA receptor subunits GABAB1 and GABAB2, but not GABAA, was observed in the TMD model. Importantly, GSE prevented suppression of GAD 65/67 and GABAB subunits, maintaining levels similar to naïve animals. CONCLUSION: Results from our study provide evidence of the downregulation of inhibitory GABAergic proteins in trigeminal ganglion neurons in a preclinical chronic TMD model and the benefits of GSE supplementation in preventing their suppression and maintaining normal levels.

The role of immune cells in resistance to oncolytic viral therapy.

Resistance to treatment poses a major challenge for cancer therapy, and oncoviral treatment encounters the issue of viral resistance as well. In this investigation, we introduce deterministic differential equation models to explore the effect of resistance on oncolytic viral therapy. Specifically, we classify tumor cells into resistant, sensitive, or infected with respect to oncolytic viruses for our analysis. Immune cells can eliminate both tumor cells and viruses. Our research shows that the introduction of immune cells into the tumor-virus interaction prevents all tumor cells from becoming resistant in the absence of conversion from resistance to sensitivity, given that the proliferation rate of immune cells exceeds their death rate. The inclusion of immune cells leads to an additional virus-free equilibrium when the immune cell recruitment rate is sufficiently high. The total tumor burden at this virus-free equilibrium is smaller than that at the virus-free and immune-free equilibrium. Therefore, immune cells are capable of reducing the tumor load under the condition of sufficient immune strength. Numerical investigations reveal that the virus transmission rate and parameters related to the immune response significantly impact treatment outcomes. However, monotherapy alone is insufficient for eradicating tumor cells, necessitating the implementation of additional therapies. Further numerical simulation shows that combination therapy with chimeric antigen receptor (CAR T-cell) therapy can enhance the success of treatment.

Macrophage subtypes inhibit breast cancer proliferation in culture.

Macrophages are a highly plastic cell type that adopt distinct subtypes and functional states depending on environmental cues. These functional states can vary wildly, with distinct macrophages capable of displaying opposing functions. We sought to understand how macrophage subtypes that exist on two ends of a spectrum influence the function of other cells. We used a co-culture system with primary human macrophages to probe the effects of macrophage subtypes on breast cancer cell proliferation. Our studies revealed a surprising phenotype in which both macrophage subtypes inhibited cancer cell proliferation compared to cancer cells alone. Of particular interest, using two different proliferation assays with two different breast cancer cell lines, we showed that differentiating macrophages into a "pro-tumor" subtype inhibited breast cancer cell proliferation. These findings are inconsistent with the prevailing interpretation that "pro-tumor" macrophages promote cancer cell proliferation and suggest a re-evaluation of how these interpretations are made.

Theranostics in Neuroendocrine Tumors.

ABSTRACT: Neuroendocrine tumors (NETs) are rare tumors that develop from cells of the neuroendocrine system and can originate in multiple organs and tissues such as the bowels, pancreas, adrenal glands, ganglia, thyroid, and lungs. This review will focus on gastroenteropancreatic NETs (more commonly called NETs) characterized by frequent somatostatin receptor (SSTR) overexpression and pheochromocytomas/paragangliomas (PPGLs), which typically overexpress norepinephrine transporter. Advancements in SSTR-targeted imaging and treatment have revolutionized the management of patients with NETs. This comprehensive review delves into the current practice, discussing the use of the various Food and Drug Administration-approved SSTR-agonist positron emission tomography tracers and the predictive imaging biomarkers, and elaborating on 177Lu-DOTATATE peptide receptor radionuclide therapy including the evolving areas of posttherapy imaging practices and peptide receptor radionuclide therapy retreatment. SSTR-targeted imaging and therapy can also be used in patients with PPGL; however, this patient population has demonstrated the best outcomes from norepinephrine transporter-targeted therapy with 131I-metaiodobenzylguanidine. Metaiodobenzylguanidine theranostics for PPGL will be discussed, noting that in 2024 it became commercially unavailable in the United States. Therefore, the use and reported success of SSTR theranostics for PPGL will also be explored.

Sleep quality differences among caregivers for persons living with and without dementia.

OBJECTIVES: This study examined the relationship between caring for a person with/without dementia and caregiver sleep quality, and analyzed the extent to which perceived benefits of caregiving and assessments of caregiver-recipient relationship quality explain the relationship between care recipient dementia status and caregiver sleep quality. METHOD: Data were analyzed from caregivers for persons with no or probable dementia who participated in the 2017 National Study of Caregiving (NSOC) and National Health and Aging Trends Study. Caregiver sleep quality was measured using NSOC time diary interview. Perceptions of caregiving and relationship quality were assessed using 4-item surveys. We used multivariable logistic regressions to examine the association between care recipient dementia status and caregiver sleep quality controlling for covariates. RESULTS: The sample consisted of 1,374 caregivers (mean age = 62.3, SD = 14, 68.3% women, 69.4% non-Hispanic White). In multivariable models adjusting for caregiver and care recipient characteristics, being a caregiver for someone with dementia was associated with 23% lower odds of reporting "excellent/very good" sleep quality (OR: 0.77, 95%CI: 0.61-0.98, p = 0.032). Greater perception of caregiving benefits was associated with 8% greater odds of "excellent/very good" sleep quality (AOR: 1.08, 95%CI: 1.02-1.15, p = 0.013), but did not explain the relationship between dementia and caregiver sleep quality. Positive ratings of relationship quality explained the relationship between care recipient dementia status and caregiver sleep quality (AOR: 0.82, 95%CI: 0.65-1.05, p = 0.12). CONCLUSION: Improving assessments of relationship quality and amplifying perceptions of caregiving benefits may reduce disparities in sleep quality between caregivers of persons living with or without dementia.

