Comparison of Adult Female and Male PMHS Pelvis and Lumbar Response to Underbody Blast.

The goal of this study was to gather and compare kinematic response and injury data on both female and male whole-body Post-mortem Human Surrogates (PMHS) responses to Underbody Blast (UBB) loading. Midsized males (50th percentile, MM) have historically been most used in biomechanical testing and were the focus of the Warrior Injury Assessment Manikin (WIAMan) program, thus this population subgroup was selected to be the baseline for female comparison. Both small female (5th percentile, SF) and large female (75th percentile, LF) PMHS were included in the test series to attempt to discern whether differences between male and female responses were predominantly driven by sex or size. Eleven tests, using 20 whole-body PMHS, were conducted by the research team. Preparation of the rig and execution of the tests took place at the Aberdeen Proving Grounds (APG) in Aberdeen, MD. Two PMHS were used in each test. The Accelerative Loading Fixture (ALF) version 2, located at APG's Bear Point range was used for all male and female whole-body tests in this series. The ALF was an outdoor test rig that was driven by a buried explosive charge, to accelerate a platform holding two symmetrically mounted seats. The platform was designed as a large, rigid frame with a deformable center section that could be tuned to simulate the floor deformation of a vehicle during a UBB event. PMHS were restrained with a 5-point harness, common in military vehicle seats. Six-degree-of-freedom motion blocks were fixed to L3, the sacrum, and the left and right iliac wings. A three-degree-of freedom block was fixed to T12. Strain gages were placed on L4 and multiple locations on the pelvis. Accelerometers on the floor and seat of the ALF provided input data for each PMHS' feet and pelvis. Time histories and mean peak responses in z-axis acceleration were similar among the three PMHS groups in this body region. Injury outcomes were different and seemed to be influenced by both sex and size contributions. Small females incurred pelvis injuries in absence of lumbar injures. Midsized males had lumbar vertebral body fractures without pelvis injuries. And large females with injuries had both pelvis and lumbar VB fractures. This study provides evidence supporting the need for female biomechanical testing to generate female response and injury thresholds. Without the inclusion of female PMHS, the differences in the injury patterns between the small female and midsized male groups would not have been recognized. Standard scaling methods assume equivalent injury patterns between the experimental and scaled data. In this study, small female damage occurred in a different anatomical structure than for the midsized males. This is an important discovery for the development of anthropomorphic test devices, injury criteria, and injury mitigating technologies. The clear separation of small female damage results, in combination with seat speeds, suggest that the small female pelvis injury threshold in UBB events lies between 4 - 5 m/s seat speed. No inference can be made about the small female lumbar threshold, other than it is likely at higher speeds and/or over longer duration. Male lumbar spine damage occurred in both the higher- and lower lower-rate tests, indicating the injury threshold would be below the seat pulses tested in these experiments. Large females exhibited injury patterns that reflected both the small female and midsized male groups - with damaged PMHS having fractures in both pelvis and lumbar, and in both higher- and lower- rate tests. The difference in damage patterns between the sex and size groups should be considered in the development of injury mitigation strategies to protect across the full population.

Clinical variables associated with major adverse cardiac events following radical cystectomy.

Objectives: The objective of this study is to investigate the association between major adverse cardiac events (MACE) and clinical factors of patients undergoing radical cystectomy (RC) for bladder cancer. Materials and Methods: A retrospective analysis using the 2015-2020 National Surgical Quality Improvement Program database was performed on patients who underwent RC for bladder cancer. MACE was defined as any report of cerebrovascular accident, myocardial infarction, or thromboembolic events (pulmonary embolism or deep vein thrombosis). A multivariable-adjusted logistic regression was conducted to identify clinical predictors of postoperative MACE. Results: A total of 10 308 (84.2%) patients underwent RC with incontinent urinary diversion (iUD), and 1938 (15.8%) underwent RC with continent urinary diversion (cUD). A total of 629 (5.1%) patients recorded a MACE, and on the multivariable-adjusted logistic regression, it was shown that MACE was significantly associated with increased age (OR = 1.035, 95% CI: 1.024-1.046, p < 0.001), obesity (OR = 1.583, 95% CI: 1.266-1.978, p < 0.001), current smokers (OR = 1.386, 95% CI: 1.130-1.700, p = 0.002), congestive heart failure before surgery (OR = 1.991, 95% CI: 1.016-3.900; p = 0.045), hypertension (OR = 1.209, 95% CI: 1.016-1.453, p = 0.043), and increase the surgical time (per 10 min increase, OR = 1.010, 95% CI: 1.003-1.017, p = 0.009). We also report that increased age, obesity, and patients undergoing cUD (OR = 1.368, 95% CI: 1.040-1.798; p = 0.025) are associated with thromboembolic events. Conclusion: By considering the preoperative characteristics of patients, including age, obesity, smoking, congestive heart failure, and hypertension status, urologists may be able to decrease the incidence of MACE in patients undergoing RC. Urologists should aim for lower operative times as this was associated with a decreased risk of thromboembolic events.

