Review of EmPATH Units for Behavioral Health Casualties in Prolonged Field Care Environments.

INTRODUCTION: Psychiatric conditions are one of the leading non-battle injury diseases resulting in medical evacuation (MEDEVAC) from combat environments. The challenge of limited MEDEVAC capability necessitating prolonged field care in future large-scale combat operations must be addressed. Therefore, a robust program is needed to address frontline care of behavioral health (BH), maximizing service members returning to duty and minimizing MEDEVAC. This review summarizes the literature on the impacts of the Emergency Psychiatric Assessment, Treatment, and Healing (EmPATH) Unit program as a solution to the challenges of treating behavioral health in future wars. MATERIALS AND METHODS: We conducted a systematic literature search and review, and a non-systematic literature critique. We then used the Johns Hopkins evidence appraisal tool to appraise the strength and quality of the evidence. The following electronic databases were utilized for the search: Google Scholar, Embase, CINAHL, and PubMed. Search terms included: included "EmPATH," "prolonged field care," and "operational," alone and combined. RESULTS: The literature review found that the EmPATH unit, a recently developed civilian hospital-based program, can work with higher acuity psychiatric crisis patients who would otherwise be admitted to an inpatient unit, showing promising results in avoiding the need for inpatient hospitalization. EmPATH units help decrease hospitalization rates, reduce restraints and violence, and shorten the patients' boarding time in a holding area. Such findings support the use of the EmPATH unit as a tactic for prolonged field care of psychiatric patients in a combat operational environment. CONCLUSIONS: This is the first literature review to consider EmPATH units for psychiatric prolonged field care based on its advantages demonstrated in the civilian sector. Studies have yet to be done on EmPATH units' usefulness in the military, showing a knowledge gap in current evidence supporting its suitability. Thus, this review recommends further studies of EmPATH units in military settings, especially prolonged field care environments.

Development and clinical implementation of a digital workflow utilizing 3D-printed oral stents for patients with head and neck cancer receiving radiotherapy.

OBJECTIVES: We describe the development of 3D-printed stents using our digital workflow and their effects on patients enrolled in the lead-in phase of a multi-center, randomized Phase-II trial. MATERIALS AND METHODS: Digital dental models were created for patients using intraoral scanning. Digital processes were implemented to develop the mouth-opening, tongue-depressing, and tongue-lateralizing stents using stereolithography. Time spent and material 3D-printing costs were measured. Physicians assessed mucositis using the Oral Mucositis Assessment Scale (OMAS) and collected MD Anderson Symptom Inventory (MDASI) reports and adverse events (AEs) from patients at various time points (TPs). OMAS and MDASI results were evaluated using paired t-test analysis. RESULTS: 18 patients enrolled into the lead-in phase across 6 independent clinical sites in the USA. 15 patients received stents (average design and fabrication time, 8 h; average material 3D-printing cost, 11 USD). 10 eligible patients with complete OMAS and MDASI reports across all TPs were assessed. OMAS increased significantly from baseline to week 3 of treatment (mean difference = 0.34; 95 % CI, 0.09-0.60; p = 0.01). MDASI increased significantly from baseline to week 3 of treatment (mean difference = 1.02; 95 % CI, 0.40-1.70; p = 0.005), and week 3 of treatment to end of treatment (mean difference = 1.90; 95 % CI, 0.90-2.92; p = 0.002). AEs (grades 1-3) were reported by patients across TPs. Mucositis and radiation dermatitis were primarily attributed to chemoradiation. CONCLUSIONS: 3D-printed stents were successfully fabricated and well tolerated by patients. As patients enroll in the randomized phase of this trial, data herein will establish a baseline for comparative analysis.

Temporally resolved single cell transcriptomics in a human model of amniogenesis.

