Clinical Trial Protocol for ROSELLA: a phase 3 study of relacorilant in combination with nab-paclitaxel versus nab-paclitaxel monotherapy in advanced platinum-resistant ovarian cancer.

BACKGROUND: Ovarian cancer has the highest mortality among gynecologic cancers, primarily because it typically is diagnosed at a late stage and because of the development of chemoresistance in recurrent disease. Improving outcomes in women with platinum-resistant ovarian cancer is a substantial unmet need. Activation of the glucocorticoid receptor (GR) by cortisol has been shown to suppress the apoptotic pathways used by cytotoxic agents, limiting their efficacy. Selective GR modulation may be able to counteract cortisol's antiapoptotic effects, enhancing chemotherapy's efficacy. A previous phase 2 study has shown that adding intermittently dosed relacorilant, a selective GR modulator, to nab-paclitaxel improved outcomes, including progression-free survival (PFS) and overall survival (OS), with minimal added toxicity, in women with recurrent platinum-resistant ovarian cancer. The ROSELLA study aims to confirm and expand on these findings in a larger population. METHODS: ROSELLA is a phase 3, randomized, 2-arm, open-label, global multicenter study in women with recurrent, platinum-resistant, high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer. Eligible participants have received 1 to 3 lines of prior systemic anticancer therapy, including ≥1 prior line of platinum therapy and prior treatment with bevacizumab, with documented progressive disease or intolerance to the most recent therapy. There is no biomarker-based requirement for participant selection. Participants are randomized 1:1 to receive intermittently dosed relacorilant in combination with nab-paclitaxel or nab-paclitaxel monotherapy. The study's primary efficacy endpoint is PFS as assessed by blinded independent central review. Secondary efficacy endpoints include OS, investigator-assessed PFS, objective response rate, best overall response, duration of response, clinical benefit rate at 24 weeks, and cancer antigen 125 response. The study is also evaluating safety and patient-reported outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05257408; European Union Drug Regulating Authorities Clinical Trials Database Identifier: 2022-000662-18.

Predictors of long-term progression-free survival in patients with ovarian cancer treated with niraparib in the PRIMA/ENGOT-OV26/GOG-3012 study.

OBJECTIVE: To identify characteristics associated with long-term progression-free survival (≥2 years) in patients with advanced ovarian cancer treated with niraparib first-line maintenance therapy in the phase III PRIMA/ENGOT-OV26/GOG-3012 study. METHODS: In this post hoc analysis of PRIMA, patients randomized to niraparib were grouped based on investigator-assessed progression-free survival (progressive disease/censoring <2 years or ≥2 years after randomization). Variables assessed for predictive value were Eastern Cooperative Oncology Group performance status, International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis, clinical response to platinum-based chemotherapy, number of prior chemotherapy cycles, primary tumor location, body mass index, categorical age, debulking surgery type, number of baseline target lesions, number of baseline non-target lesions, BRCA/homologous recombination-deficiency status, residual disease status, and duration from end of chemotherapy to randomization. Logistic regression modeling using backward elimination (significance level=0.15) identified covariates associated with long-term progression-free survival (clinical cut-off date November 17, 2021). RESULTS: Of 487 patients randomized to niraparib, 152 (31%) had progressive disease/censoring ≥2 years after randomization. Multivariable logistic regression modeling using backward elimination identified BRCA1/2 mutation/homologous recombination deficiency status (p<0.0001), FIGO stage (p=0.041), primary tumor location (p=0.095), and number of baseline non-target lesions (p=0.0001) to be associated with long-term progression-free survival. Patients significantly more likely to achieve progression-free survival of ≥2 years in the final model were those with BRCA1- and BRCA2-mutated/homologous recombination-deficient tumors or BRCA wild-type/not determined/homologous recombination-deficient tumors (vs BRCA wild-type/homologous recombination-proficient/not determined tumors), FIGO stage III (vs IV), and 0 or 1 baseline non-target lesions (vs ≥2 baseline non-target lesions). CONCLUSIONS: The hypothesis-generating results of this analysis suggest that BRCA1/2 mutation/homologous recombination-deficiency status, FIGO stage, and number of baseline non-target lesions may predict progression-free survival of ≥2 years in patients with advanced ovarian cancer receiving niraparib first-line maintenance therapy. TRIAL REGISTRATION NUMBER: NCT02655016.

Phylogenetic assessment within a species complex of a subterranean rodent (Geomys bursarius) with conservation implications for isolated subspecies.