Structure and scaling of the middle ear in domestic dog breeds.

Although domestic dogs vary considerably in both body size and skull morphology, behavioural audiograms have previously been found to be similar in breeds as distinct as a Chihuahua and a St Bernard. In this study, we created micro-CT reconstructions of the middle ears and bony labyrinths from the skulls of 17 dog breeds, including both Chihuahua and St Bernard, plus a mongrel and a wolf. From these reconstructions, we measured middle ear cavity and ossicular volumes, eardrum and stapes footplate areas and bony labyrinth volumes. All of these ear structures scaled with skull size with negative allometry and generally correlated better with condylobasal length than with maximum or interaural skull widths. Larger dogs have larger ear structures in absolute terms: the volume of the St Bernard's middle ear cavity was 14 times that of the Chihuahua. The middle and inner ears are otherwise very similar in morphology, the ossicular structure being particularly well-conserved across breeds. The expectation that larger ear structures in larger dogs would translate into hearing ranges shifted towards lower frequencies is not consistent with the existing audiogram data. Assuming that the audiograms accurately reflect the hearing of the breeds in question, oversimplifications in existing models of middle ear function or limitations imposed by other parts of the auditory system may be responsible for this paradox.

Comparative morphology of the avian bony columella.

In birds, the columella is the only bony element of the sound conducting apparatus, conveying vibrations of the cartilaginous extracolumella to the fluid of the inner ear. Although avian columellar morphology has attracted some attention over the past century, it nonetheless remains poorly described in the literature. The few existing studies mostly focus on morphological descriptions in relatively few taxa, with no taxonomically broad surveys yet published. Here we use observations of columellae from 401 extant bird species to provide a comprehensive survey of columellar morphology in a phylogenetic context. We describe the columellae of several taxa for the first time and identify derived morphologies characterizing higher-level clades based on current phylogenies. In particular, we identify a derived columellar morphology diagnosing a major subclade of Accipitridae. Within Suliformes, we find that Fregatidae, Sulidae, and Phalacrocoracidae share a derived morphology that is absent in Anhingidae, suggesting a secondary reversal. Phylogenetically informed comparisons allow recognition of instances of homoplasy, including the distinctive bulbous columellae in suboscine passerines and taxa belonging to Eucavitaves, and bulging footplates that appear to have evolved at least twice independently in Strigiformes. We consider phylogenetic and functional factors influencing avian columellar morphology, finding that aquatic birds possess small footplates relative to columellar length, possibly related to hearing function in aquatic habitats. By contrast, the functional significance of the distinctive bulbous basal ends of the columellae of certain arboreal landbird taxa remains elusive.

Medical School Curricula and the Role of Third-Party Resources in Medical Student Urology Education.

OBJECTIVE: To assess the quality and extent of the urology education provided to medical students both by third-party resources (TPRs) and by the curriculum provided by medical schools METHODS: TPRs were assessed by systematically comparing the content of the 4 most common resources (Anking, Pathoma, Uworld, and First Aid) to the American Urological Association's Medical Student Curriculum (AUA-MSC). Medical school curricula were assessed via a survey sent to the top-150 allopathic medical schools in the United States. The survey asked about clinical and pre-clinical exposure to urology received by medical students at their school. RESULTS: The TPRs for Step 1 together covered 73.3% of the AUA-MSC topics, and for Step 2 covered 81.9%. First Aid covered 49.5% of Step 1 topics and 58.4% of Step 2 topics, Uworld covered 58.6% and 67.9%, respectively, and Anking covered 61.8% and 58.8%, respectively. Pathoma covered 28.1% of Step 1 topics. Survey results showed that 33/39 (84.6%) of schools have required urology coursework in preclinical years, but only 3/39 (7.7%) have required urology rotations in the third or fourth years. Of those without required rotations, 35/36 (97.2%) indicated that they offer an elective rotation in urology. CONCLUSION: There is little emphasis placed on urology after the preclinical years of medical school, pointing to a need for greater exposure to these topics regardless of the student's selected specialty. This need stems from incomplete knowledge provided by TPRs compared to the AUA-MSC. Drawing attention to this gap can provide insight for those creating future iterations of medical curricula and shed light on areas in need of improvement, which would ultimately benefit both patients and providers.