Amniogenesis is triggered in a collection of pluripotent epiblast cells as the human embryo implants. To gain insights into the critical but poorly understood transcriptional machinery governing amnion fate determination, we examined the evolving transcriptome of a developing human pluripotent stem cell-derived amnion model at the single cell level. This analysis revealed five continuous amniotic fate progressing states with state-specific markers, which include a previously unrecognized CLDN10+ amnion progenitor state. Strikingly, we found that expression of CLDN10 is restricted to the amnion-epiblast boundary region in the human post-implantation amniotic sac model as well as in a peri-gastrula cynomolgus macaque embryo, bolstering the growing notion that, at this stage, the amnion-epiblast boundary is a site of active amniogenesis. Bioinformatic analysis of published primate peri-gastrula single cell sequencing data further confirmed that CLDN10 is expressed in cells progressing to amnion. Additionally, our loss of function analysis shows that CLDN10 promotes amniotic but suppresses primordial germ cell-like fate. Overall, this study presents a comprehensive amniogenic single cell transcriptomic resource and identifies a previously unrecognized CLDN10+ amnion progenitor population at the amnion-epiblast boundary of the primate peri-gastrula.

Community-Level Disadvantage of Adults With Firearm- vs Motor Vehicle-Related Injuries.

Importance: Motor vehicle crash (MVC) and firearm injuries are 2 of the top 3 mechanisms of adult injury-related deaths in the US. Objective: To understand the differing associations between community-level disadvantage and firearm vs MVC injuries to inform mechanism-specific prevention strategies and appropriate postdischarge resource allocation. Design, Setting, and Participants: This multicenter cross-sectional study analyzed prospectively collected data from the American College of Surgeons (ACS) Firearm Study. Included patients were treated either for firearm injury between March 1, 2021, and February 28, 2022, or for MVC-related injuries between January 1 and December 31, 2021, at 1 of 128 participating ACS trauma centers. Exposures: Community distress. Main outcome and Measure: Odds of presenting with a firearm as compared with MVC injury based on levels of community distress, as measured by the Distressed Communities Index (DCI) and categorized in quintiles. Results: A total of 62 981 patients were included (mean [SD] age, 42.9 [17.7] years; 42 388 male [67.3%]; 17 737 Black [28.2%], 9052 Hispanic [14.4%], 36 425 White [57.8%]) from 104 trauma centers. By type, there were 53 474 patients treated for MVC injuries and 9507 treated for firearm injuries. Patients with firearm injuries were younger (median [IQR] age, 31.0 [24.0-40.0] years vs 41.0 [29.0-58.0] years); more likely to be male (7892 of 9507 [83.0%] vs 34 496 of 53 474 [64.5%]), identified as Black (5486 of 9507 [57.7%] vs 12 251 of 53 474 [22.9%]), and Medicaid insured or uninsured (6819 of 9507 [71.7%] vs 21 310 of 53 474 [39.9%]); and had a higher DCI score (median [IQR] score, 74.0 [53.2-94.8] vs 58.0 [33.0-83.0]) than MVC injured patients. Among admitted patients, the odds of presenting with a firearm injury compared with MVC injury were 1.50 (95% CI, 1.35-1.66) times higher for patients living in the most distressed vs least distressed ZIP codes. After controlling for age, sex, race, ethnicity, and payer type, the DCI components associated with the highest adjusted odds of presenting with a firearm injury were a high housing vacancy rate (OR, 1.11; 95% CI, 1.04-1.19) and high poverty rate (OR, 1.17; 95% CI, 1.10-1.24). Among patients sustaining firearm injuries patients, 4333 (54.3%) received no referrals for postdischarge rehabilitation, home health, or psychosocial services. Conclusions and Relevance: In this cross-sectional study of adults with firearm- and motor vehicle-related injuries, we found that patients from highly distressed communities had higher odds of presenting to a trauma center with a firearm injury as opposed to an MVC injury. With two-thirds of firearm injury survivors treated at trauma centers being discharged without psychosocial services, community-level measures of disadvantage may be useful for allocating postdischarge care resources to patients with the greatest need.

Females have lower salivary flow than males, before and after radiation therapy for head/neck cancer.