Range contraction and expansion from glaciation has led to genetic divergence that may be particularly pronounced in fossorial species with low dispersal. The plains pocket gopher (Geomys bursarius) is a fossorial species that ranges widely across North America but has a poorly understood phylogeny. We used mitogenomes (14,996 base pairs) from 56 individuals across seven subspecies, plus two outgroup species, to assess genetic divergence from minimum spanning trees, measure genetic distances, and infer phylogenetic trees using BEAST. We found G. b. wisconsinensis was monophyletic with recent divergence. Further assessment is needed for G. b. major because it was paraphyletic and exhibited inconsistent groupings with other clades. Importantly, we identified G. b. illinoensis as being genetically distinct and monophyletic likely due to a unique colonization event eastward across the Mississippi River. Because G. b. illinoensis faces continued pressures from niche reduction and habitat loss, we recommend that G. b. illinoensis be considered an evolutionary significant unit warranting conservation actions to promote connectivity and restore suitable habitat. Such conservation efforts should benefit other grassland species including those originating from clades west of the Mississippi River that may also be evolutionary significant units.

A Plain Language Summary of "Dostarlimab for primary advanced or recurrent endometrial cancer".

What is this summary about? Dostarlimab, also known by the brand name JEMPERLI, is a medicine that uses a patient's own immune system to treat endometrial cancer. Dostarlimab is a type of medicine called an immunotherapy. Immunotherapies help the immune system find and attack cancer cells. Dostarlimab stops cancer cells from being able to hide from the immune system, which allows the patient to have a boosted immune response against their cancer.The RUBY study is a phase 3 clinical study of primary advanced (cancer that has spread outside the uterus) or recurrent (cancer that has come back) endometrial cancer. A phase 3 clinical study looks at how well a new treatment works compared to the standard, or usual, treatment in a large patient population. The RUBY study is testing how well dostarlimab given with chemotherapy, followed by dostarlimab alone, works at delaying primary advanced or recurrent endometrial cancer from getting worse and preventing patients from dying, compared to chemotherapy given alone (the current standard treatment for primary advanced or recurrent endometrial cancer).What were the results? When dostarlimab was given with chemotherapy, this combination was found to delay primary advanced or recurrent endometrial cancer from getting worse and to prevent patients from dying, compared with chemotherapy given alone (without dostarlimab). Patients in the study who received dostarlimab with chemotherapy had a 36% lower risk of dying or having their cancer get worse.What do the results mean? The results from this study contributed to the approval of dostarlimab with chemotherapy as a new treatment option for patients with mismatch repair deficient/microsatellite instability-high primary advanced or recurrent endometrial cancer. As of the publication of this plain language summary of publication (PLSP), this combination of dostarlimab with chemotherapy has been approved in the United States of America, the United Kingdom, the European Union and Hong Kong.Clinical Trial Registration: NCT03981796 (RUBY).

Niraparib Population Pharmacokinetics and Exposure-Response Relationships in Patients With Newly Diagnosed Advanced Ovarian Cancer.

PURPOSE: Niraparib is a poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor approved for the maintenance treatment of advanced ovarian cancer (OC). Niraparib was originally approved in recurrent OC at a fixed starting dose (FSD) of 300 mg once daily (QD). This analysis characterized the population pharmacokinetics (PK) of niraparib and evaluated the relationships between exposure, efficacy, and safety to support clinical use of an individualized dosing strategy, in which the starting dose of niraparib was adjusted based on patient characteristics to improve the benefit-risk profile. METHODS: A population PK model was developed by pooling data from four niraparib clinical trials (PN001 [n = 104], QUADRA [n = 455], NOVA [n = 403], and PRIMA [n = 480]) in patients with solid tumors, including OC. Exposure-response analyses were conducted to explore the relationships of niraparib exposure with progression-free survival (PFS) and adverse events in the PRIMA study. A multivariate logistic regression model was also developed to estimate the probability of grade ≥3 thrombocytopenia, using data from patients enrolled in PRIMA and NOVA. The impact of an individualized starting dose (ISD) regimen (200 mg QD in patients with body weight [BW] <77 kg or platelet count [PLT] <150,000/µL, or 300 mg QD in patients with BW ≥77 kg and PLT ≥150,000/µL) on systemic exposure, efficacy, and safety was assessed. FINDINGS: Niraparib disposition was best described by a 3-compartment model with linear elimination. Key covariates included baseline creatinine clearance, BW, albumin, and age, all of which had minor effects on niraparib exposure. Comparable model-predicted exposure up to the time of disease progression/death or censoring in the 300-mg FSD and 200-/300-mg ISD groups was consistent with the lower rate of dose reduction in the ISD groups. No consistent niraparib exposure-response relationship was observed for efficacy in all PRIMA patients (first-line OC), and no statistically significant difference was seen in PFS curves for patients receiving a niraparib dose of 200 mg versus 300 mg. In the multivariate regression model, performed using combined data from PRIMA and NOVA, higher niraparib exposure (area under the concentration-time curve at steady-state [AUCss]), lower BW, and lower PLT were associated with an increased risk of grade ≥3 thrombocytopenia. IMPLICATIONS: Population PK and exposure-response analyses support use of an ISD to improve the safety profile of niraparib, including reducing the rate of grade ≥3 thrombocytopenia, without compromising efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01847274 (NOVA), NCT00749502 (PN001), NCT02655016 (PRIMA), NCT02354586 (QUADRA), www. CLINICALTRIALS: gov.