Factors associated with urinary incontinence among Hispanic/Latina women in the United States: Findings from The Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

PURPOSE: To identify factors associated with urinary incontinence (UI) in women of various Hispanic/Latina backgrounds. MATERIALS AND METHODS: We analyzed data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a multicenter, community-based cohort study which includes a health-related questionnaire assessing presence and type of UI. Complex survey logistic regression analysis was used to assess the cross-sectional association of Hispanic/Latina backgrounds and other factors of UI. All estimates accounted for HCHS/SOL survey design. RESULTS: Of 5027 women, 33.4% answered "yes" to UI. Rates of any UI ranged from approximately 21.9% to 40.3% in women of Dominican and Puerto-Rican background, respectively. Any UI and UI subtypes were associated with age older than 65 years, increasing body mass index, smoking status, any alcohol use, parity ≥3, and postmenopausal status. After controlling for covariates and when compared with women of Mexican background, women of Dominican background were less likely to have any UI (OR = 0.42, 95% CI 0.30-0.57), as were women of Cuban (OR = 0.48, 95% CI 0.37-0.62), Puerto-Rican (OR = 0.79, 95% CI 0.62-1.0), and mixed (OR = 0.62, 95% CI 0.39-0.99) background; and women of every other background except for South American were less likely to have stress UI. In addition, women of Cuban (OR = 0.53, 95% CI 0.32-0.86) and mixed (OR = 0.38, 95% CI 0.16-0.87) background were less likely to have urge UI than women of Mexican background. CONCLUSIONS: Our study demonstrates differences in UI by Hispanic/Latina background, suggesting collective designation of Hispanics/Latinas as a single ethnic group does not adequately describe UI among this diverse group.

Structure-function relationships in the nasal cavity of Arctic and subtropical seals.

The heating and moistening of inhaled air, and the cooling and moisture removal from exhaled air, are crucial for the survival of animals under severe environmental conditions. Arctic mammals have evolved specific adaptive mechanisms to retain warmth and water and restrict heat loss during breathing. Here, the role of the porous turbinates of the nasal cavities of Arctic and subtropical seals is studied with this in mind. Mass and energy balance equations are used to compute the time-dependent temperature and water vapor profiles along the nasal passage. A quasi-1D model based on computed tomography images of seal nasal cavities is used in numerical simulations. Measured cross-sectional areas of the air channel and the perimeters of the computed tomography slices along the nasal cavities of the two seal species are used. The model includes coupled heat and vapor transfer at the air-mucus interface and heat transfer at the interfaces between the tissues and blood vessels. The model, which assumes constant blood flow to the nose, can be used to predict the temperature of the exhaled air as a function of ambient temperature. The energy dissipation (entropy production) in the nasal passages was used to measure the relative importance of structural parameters for heat and water recovery. We found that an increase in perimeter led to significant decreases in the total energy dissipation. This is explained by improved conditions for heat and water transfer with a larger complexity of turbinates. Owing to differences in their nasal cavity morphology, the Arctic seal is expected to be advantaged in these respects relative to the subtropical seal.

Effectiveness of fit testing versus fit checking for healthcare workers respiratory protective equipment: A systematic review.