OBJECTIVE: To compare salivary flow rates between females and males, before and after radiation therapy (RT) for head and neck cancer (HNC). METHODS: Prospective observational multicenter cohort study (OraRad). Stimulated whole salivary flow was measured before RT and at 6 and 18 months after RT. RESULTS: Mean (95% confidence interval) salivary flow in g/min before RT was 0.81 (0.71, 0.90) in females (n = 107) and 1.20 (1.15, 1.25) in males (n = 391) (p < 0.001); at 6 months was 0.34 (0.24, 0.44) in females and 0.50 (0.44, 0.55) in males (p = 0.01); at 18 months was 0.49 (0.38, 0.59) in females and 0.70 (0.64, 0.75) in males (p < 0.001). Median nadir salivary flow after RT was 0.22 in females and 0.35 in males (p < 0.001). A lower nadir salivary flow in females, but not males, was associated with an increased risk for tooth failure (p = 0.02). CONCLUSIONS: Females with HNC have lower stimulated whole salivary flow than males, before and after RT. Low salivary flow after RT may be a risk factor for tooth failure among females. The lower pre-RT salivary flow rates in females, combined with prior literature in other populations, indicates that, in general, females have lower stimulated salivary flow than males.

Health Literacy, Individual and Community Engagement, and Cardiovascular Risks and Disparities: JACC: CardioOncology State-of-the-Art Review.

Cardiovascular and cancer outcomes intersect within the realm of cardio-oncology survivorship care, marked by disparities across ethnic, racial, social, and geographical landscapes. Although the clinical community is increasingly aware of this complex issue, effective solutions are trailing. To attain substantial public health impact, examinations of cancer types and cardiovascular risk mitigation require complementary approaches that elicit the patient's perspective, scale it to a population level, and focus on actionable population health interventions. Adopting such a multidisciplinary approach will deepen our understanding of patient awareness, motivation, health literacy, and community resources for addressing the unique challenges of cardio-oncology. Geospatial analysis aids in identifying key communities in need within both granular and broader contexts. In this review, we delineate a pathway that navigates barriers from individual to community levels. Data gleaned from these perspectives are critical in informing interventions that empower individuals within diverse communities and improve cardio-oncology survivorship.

Inequalities in accelerated cognitive decline: Resolving observational window bias using nested non-linear regression.

INTRODUCTION: Limited observational windows lead to conflicting results in studies examining educational differences in Alzheimer's disease and related dementias (ADRD) risk, due to observational window bias relative to onset of accelerated cognitive decline. This study tested a novel model to address observational window bias and tested for the presence and sources of disparities in accelerated cognitive declines due to ADRD. METHODS: The sample examined 167,314 cognitive assessments from 32,441 Health and Retirement Study participants. We implemented a parametric non-linear nested longitudinal regression and reported multivariable-adjusted nodal incidence ratios (aNIR). RESULTS: University degrees were associated with lower incidence (aNIR = 0.253, 95% confidence interval [CI] = [0.221 to 0.289], p < 0.001), while black participants had a higher incidence (aNIR = 1.995, [1.858 to 2.141], p < 0.001) of accelerated cognitive decline, adjusting for demographic, sociobehavioral, and medical risk factors. Sex-stratified analyses identified diminished educational returns for women and increased incidence among minoritized women. DISCUSSION: Addressing observational window bias reveals large social inequalities in the onset of accelerated cognitive declines indicative of ADRD. HIGHLIGHTS: This study identifies observational window bias as a source of conflicting results among previous studies of educational achievement in Alzheimer's disease and related dementias (ADRD) disparities. The study locates preclinical accelerated cognitive decline, which is indicative of ADRD while occurring 10+ years prior to symptom onset, as a site to study ADRD disparities that mitigates observational window bias. A novel method, nested non-linear regression, is developed to test for differences in the onset of accelerated cognitive decline. Educational and racial/ethnic disparities are demonstrated in the onset of accelerated cognitive decline, as are their intersecting differences with sex/gender.

Total Synthesis of Homoseongomycin Enantiomers and Evaluation of Their Optical Rotation.

A total synthesis of each homoseongomycin enantiomer was accomplished in 17 total steps (longest linear sequence = 12 steps) and 10 chromatographic purifications. Several schemes were attempted to forge the key 5-membered ring, but only a Suzuki coupling-intramolecular Friedel-Crafts acylation sequence proved viable. Challenges encountered during the optical rotation characterization of the natural product left us with two important takeaways. First, highly colored compounds like homoseongomycin that absorb near/at the sodium d-line may require optical rotation measurements at other wavelengths. Second, high dilution of such compounds to obtain measurement at the sodium d-line could result in artificially large and incorrectly assigned specific rotations. To verify the optical rotation, electronic circular dichroism spectra were acquired for both homoseongomycin enantiomers and were transformed into optical rotary dispersions via the Kramers-Kronig transform. We note the wavelength dependency on rotation, and at the sodium d-line 589 nm, we reassign the optical rotation of L-homoseongomycin from (-) to (+).