Effects of aging on diaphragm hyperemia and blood flow distribution in male and female Fischer 344 rats.

Aging is associated with inspiratory muscle dysfunction, however, the impact of aging on diaphragm blood flow (BF) regulation, and whether sex-differences exist, is unknown. We tested the hypotheses in young animals, that diaphragm BF and vascular conductance (VC) would be greater in females and that aging would decrease the diaphragm's ability to increase BF with contractions. Young (4-6 months) and old (22-24 months) Fischer-344 rats were divided into four groups: Young Female (YF, n=7), Young Male (YM, n=8), Old Female (OF, n=9), and Old Male (OM, n=9). Diaphragm BF (ml/min/100g) and VC (ml/mmHg/min/100g) were determined, via fluorescent microspheres, at rest and during 1Hz contractions. In YF versus OF, aging blunted the increase in medial costal diaphragm BF (44 ± 5% vs. 16 ± 12%; P < 0.05) and VC (43 ± 7% vs. 21 ± 12%; P < 0.05). Similarly, in YM versus OM, aging blunted the increase in medial costal diaphragm BF (43 ± 6% vs. 24 ± 12%; P < 0.05) and VC (50 ± 6% vs. 34 ± 10%; P < 0.05). Compared to young, dorsal costal diaphragm BF was increased in OF while crural diaphragm BF was increased in OM (P < 0.05). Compared to age-matched females, dorsal costal diaphragm BF was lower in YM and OM (P < 0.05). Aging results in an inability to augment medial costal diaphragm BF and alters regional diaphragm BF distribution in response to muscular contractions. Further, sex differences in regional diaphragm BF are present in young and old animals.

Targeted mapping and utilization of the perihepatic surface for therapeutic beta cell replacement and retrieval in diabetic non-human primates.

Introduction: Successful diabetes reversal using pancreatic islet transplantation by various groups illustrates the significant achievements made in cell-based diabetes therapy. While clinically, intraportal islet delivery is almost exclusively used, it is not without obstacles, including instant blood-mediated inflammatory reaction (IBMIR), relative hypoxia, and loss of function over time, therefore hindering long-term success. Here we demonstrate the perihepatic surface of non-human primates (NHPs) as a potential islet delivery site maximizing favorable characteristics, including proximity to a dense vascular network for adequate oxygenation while avoiding IBMIR exposure, maintenance of portal insulin delivery, and relative ease of accessibility through minimally invasive surgery or percutaneous means. In addition, we demonstrate a targeted mapping technique of the perihepatic surface, allowing for the testing of multiple experimental conditions, including a semi-synthetic hydrogel as a possible three-dimensional framework to improve islet viability. Methods: Perihepatic allo-islet cell transplants were performed in immunosuppressed cynomolgus macaques using a targeted mapping technique to test multiple conditions for biocompatibility. Transplant conditions included islets or carriers (including hydrogel, autologous plasma, and media) alone or in various combinations. Necropsy was performed at day 30, and histopathology was performed to assess biocompatibility, immune response, and islet viability. Subsequently, single-injection perihepatic allo-islet transplant was performed in immunosuppressed diabetic cynomolgus macaques. Metabolic assessments were measured frequently (i.e., blood glucose, insulin, C-peptide) until final graft retrieval for histopathology. Results: Targeted mapping biocompatibility studies demonstrated mild inflammatory changes with islet-plasma constructs; however, significant inflammatory cell infiltration and fibrosis were seen surrounding sites with the hydrogel carrier affecting islet viability. In diabetic NHPs, perihepatic islet transplant using an autologous plasma carrier demonstrated prolonged function up to 6 months with improvements in blood glucose, exogenous insulin requirements, and HbA1c. Histopathology of these islets was associated with mild peri-islet mononuclear cell infiltration without evidence of rejection. Discussion: The perihepatic surface serves as a viable site for islet cell transplantation demonstrating sustained islet function through 6 months. The targeted mapping approach allows for the testing of multiple conditions simultaneously to evaluate immune response to biomaterials at this site. Compared to traditional intraportal injection, the perihepatic site is a minimally invasive approach that allows the possibility for graft recovery and avoids IBMIR.