PET Imaging of Metabolism, Perfusion, and Hypoxia: FDG and Beyond.

ABSTRACT: Imaging glucose metabolism with [18F]fluorodeoxyglucose positron emission tomography has transformed the diagnostic and treatment algorithms of numerous malignancies in clinical practice. The cancer phenotype, though, extends beyond dysregulation of this single pathway. Reprogramming of other pathways of metabolism, as well as altered perfusion and hypoxia, also typifies malignancy. These features provide other opportunities for imaging that have been developed and advanced into humans. In this review, we discuss imaging metabolism, perfusion, and hypoxia in cancer, focusing on the underlying biology to provide context. We conclude by highlighting the ability to image multiple facets of biology to better characterize cancer and guide targeted treatment.

Considerations for effective dissemination of evidence-based early intervention approaches.

LAY ABSTRACT: Dissemination, or the widespread sharing of information, is important for moving research evidence into community practice. Early intervention programs for young autistic children have not yet been widely disseminated to the early childhood workforce. This letter describes factors that may support or prevent dissemination to community-based settings, such as packaging and branding early intervention approaches. We argue that an increased focus on dissemination research is needed.

Outcomes of Human Leukocyte Antigen-Matched Related Donor and Haploidentical Allogeneic Hematopoietic Cell Transplantation Recipients by Immune Profiles of Recipients and Donors.

Haploidentical (Haplo) allogeneic HCTs (alloHCT) have been used more frequently over the last decade as survival is similar to HLA-matched related donor (MRD) alloHCTs. We aimed to identify donor and recipient immune signatures before alloHCT that are associated with clinically meaningful outcomes in MRD vs Haplo alloHCT recipients. This retrospective cohort study of 165 MRD (n = 132) and Haplo (n = 33) alloHCT recipients and their related donors between 2007-2019 with paired peripheral blood samples immunophenotyped for T-cell, B-cell, NK cell and dendritic cell (DC) subsets. Immune cells were quantified before alloHCT in donors and recipients; calculations of immune cell ratios were classified as high, intermediate, and low and analyzed with alloHCT outcomes. Haplo donors were younger than MRD donors (median: 35 vs 51 years), whereas Haplo recipients were older than MRD recipients (median: 68 vs 54 years), were more likely to have a Karnofsky Performance Score ≤ 70 (76% vs 57%), 3+ comorbidities (54% vs 47%), and were in complete remission prior to alloHCT (58% vs 42%). In MRD alloHCT, a lower ratio of CD4+ to CD8+ effector memory cells in the donor was associated with lower 4-yr overall survival (OS; 25% vs 61%; P = .009), lower 4-yr progression free survival (PFS; 25% vs 58%; P = .014) and higher incidence of 1-yr transplant-related mortality (TRM; 39% vs 7%; P = .009) in recipients. A higher ratio of CD8+ effector memory to total NK cells measured in MRD recipients was associated with a higher incidence of grade II-IV aGvHD (63% vs 37%; P = .004) but was not statistically significant for III-IV aGvHD (23% vs 12%). In Haplo alloHCT, a lower ratio of total T-regulatory to CD4+ central memory cells in the donor was associated with lower 4-yr PFS (22% vs 60%; P = .0091). A higher ratio of CD4+ effector memory to CD8+ effector memory cells measured in Haplo recipients pre-alloHCT was associated with lower 4-yr OS (25% vs 88%; P = .0039). In both MRD and Haplo recipients, a higher ratio of CD4+ naïve to CD4+ central memory cells was associated with a higher incidence of grade II-IV aGvHD (64% vs 38%; P = .04). Evaluation of pre-alloHCT immune signatures of the donor and recipient may influence clinically meaningful patient outcomes in both MRD and Haplo transplants.

Abbreviated Breast MRI for Supplemental Screening in Patients With Dense Breasts: Comparison of Baseline Versus Subsequent-Round Examinations.