Non-endoscopic screening for Barrett's esophagus and Esophageal Adenocarcinoma in at risk Veterans.

BACKGROUND: While rates of Esophageal Adenocarcinoma (EAC) in the US continue to rise, many patients at risk of disease are not screened. EsoCheck (EC), a non-endoscopic esophageal balloon sampling device coupled with EsoGuard (EG), a DNA based screening assay, is an FDA-approved minimally invasive alternative to the traditional screening method of upper endoscopy. AIM: To prospectively determine the diagnostic accuracy, tolerance, and acceptability of the EC/EG test in a screening population. METHODS: We recruited Veterans who met the American College of Gastroenterology (ACG) Guideline criteria for endoscopic Barrett's Esophagus (BE) and EAC screening at Louis Stokes Cleveland Veteran Affairs Medical Center. All study participants completed unsedated EC guided distal esophageal sampling followed by a sedated esophagogastroduodenoscopy (EGD). Diagnostic yield of the EG assay and EGD was recorded and used in calculation of sensitivity and specificity of EC/EG in prospective screening. The abbreviated Spielberger State-Trait Anxiety Inventory (STAI-6) questionnaire was administered before and after completion of EC. Overall tolerance of EC sampling was evaluated on a 10-point Likert scale. RESULTS: Esophageal cancer screening was accepted by 130/782 (16.6%) eligible veterans and we analyzed results of those who completed both screening tests (N = 124). Prevalence of BE/EAC among studied veterans was 12.9% (16/124), based on EGD. Sensitivity and specificity of EC/EG for EGD-detected BE/EAC were 92.9% (95% CI 66.1, 99.8) and 72.2% (95% CI 62.1, 80.8), respectively. Positive and negative predictive values were 32.5% (95% CI 18.6, 49.1) and 98.6% (95% CI 92.4, 100), respectively. Baseline STAI-6 scores were reflective of notable levels of anxiety among veterans in the peri-procedural setting. Mean post-procedure acceptability score for Esocheck test was 7.23 (SD 2.45). CONCLUSIONS: Our data suggest excellent sensitivity and negative predictive value of EC/EG in a screening population of veterans, making this modality a powerful screening tool for BE and EAC.

A Visualization and Radiation Treatment Plan Quality Scoring Method for Triage in a Population-Based Context.

Purpose: Our purpose was to develop a clinically intuitive and easily understandable scoring method using statistical metrics to visually determine the quality of a radiation treatment plan. Methods and Materials: Data from 111 patients with head and neck cancer were used to establish a percentile-based scoring system for treatment plan quality evaluation on both a plan-by-plan and objective-by-objective basis. The percentile scores for each clinical objective and the overall treatment plan score were then visualized using a daisy plot. To validate our scoring method, 6 physicians were recruited to assess 60 plans, each using a scoring table consisting of a 5-point Likert scale (with scores ≥3 considered passing). Spearman correlation analysis was conducted to assess the association between increasing treatment plan percentile rank and physician rating, with Likert scores of 1 and 2 representing clinically unacceptable plans, scores of 3 and 4 representing plans needing minor edits, and a score of 5 representing clinically acceptable plans. Receiver operating characteristic curve analysis was used to assess the scoring system's ability to quantify plan quality. Results: Of the 60 plans scored by the physicians, 8 were deemed as clinically acceptable; these plans had an 89.0th ± 14.5 percentile value using our scoring system. The plans needing minor edits or deemed unacceptable had more variation, with scores falling in the 62.6nd ± 25.1 percentile and 35.6th ± 25.7 percentile, respectively. The estimated Spearman correlation coefficient between the physician score and treatment plan percentile was 0.53 (P < .001), indicating a moderate but statistically significant correlation. Receiver operating characteristic curve analysis demonstrated discernment between acceptable and unacceptable plan quality, with an area under the curve of 0.76. Conclusions: Our scoring system correlates with physician ratings while providing intuitive visual feedback for identifying good treatment plan quality, thereby indicating its utility in the quality assurance process.