Preinjection With Ligation-Assisted Endoscopic Mucosal Resection for Barrett's Dysplasia and Early Esophageal Adenocarcinoma: Characteristic Histological Features of the Depth of Resection.

BACKGROUND AND AIM: Endoscopic mucosal resection (EMR) is an established technique for the diagnosis and treatment of high-grade dysplasia (HGD) and early esophageal adenocarcinoma (EAC) in Barrett's esophagus. Submucosal preinjection is not universally used or generally recommended when performing routine ligation-assisted EMR. Prior studies, however, have demonstrated evidence of at least superficial muscle injury on ligation-assisted EMR without submucosal injection. There are limited published data supporting any potential benefit of submucosal preinjection. Our aim was to review this technique and determine the rate of any degree of muscle injury in patients with Barrett's HGD and EAC treated with submucosal preinjection before ligation-assisted EMR. METHODS: Patients undergoing submucosal preinjection before ligation-assisted EMR for Barrett's esophagus at a single institution between 2012 and 2016 were identified. Data were collected regarding patient demographics and medical history, endoscopy and histopathology findings, adverse events, and subsequent outcomes. All EMR specimens were reviewed by an expert gastrointestinal pathologist. RESULTS: One hundred fifty consecutive EMR procedures were performed on 70 patients. Of 70 patients, 85.7% of patients were men, with a median age of 68 years. EAC was identified in 75 specimens (50%) and HGD in 44 specimens (29.3%). Deep resection margins were clear of adenocarcinoma in all specimens. Muscularis propria was not identified in any of the 150 specimens. There were no cases of post-EMR perforation. CONCLUSIONS: Preinjection before ligation-assisted EMR achieved complete excision with histologically clear margins, without histological evidence of any inadvertent muscularis propria.

Analysis of Popular Gastroesophageal Reflux Disease Content on TikTok.

Researchers used the TikTok platform to investigate the quality of select TikTok educational content regarding gastroesophageal reflux disease (GERD). One hundred TikTok videos that fit the inclusion criteria were analyzed using DISCERN, a tool that evaluates the quality of consumer health information on the internet. There was no substantial difference in DISCERN scores between physicians and non-physician content creators. Nevertheless, both groups consistently scored low (<3) in areas such as providing sources of information, indicating the publication date of their sources, discussing treatment risks, and outlining potential consequences if no treatment is pursued.

A pre-Darwinian account of the facial expression of emotion: Thomas Wright's The Passions of the Minde in Generall (1604).

"The study of emotional expression," it has recently been said, "has long been the provenance of scientific discovery and heated controversy" (Keltner et al., 2016, p. 467)-and nothing has been more central to this inquiry than attempts to understand the precise connection between affective experience and human facial expression. But as science moves forward, it is also wise to consider where it has been. This Brief Report reproduces a pre-Darwinian account of the facial expression of emotion from Thomas Wright's The Passions of the Minde in Generall (1604), one of the most interesting books on emotion from the English Renaissance. Before the modern scientific revolution, Wright's theorization anticipates several key aspects of 21st Century thought on the facial expression of emotion, an intriguing reminder of the connection between historical folk understanding and modern research. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Investigating Lipid Transporter Protein and Lipid Interactions Using Variable Temperature Electrospray Ionization, Ultraviolet Photodissociation Mass Spectrometry, and Collision Cross Section Analysis.

Gram-negative bacteria develop and exhibit resistance to antibiotics, owing to their highly asymmetric outer membrane maintained by a group of six proteins comprising the Mla (maintenance of lipid asymmetry) pathway. Here, we investigate the lipid binding preferences of one Mla protein, MlaC, which transports lipids through the periplasm. We used ultraviolet photodissociation (UVPD) to identify and characterize modifications of lipids endogenously bound to MlaC expressed in three different bacteria strains. UVPD was also used to localize lipid binding to MlaC residues 130-140, consistent with the crystal structure reported for lipid-bound MlaC. The impact of removing the bound lipid from MlaC on its structure was monitored based on collision cross section measurements, revealing that the protein unfolded prior to release of the lipid. The lipid selectivity of MlaC was evaluated based on titrimetric experiments, indicating that MlaC-bound lipids in various classes (sphingolipids, glycerophospholipids, and fatty acids) as long as they possessed no more than two acyl chains.