BACKGROUND. Abbreviated breast MRI (AB-MRI) achieves a higher cancer detection rate (CDR) than digital breast tomosynthesis when applied for baseline (i.e., first-round) supplemental screening of individuals with dense breasts. Limited literature has evaluated subsequent (i.e., sequential) AB-MRI screening rounds. OBJECTIVE. This study aimed to compare outcomes between baseline and subsequent rounds of screening AB-MRI in individuals with dense breasts who otherwise had an average risk for breast cancer. METHODS. This retrospective study included patients with dense breasts who otherwise had an average risk for breast cancer and underwent AB-MRI for supplemental screening between December 20, 2016, and May 10, 2023. The clinical interpretations and results of recommended biopsies for AB-MRI examinations were extracted from the EMR. Baseline and subsequent-round AB-MRI examinations were compared. RESULTS. The final sample included 2585 AB-MRI examinations (2007 baseline and 578 subsequent-round examinations) performed for supplemental screening of 2007 women (mean age, 57.1 years old) with dense breasts. Of 2007 baseline examinations, 1658 (82.6%) were assessed as BI-RADS category 1 or 2, 171 (8.5%) as BI-RADS category 3, and 178 (8.9%) as BI-RADS category 4 or 5. Of 578 subsequent-round examinations, 533 (92.2%) were assessed as BI-RADS category 1 or 2, 20 (3.5%) as BI-RADS category 3, and 25 (4.3%) as BI-RADS category 4 or 5 (p < .001). The abnormal interpretation rate (AIR) was 17.4% (349/2007) for baseline examinations versus 7.8% (45/578) for subsequent-round examinations (p < .001). For baseline examinations, PPV2 was 21.3% (38/178), PPV3 was 26.6% (38/143), and the CDR was 18.9 cancers per 1000 examinations (38/2007). For subsequent-round examinations, PPV2 was 28.0% (7/25) (p = .45), PPV3 was 29.2% (7/24) (p = .81), and the CDR was 12.1 cancers per 1000 examinations (7/578) (p = .37). All 45 cancers diagnosed by baseline or subsequent-round AB-MRI were stage 0 or 1. Seven cancers diagnosed by subsequent-round AB-MRI had a mean interval of 872 ± 373 (SD) days since prior AB-MRI and node-negative status at surgical axillary evaluation; six had an invasive component, all measuring 1.2 cm or less. CONCLUSION. Subsequent rounds of AB-MRI screening of individuals with dense breasts had lower AIR than baseline examinations while maintaining a high CDR. All cancers detected by subsequent-round examinations were early-stage node-negative cancers. CLINICAL IMPACT. The findings support sequential AB-MRI for supplemental screening in individuals with dense breasts. Further investigations are warranted to optimize the screening interval.

Classification of Documented Goals of Care Among Hospitalized Patients with High Mortality Risk: a Mixed-Methods Feasibility Study.

BACKGROUND: The ability to classify patients' goals of care (GOC) from clinical documentation would facilitate serious illness communication quality improvement efforts and pragmatic measurement of goal-concordant care. Feasibility of this approach remains unknown. OBJECTIVE: To evaluate the feasibility of classifying patients' GOC from clinical documentation in the electronic health record (EHR), describe the frequency and patterns of changes in patients' goals over time, and identify barriers to reliable goal classification. DESIGN: Retrospective, mixed-methods chart review study. PARTICIPANTS: Adults with high (50-74%) and very high (≥ 75%) 6-month mortality risk admitted to three urban hospitals. MAIN MEASURES: Two physician coders independently reviewed EHR notes from 6 months before through 6 months after admission to identify documented GOC discussions and classify GOC. GOC were classified into one of four prespecified categories: (1) comfort-focused, (2) maintain or improve function, (3) life extension, or (4) unclear. Coder interrater reliability was assessed using kappa statistics. Barriers to classifying GOC were assessed using qualitative content analysis. KEY RESULTS: Among 85 of 109 (78%) patients, 338 GOC discussions were documented. Inter-rater reliability was substantial (75% interrater agreement; Cohen's kappa = 0.67; 95% CI, 0.60-0.73). Patients' initial documented goal was most frequently "life extension" (N = 37, 44%), followed by "maintain or improve function" (N = 28, 33%), "unclear" (N = 17, 20%), and "comfort-focused" (N = 3, 4%). Among the 66 patients whose goals' classification changed over time, most changed to "comfort-focused" goals (N = 49, 74%). Primary reasons for unclear goals were the observation of concurrently held or conditional goals, patient and family uncertainty, and limited documentation. CONCLUSIONS: Clinical notes in the EHR can be used to reliably classify patients' GOC into discrete, clinically germane categories. This work motivates future research to use natural language models to promote scalability of the approach in clinical care and serious illness research.

Molecular Imaging of Steroid Receptors in Breast Cancer.

ABSTRACT: Steroid receptors regulate gene expression for many important physiologic functions and pathologic processes. Receptors for estrogen, progesterone, and androgen have been extensively studied in breast cancer, and their expression provides prognostic information as well as targets for therapy. Noninvasive imaging utilizing positron emission tomography and radiolabeled ligands targeting these receptors can provide valuable insight into predicting treatment efficacy, staging whole-body disease burden, and identifying heterogeneity in receptor expression across different metastatic sites. This review provides an overview of steroid receptor imaging with a focus on breast cancer and radioligands for estrogen, progesterone, and androgen receptors.