Neural population dynamics in songbird RA and HVC during learned motor-vocal behavior.

Complex, learned motor behaviors involve the coordination of large-scale neural activity across multiple brain regions, but our understanding of the population-level dynamics within different regions tied to the same behavior remains limited. Here, we investigate the neural population dynamics underlying learned vocal production in awake-singing songbirds. We use Neuropixels probes to record the simultaneous extracellular activity of populations of neurons in two regions of the vocal motor pathway. In line with observations made in non-human primates during limb-based motor tasks, we show that the population-level activity in both the premotor nucleus HVC and the motor nucleus RA is organized on low-dimensional neural manifolds upon which coordinated neural activity is well described by temporally structured trajectories during singing behavior. Both the HVC and RA latent trajectories provide relevant information to predict vocal sequence transitions between song syllables. However, the dynamics of these latent trajectories differ between regions. Our state-space models suggest a unique and continuous-over-time correspondence between the latent space of RA and vocal output, whereas the corresponding relationship for HVC exhibits a higher degree of neural variability. We then demonstrate that comparable high-fidelity reconstruction of continuous vocal outputs can be achieved from HVC and RA neural latents and spiking activity. Unlike those that use spiking activity, however, decoding models using neural latents generalize to novel sub-populations in each region, consistent with the existence of preserved manifolds that confine vocal-motor activity in HVC and RA.

Microglia contribute to methamphetamine reinforcement and reflect persistent transcriptional and morphological adaptations to the drug.

Methamphetamine use disorder (MUD) is a chronic, relapsing disease that is characterized by repeated drug use despite negative consequences and for which there are currently no FDA-approved cessation therapeutics. Repeated methamphetamine (METH) use induces long-term gene expression changes in brain regions associated with reward processing and drug-seeking behavior, and recent evidence suggests that methamphetamine-induced neuroinflammation may also shape behavioral and molecular responses to the drug. Microglia, the resident immune cells in the brain, are principal drivers of neuroinflammatory responses and contribute to the pathophysiology of substance use disorders. Here, we investigated transcriptional and morphological changes in dorsal striatal microglia in response to methamphetamine-taking and during methamphetamine abstinence, as well as their functional contribution to drug-taking behavior. We show that methamphetamine self-administration induces transcriptional changes associated with protein folding, mRNA processing, immune signaling, and neurotransmission in dorsal striatal microglia. Importantly, many of these transcriptional changes persist through abstinence, a finding supported by morphological analyses. Functionally, we report that microglial ablation increases methamphetamine-taking, possibly involving neuroimmune and neurotransmitter regulation. In contrast, microglial depletion during abstinence does not alter methamphetamine-seeking. Taken together, these results suggest that methamphetamine induces both short and long-term changes in dorsal striatal microglia that contribute to altered drug-taking behavior and may provide valuable insights into the pathophysiology of MUD.

Incidence of Dementia Before Age 65 Years Among World Trade Center Attack Responders.