Prospective study of Candida auris nucleic acids in wastewater solids in 190 wastewater treatment plants in the United States suggests widespread occurrence.

Candida auris is an emerging, multidrug-resistant fungal pathogen that poses a significant public health threat in healthcare settings. Despite yearly clinical cases rapidly increasing from 77 to 8,131 in the last decade, surveillance data on its distribution and prevalence remain limited. We implemented a novel assay for C. auris detection on a nationwide scale prospectively from September 2023 to March 2024, analyzing a total of 13,842 samples from 190 wastewater treatment plants across 41 U.S. states. Assays were extensively validated through comparison to other known assays and internal controls. Of these 190 wastewater treatment plants, C. auris was detected in the wastewater solids of 65 of them (34.2%) with 1.45% of all samples having detectable levels of C. auris nucleic-acids. Detections varied seasonally, with 2.00% of samples positive in autumn vs 1.01% in winter (P < 0.0001). The frequency of detection in wastewater was significantly associated with states having older populations (P < 0.001), sewersheds containing more hospitals (P < 0.0001), and sewersheds containing more nursing homes (P < 0.001). These associations are in agreement with known C. auris epidemiology. This nationwide study demonstrates the viability of wastewater surveillance for C. auris surveillance and further highlights the value of wastewater surveillance when clinical testing is constrained. IMPORTANCE: This study highlights the viability of wastewater surveillance when dealing with emerging pathogens. By leveraging an existing framework of wastewater surveillance, we reveal the widespread presence of C. auris in the United States. We further demonstrate that these wastewater detections are consistent with demographic factors relevant to C. auris epidemiology like age and number of hospitals or nursing homes. As C. auris and other pathogens continue to emerge, the low-cost and rapid nature of wastewater surveillance will provide public health officials with the information necessary to enact targeted prevention and control strategies.

Cerebral blood flow in relation to peripheral endothelial function in youth bipolar disorder.

INTRODUCTION: Anomalous cerebral blood flow (CBF) is evident in bipolar disorder (BD), however the extent to which CBF reflects peripheral vascular function in BD is unknown. This study investigated endothelial function, an index of early atherosclerosis and cardiovascular disease risk, in relation to CBF among youth with BD. METHODS: Participants included 113 youth, 13-20 years old (66 BD; 47 healthy controls [HC]). CBF was measured using arterial spin labeling with 3T MRI. Region of interest analyses (ROI; global grey matter, middle frontal gyrus, anterior cingulate cortex, temporal cortex, caudate) were undertaken alongside voxel-wise analyses. Reactive hyperemia index (RHI), a measure of endothelial function, was assessed non-invasively via pulse amplitude tonometry. General linear models were used to examine RHI and RHI-by-diagnosis associations with CBF, controlling for age, sex, and body mass index. Bonferroni correction for multiple comparisons was used for ROI analyses, such that the significance level was divided by the number of ROIs (α = 0.05/5 = 0.01). Cluster-extent thresholding was used to correct for multiple comparisons for voxel-wise analyses. RESULTS: ROI findings were not significant after correction. Voxel-wise analyses found that higher RHI was associated with lower left thalamus CBF in the whole group (p < 0.001). Additionally, significant RHI-by-diagnosis associations with CBF were found in three clusters: left intracalcarine cortex (p < 0.001), left thalamus (p < 0.001), and right frontal pole (p = 0.006). Post-hoc analyses showed that in each cluster, higher RHI was associated with lower CBF in BD, but higher CBF in HC. CONCLUSION: We found that RHI was differentially associated with CBF in youth with BD versus HC. The unanticipated association of higher RHI with lower CBF in BD could potentially reflect a compensatory mechanism. Future research, including prospective studies and experimental designs are warranted to build on the current findings.

Patterns of initial ovarian cancer recurrence on niraparib maintenance monotherapy in patients with no baseline evidence of disease after first-line chemotherapy: An ad hoc subgroup analysis of PRIMA/ENGOT-OV26/GOG-3012.

OBJECTIVES: Patterns of disease recurrence on poly(ADP-ribose) polymerase inhibitor maintenance therapy are unclear and may affect subsequent treatment. This ad hoc subgroup analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study evaluated patterns of initial recurrence in patients with advanced ovarian cancer (AOC). METHODS: PRIMA included participants at high risk for disease progression. This ad hoc analysis only evaluated participants randomized to niraparib maintenance without evidence of disease at baseline. The number and site(s) of initial recurrent lesions at investigator-assessed progressive disease (PD) were evaluated. RESULTS: Of the 314 niraparib-treated patients analyzed, 190 developed ≥1 new lesion (median number of new lesions, 1.0; interquartile range, 1-2). In total, 93.2% (177/190) of patients developed 1-3 lesions at first disease progression. The most common sites of recurrence were the peritoneum (30.0% [57/190]), lymph nodes (26.3% [50/190]), and liver (20.5% [39/190]). Similar results were observed when patients with PD were stratified by biomarker status, disease stage at diagnosis, and type of debulking surgery. Patients with homologous recombination-proficient tumors, stage III disease, or a history of primary debulking developed a median of 2.0 new lesions at first progression; patients with homologous recombination-deficient tumors, stage IV disease, or a history of interval debulking developed a median of 1.0 new lesion. CONCLUSIONS: Many patients with AOC without lesions at first-line maintenance treatment initiation develop oligometastatic disease at first recurrence. Prospective evaluation is required to determine whether these patients have improved outcomes when local therapies are combined with continuous, systemic, targeted maintenance therapy.

A Hospice Transitions Program for Patients in the Emergency Department.

Importance: Patients often visit the emergency department (ED) near the end of life. Their common disposition is inpatient hospital admission, which can result in a delayed transition to hospice care and, ultimately, an inpatient hospital death that may be misaligned with their goals of care. Objective: To assess the association of hospice use with a novel multidisciplinary hospice program to rapidly identify and enroll eligible patients presenting to the ED near end of life. Design, Setting, and Participants: This pre-post quality improvement study of a novel, multifaceted care transitions program involving a formalized pathway with email alerts, clinician training, hospice vendor expansion, metric creation, and data tracking was conducted at a large, urban tertiary care academic medical center affiliated with a comprehensive cancer center among adult patients presenting to the ED near the end of life. The control period before program launch was from September 1, 2018, to January 31, 2020, and the intervention period after program launch was from August 1, 2021, to December 31, 2022. Main Outcome and Measures: The primary outcome was a transition to hospice without hospital admission and/or hospice admission within 96 hours of the ED visit. Secondary outcomes included length of stay and in-hospital mortality. Results: This study included 270 patients (median age, 74.0 years [IQR, 62.0-85.0 years]; 133 of 270 women [49.3%]) in the control period, and 388 patients (median age, 73.0 years [IQR, 60.0-84.0 years]; 208 of 388 women [53.6%]) in the intervention period, identified as eligible for hospice transition within 96 hours of ED arrival. In the control period, 61 patients (22.6%) achieved the primary outcome compared with 210 patients (54.1%) in the intervention period (P < .001). The intervention was associated with the primary outcome after adjustment for age, race and ethnicity, primary payer, Charlson Comorbidity Index, and presence of a Medical Order for Life-Sustaining Treatment (MOLST) (adjusted odds ratio, 5.02; 95% CI, 3.17-7.94). In addition, the presence of a MOLST was independently associated with hospice transition across all groups (adjusted odds ratio, 1.88; 95% CI, 1.18-2.99). There was no significant difference between the control and intervention periods in inpatient length of stay (median, 2.0 days [IQR, 1.1-3.0 days] vs 1.9 days [IQR, 1.1-3.0 days]; P = .84), but in-hospital mortality was lower in the intervention period (48.5% [188 of 388] vs 64.4% [174 of 270]; P < .001). Conclusions and Relevance: In this quality improvement study, a multidisciplinary program to facilitate ED patient transitions was associated with hospice use. Further investigation is needed to examine the generalizability and sustainability of the program.

Engaging Mood Brain Circuits with Psilocybin (EMBRACE): a study protocol for a randomized, placebo-controlled and delayed-start, neuroimaging trial in depression.

BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability worldwide across domains of health and cognition, affecting overall quality of life. Approximately one third of individuals with depression do not fully respond to treatments (e.g., conventional antidepressants, psychotherapy) and alternative strategies are needed. Recent early phase trials suggest psilocybin may be a safe and efficacious intervention with rapid-acting antidepressant properties. Psilocybin is thought to exert therapeutic benefits by altering brain network connectivity and inducing neuroplastic changes that endure for weeks post-treatment. Although early clinical results are encouraging, psilocybin's acute neurobiological effects on neuroplasticity have not been fully investigated. We aim to examine for the first time how psilocybin acutely (intraday) and subacutely (weeks) alters functional brain networks implicated in depression. METHODS: Fifty participants diagnosed with MDD or persistent depressive disorder (PDD) will be recruited from a tertiary mood disorders clinic and undergo 1:1 randomization into either an experimental or control arm. Participants will be given either 25 mg psilocybin or 25 mg microcrystalline cellulose (MCC) placebo for the first treatment. Three weeks later, those in the control arm will transition to receiving 25 mg psilocybin. We will investigate whether treatments are associated with changes in arterial spin labelling and blood oxygenation level-dependent contrast neuroimaging assessments at acute and subacute timepoints. Primary outcomes include testing whether psilocybin demonstrates acute changes in (1) cerebral blood flow and (2) functional brain activity in networks associated with mood regulation and depression when compared to placebo, along with changes in MADRS score over time compared to placebo. Secondary outcomes include changes across complementary clinical psychiatric, cognitive, and functional scales from baseline to final follow-up. Serum peripheral neurotrophic and inflammatory biomarkers will be collected at baseline and follow-up to examine relationships with clinical response, and neuroimaging measures. DISCUSSION: This study will investigate the acute and additive subacute neuroplastic effects of psilocybin on brain networks affected by depression using advanced serial neuroimaging methods. Results will improve our understanding of psilocybin's antidepressant mechanisms versus placebo response and whether biological measures of brain function can provide early predictors of treatment response. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06072898. Registered on 6 October 2023.

A Multi-View Deep Learning Model for Thyroid Nodules Detection and Characterization in Ultrasound Imaging.

Thyroid Ultrasound (US) is the primary method to evaluate thyroid nodules. Deep learning (DL) has been playing a significant role in evaluating thyroid cancer. We propose a DL-based pipeline to detect and classify thyroid nodules into benign or malignant groups relying on two views of US imaging. Transverse and longitudinal US images of thyroid nodules from 983 patients were collected retrospectively. Eighty-one cases were held out as a testing set, and the rest of the data were used in five-fold cross-validation (CV). Two You Look Only Once (YOLO) v5 models were trained to detect nodules and classify them. For each view, five models were developed during the CV, which was ensembled by using non-max suppression (NMS) to boost their collective generalizability. An extreme gradient boosting (XGBoost) model was trained on the outputs of the ensembled models for both views to yield a final prediction of malignancy for each nodule. The test set was evaluated by an expert radiologist using the American College of Radiology Thyroid Imaging Reporting and Data System (ACR-TIRADS). The ensemble models for each view achieved a mAP0.5 of 0.797 (transverse) and 0.716 (longitudinal). The whole pipeline reached an AUROC of 0.84 (CI 95%: 0.75-0.91) with sensitivity and specificity of 84% and 63%, respectively, while the ACR-TIRADS evaluation of the same set had a sensitivity of 76% and specificity of 34% (p-value = 0.003). Our proposed work demonstrated the potential possibility of a deep learning model to achieve diagnostic performance for thyroid nodule evaluation.

Cytochrome P450-soluble epoxide hydrolase oxylipins, depression and cognition in type 2 diabetes.

AIMS: This study examined serum cytochrome P450-soluble epoxide hydrolase (CYP450-sEH) oxylipins and depressive symptoms together in relation to cognitive performance in individuals with type 2 diabetes mellitus (T2DM). METHODS: Clinically cognitively normal T2DM individuals were recruited (NCT04455867). Depressive symptom severity was assessed using the Beck Depression Inventory-II (BDI-II; total scores ≤13 indicated minimal depressive symptoms and ≥ 14 indicated significant depressive symptoms). Executive function and verbal memory were assessed. Fasting serum oxylipins were quantified by ultra-high-performance liquid chromatography tandem mass-spectrometry. RESULTS: The study included 85 participants with minimal depressive symptoms and 27 with significant symptoms (mean age: 63.3 ± 9.8 years, 49 % women). In all participants, higher concentrations of linoleic acid derived sEH (12,13-dihydroxyoctadecamonoenoic acid; DiHOME) and CYP450 (12(13)-epoxyoctadecamonoenoic acid; EpOME) metabolites were associated with poorer executive function (F1,101 = 6.094, p = 0.015 and F1,101 = 5.598, p = 0.020, respectively). Concentrations of multiple sEH substrates interacted with depressive symptoms to predict 1) poorer executive function, including 9(10)-EpOME (F1,100 = 12.137, p < 0.001), 5(6)-epoxyeicosatrienoic acid (5(6)-EpETrE; F1,100 = 6.481, p = 0.012) and 11(12)-EpETrE (F1,100 = 4.409, p = 0.038), and 2) verbal memory, including 9(10)-EpOME (F1,100 = 4.286, p = 0.041), 5(6)-EpETrE (F1,100 = 6.845, p = 0.010), 11(12)-EpETrE (F1,100 = 3.981, p = 0.049) and 14(15)-EpETrE (F1,100 = 5.019, p = 0.027). CONCLUSIONS: Associations of CYP450-sEH metabolites and depressive symptoms with cognition highlight the biomarker and therapeutic potential of the CYP450-sEH pathway in T2DM.