Importance: Reports suggest that the individuals who served in rescue operations following the terrorist attacks on the World Trade Center (WTC) have poorer brain health than expected. Objective: To assess the incidence of dementia before age 65 years in a prospective study of WTC responders and to compare incidence among responders with severe exposures to debris vs responders not exposed to building debris or who wore personalized protective equipment (PPE). Design, Setting, and Participants: This prospective cohort study was conducted from November 1, 2014, to January 1, 2023, in an academic medical monitoring program available to verified WTC responders residing on Long Island, New York. Responders 60 years of age or younger without dementia at the time of their first cognitive assessment were followed up every 18 months, on average, for up to 5 years. Exposures: Exposure severity was based on responses to a detailed questionnaire of WTC exposures and exposure-related activities that included exposures to fine particulate dust and potentially neurotoxic debris, duration of work, and the use of PPE. Exposure level was divided into 5 categories ranging from low to severe. Main Outcomes and Measures: Incidence of all-cause dementia before age 65 years was the primary outcome. Dementia was diagnosed following standard guidelines relying on repeated measures of cognition. Results: Of 9891 responders, 5010 were eligible for inclusion in this study of cognitive function (median [IQR] age, 53 [48-57] years; 4573 [91.3%] male). There were 228 cases of dementia identified during 15 913.1 person-years of follow-up. Increasing WTC exposure severity was associated with incremental increases in the incidence rate of dementia per 1000 person-years (low, 2.95 [95% CI, 1.07-11.18]; mild, 12.16 [95% CI, 10.09-14.79]; moderate, 16.53 [95% CI, 13.30-20.81]; high, 30.09 [95% CI, 21.35-43.79]; and severe, 42.37 [95% CI, 24.86-78.24]). Adjusting for social, demographic, and relevant medical factors, each unit increase in exposure severity was associated with increased incidence of dementia (adjusted hazard ratio, 1.42 [95% CI, 1.18-1.71]; P < .001; mean risk difference, 9.74 [95% CI, 2.94-32.32] per 1000 person-years; P < .001). Conclusions and Relevance: In this cohort study of WTC responders who survived these unique exposures and participated in a longitudinal follow-up study of cognition from 2014 through 2022, when compared with responders with the lowest exposure levels or responders who used PPE, more severe exposure to dust or debris was significantly associated with a higher risk of dementia before 65 years of age. This study suggests that the reliable use of PPE might help prevent the onset of dementia before age 65 years among individuals exposed to an uncontrolled building collapse. Future research is warranted to determine cerebral biomarkers for individuals with exposure-associated dementia.

Working Through It: Lifetime Experiences of Employment Discrimination Among Older Black Americans and Implications for Labor Force Participation, Job Dissatisfaction, and Mental Health in Older Adulthood.

OBJECTIVES: To examine lifetime experiences of employment discrimination and their association with Black older adults' employment status and well-being. METHODS: We use data from the Health and Retirement Study's leave-behind questionnaire to characterize lifetime experiences of being unfairly fired, not hired, or not promoted among Black older adults (N = 2948) and test associations with labor force status at age 62, job satisfaction among those working, and depressive symptoms. RESULTS: Employment discrimination was commonly reported by Black older adults, especially among men and those with college educations. Employment discrimination was not associated with employment status at age 62 but was associated with job dissatisfaction (OR = 2.00, p = .001) and depressive symptoms (Beta = 0.34, p < .001). DISCUSSION: Findings suggest a negative association between employment discrimination at any point in the life course and Black older adults' well-being. Employment discrimination is an obstacle to healthy aging, yet improved discrimination survey items are needed to fully capture its impact on Black Americans.

Accelerated biological aging six decades after prenatal famine exposure.

To test the hypothesis that early-life adversity accelerates the pace of biological aging, we analyzed data from the Dutch Hunger Winter Families Study (DHWFS, N = 951). DHWFS is a natural-experiment birth-cohort study of survivors of in-utero exposure to famine conditions caused by the German occupation of the Western Netherlands in Winter 1944 to 1945, matched controls, and their siblings. We conducted DNA methylation analysis of blood samples collected when the survivors were aged 58 to quantify biological aging using the DunedinPACE, GrimAge, and PhenoAge epigenetic clocks. Famine survivors had faster DunedinPACE, as compared with controls. This effect was strongest among women. Results were similar for GrimAge, although effect-sizes were smaller. We observed no differences in PhenoAge between survivors and controls. Famine effects were not accounted for by blood-cell composition and were similar for individuals exposed early and later in gestation. Findings suggest in-utero undernutrition may accelerate biological aging in later life.

Recommendations for Tumor Mutational Burden Assay Validation and Reporting: A Joint Consensus Recommendation of the Association for Molecular Pathology, College of American Pathologists, and Society for Immunotherapy of Cancer.

Tumor mutational burden (TMB) has been recognized as a predictive biomarker for immunotherapy response in several tumor types. Several laboratories offer TMB testing, but there is significant variation in how TMB is calculated, reported, and interpreted among laboratories. TMB standardization efforts are underway, but no published guidance for TMB validation and reporting is currently available. Recognizing the current challenges of clinical TMB testing, the Association for Molecular Pathology convened a multidisciplinary collaborative working group with representation from the American Society of Clinical Oncology, the College of American Pathologists, and the Society for the Immunotherapy of Cancer to review the laboratory practices surrounding TMB and develop recommendations for the analytical validation and reporting of TMB testing based on survey data, literature review, and expert consensus. These recommendations encompass pre-analytical, analytical, and postanalytical factors of TMB analysis, and they emphasize the relevance of comprehensive methodological descriptions to allow comparability between assays.

Molecular Pathology of Ovarian Epithelial Neoplasms: Predictive, Prognostic, and Emerging Biomarkers.

This review focuses on the diagnostic, prognostic, and predictive molecular biomarkers in ovarian epithelial neoplasms in the context of their morphologic classifications. Currently, most clinically actionable molecular findings are reported in high-grade serous carcinomas; however, the data on less common tumor types are rapidly accelerating. Overall, the advances in genomic knowledge over the last decade highlight the significance of integrating molecular findings with morphology in ovarian epithelial tumors for a wide-range of clinical applications, from assistance in diagnosis to predicting response to therapy.

Stress-induced dysfunction of neurovascular astrocytes contributes to sex-specific behavioral deficits.

Astrocytes form an integral component of the neurovascular unit, ensheathing brain blood vessels with projections high in aquaporin-4 (AQP4) expression. These AQP4-rich projections facilitate interaction between the vascular endothelium, astrocytes, and neurons, and help stabilize vascular morphology. Studies using preclinical models of psychological stress and post-mortem tissue from patients with major depressive disorder (MDD) have reported reductions in AQP4, loss of astrocytic structures, and vascular impairment in the prefrontal cortex (PFC). Though compelling, the role of AQP4 in mediating stress-induced alterations in blood vessel function and behavior remains unclear. Here, we address this, alongside potential sex differences in chronic unpredictable stress (CUS) effects on astrocyte phenotype, blood-brain barrier integrity, and behavior. CUS led to pronounced shifts in stress-coping behavior and working memory deficits in male -but not female- mice. Following behavioral testing, astrocytes from the frontal cortex were isolated for gene expression analyses. We found that CUS increased various transcripts associated with blood vessel maintenance in astrocytes from males, but either had no effect on- or decreased- these genes in females. Furthermore, CUS caused a reduction in vascular-localized AQP4 and elevated extravasation of a small molecule fluorescent reporter (Dextran) in the PFC in males but not females. Studies showed that knockdown of AQP4 in the PFC in males is sufficient to disrupt astrocyte phenotype and increase behavioral susceptibility to a sub-chronic stressor. Collectively, these findings provide initial evidence that sex-specific alterations in astrocyte phenotype and neurovascular integrity in the PFC contribute to behavioral and cognitive consequences following chronic stress.

Rapid Tumor DNA Analysis of Cerebrospinal Fluid Accelerates Treatment of Central Nervous System Lymphoma.

Delays and risks associated with neurosurgical biopsies preclude timely diagnosis and treatment of central nervous system (CNS) lymphoma and other CNS neoplasms. We prospectively integrated targeted rapid genotyping of cerebrospinal fluid (CSF) into the evaluation of 70 patients with CNS lesions of unknown etiology. Participants underwent genotyping of CSF-derived DNA using a qPCR-based approach for parallel detection of single-nucleotide variants in the MYD88, TERT promoter, IDH1, IDH2, BRAF and H3F3A genes within 80 minutes of sample acquisition. Canonical mutations were detected in 42% of patients with neoplasms, including cases of primary and secondary CNS lymphoma, glioblastoma, IDH-mutant brainstem glioma and H3K27M-mutant diffuse midline glioma. Genotyping results eliminated the need for surgical biopsies in 7/33 (21.2%) cases of newly diagnosed neoplasms, resulting in significantly accelerated initiation of disease-directed treatment (median 3 vs 12 days; p = 0.027). This assay was then implemented in a Clinical Laboratory Improvement Amendments (CLIA) environment, with 2-day median turnaround for diagnosis of central nervous system lymphoma from 66 patients across 4 clinical sites. Our study prospectively demonstrates that targeted rapid CSF genotyping influences oncologic management for suspected CNS tumors.