Intramedullary Threaded Nail Fixation of Distal Ulnar Fractures: The Surgical Technique and Case Series.

BACKGROUND:  To describe the surgical technique of non-compressive intramedullary threaded nail (IMTN) fixation of distal ulnar neck fractures and present the clinical and radiographic outcomes of four patients treated with this novel technique. METHODS: At a single Level 1 Trauma Center, a retrospective review was conducted for patients with distal ulnar neck fractures treated with retrograde IMTN between 2022 and 2024. Exclusion criteria included inadequate follow-up. A single surgeon performed all procedures using percutaneous retrograde IMTN fixation through the central disc of the triangular fibrocartilage complex (TFCC). Patients initiated a range of motion (ROM) protocol two weeks post-operatively. Post-operative radiographic images were used to calculate the ratio of IMTN diameter to the distal ulnar medullary isthmus diameter proximal to the fracture site. Radiographic changes in displacement, angulation, and ulnar variance were calculated between the first and last follow-up radiographs. Functional outcomes including grip strength and ROM were collected. RESULTS: Four patients with distal ulnar neck fractures were treated with retrograde IMTN between 2022 and 2024. They were followed for a minimum of three months post-operatively. All were female with an average age of 65 years. All distal ulna fractures were associated with operatively treated intraarticular distal radius fractures. All patients were treated with 75 mm length and 4.5 mm diameter IMTNs. IMTN-to-Isthmus ratio was greater than 60% in all cases. Average radiographic displacement and angulation were unchanged at the final follow-up. The average ulnar variance increased by 1.2 mm. At the final follow-up, there were no post-operative complications. No cases demonstrated ulnar-sided wrist pain, nonunion, or required revision surgery. CONCLUSIONS: Retrograde IMTN fixation is a novel surgical technique for the treatment of distal ulnar neck fractures. We found limited but promising post-operative radiographic and functional outcomes in our patients without reported ulnar-sided wrist pain, nonunion, or need for hardware removal.

The prognostic effect of mechanical, ultrastructural, and ECM signatures in glioblastoma core and rim.

Glioblastoma (GBM) is a highly invasive, aggressive brain cancer that carries a median survival of 15 months and is resistant to standard therapeutics. Recent studies have demonstrated that intratumoral heterogeneity plays a critical role in promoting resistance by mediating tumor adaptation through microenvironmental cues. GBM can be separated into two distinct regions-a core and a rim, which are thought to drive specific aspects of tumor evolution. These differences in tumor progression are regulated by the diverse biomolecular and biophysical signals in these regions, but the acellular biophysical characteristics remain poorly described. This study investigates the mechanical and ultrastructural characteristics of the tumor extracellular matrix (ECM) in patient-matched GBM core and rim tissues. Seven patient-matched tumor core and rim samples and one non-neoplastic control were analyzed using atomic force microscopy, scanning electron microscopy, and immunofluorescence imaging to quantify mechanical, ultrastructural, and ECM composition changes. The results reveal significant differences in biophysical parameters between GBM core, rim, and non-neoplastic tissues. The GBM core is stiffer, denser, and is rich in ECM proteins hyaluronic acid and tenascin-C when compared to tumor rim and non-neoplastic tissues. These alterations are intimately related and have prognostic effect with stiff, dense tissue correlating with longer progression-free survival. These findings reveal new insights into the spatial heterogeneity of biophysical parameters in the GBM tumor microenvironment and identify a set of characteristics that may correlate with patient prognosis. In the long term, these characteristics may aid in the development of strategies to combat therapeutic resistance.