Objectives: Respiratory protection is critical in healthcare to minimise the risk of airborne infections for healthcare workers (HCWs). It emphasizes the use of proper fitting of particulate filter respirators and equivalent respiratory protective equipment (RPE) to ensure a good facial seal. The systematic review aimed to compare the effectiveness of fit testing and fit checking for HCWs' respiratory protective equipment. Methods: A systematic review of the literature exploring RPE for HCWs to determine the effectiveness of fit-testing versus fit-checking from January 2003 to April 2022 was identified using CINAHL Complete via EBSCO Host, Cochrane Library, EMBASE, PubMed, and MEDLINE via Ovid electronic databases, and grey literature. The study protocol was registered with PROSPERO (registration number: CRD42020213968). Results: Of the 561 articles identified in the search, 25 articles (22 quantitative studies and three guidelines) were included in this review. Overall, these studies suggest fit-testing as a method that is more effective, widely adopted, and reliable in assessing the effectiveness of RPE; however, a respiratory program should include both fit-testing and fit-checking to maximise effectiveness of the RPE. The COVID-19 epidemic highlighted a lack of knowledge among HCWs regarding fit-checking and fit-testing, and relevant education increased the effectiveness of respiratory equipment protection. Conclusion: It is imperative that both fit-testing and fit-checking is implemented in order to ensure HCW safety. It is recommended to integrate education, fit-testing and fit-checking into a comprehensive respiratory protective program run by trained fit-testers. There is also a need for practical testing methods that incorporate the clinical environment.

Racial disparity in the utilization of immunotherapy for advanced prostate cancer.

PURPOSE: To identify whether there was a disparity in the utilization of immunotherapy in the treatment of black patients with metastatic castration resistant prostate cancer (mCRPC). METHODS: Using the National Cancer Database, we identified patients between 2010- 2015 with likely minimally/asymptomatic mCRPC. We analyzed annual trends for chemotherapy and immunotherapy use and compared utilization by demographic and clinical features. Multivariable analysis was performed to determine predictors of receiving immunotherapy vs chemotherapy. RESULTS: We identified 1301 patients with likely mCRPC. The majority were non Hispanic White (NHW - 63 %) and 23 % were non-Hispanic Black (NHB). Overall, there was increased utilization of immunotherapy in mCRPC from 2010 onwards, with the peak occurring in 2014 (4.6 %). Chemotherapy use increased significantly, peaking in 2014 to 26.1 %. However, the increased utilization of immunotherapy in the mCRPC was mainly seen in White patients: from 50 % to 74.2 % of the cohort. Conversely, there was a decrease in utilization of immunotherapy among Black mCPRC patients: from 50 % to 25.8 %. On multivariable analysis, there was no statistically significant difference between treatment types by race. CONCLUSION: FDA approval of Sipuleucel-T for mCRPC led to increased utilization of immunotherapy shortly thereafter, but this was mainly noted in white patients. Black patients comparatively did not exhibit increased utilization of this novel agent after 2010. Further studies are necessary to help understand barriers to access to new treatment in mCRPC and eliminate the burden of disease in minority populations."

An Australian convective wind gust climatology using Bayesian hierarchical modelling.

To quantify the hazard or risks associated with severe convective wind gusts, it is necessary to have a reliable and spatially complete climatology of these events. The coupling of observational and global reanalysis (ERA-Interim) data over the period 2005-2015 is used here to facilitate the development of a spatially complete convective wind gust climatology for Australia. This is done through the development of Bayesian Hierarchical models that use both weather station-based wind gust observations and seasonally averaged severe weather indices (SWI), calculated using reanalysis data, to estimate seasonal gust frequencies across the country while correcting for observational biases specifically, the sparse observational network to record events. Different SWI combinations were found to explain event counts for different seasons. For example, combinations of Lifted Index and low level wind shear were found to generate the best results for autumn and winter. While for spring and summer, the composite Microburst Index and the combination of most unstable CAPE and 0-1 km wind shear were found to be most successful. Results from these models showed a minimum in event counts during the winter months, with events that do occur mainly doing so along the southwest coast of Western Australia or along the coasts of Tasmania and Victoria. Summer is shown to have the largest event counts across the country, with the largest number of gusts occurring in northern Western Australia extending east into the Northern Territory with another maximum over northeast New South Wales. Similar trends were found with an extended application of the models to the period 1979-2015 when utilizing only reanalysis data as input. This implementation of the models highlights the versatility of the Bayesian hierarchical modelling approach and its ability, when trained, to be used in the absence of observations.

Optimum threshold of the 4Kscore for biopsy in men with negative or indeterminate multiparametric magnetic resonance imaging.

Objective: The study aims to identify the optimal 4Kscore thresholds to determine the need for a prostate biopsy when multiparametric magnetic resonance imaging (MRI) (mpMRI) is negative or indeterminate. Materials and methods: We analysed retrospective data from men in eight different institutions who underwent an mpMRI, 4Kscore and prostate biopsy for evaluation of prostate cancer. We selected men with a negative (PIRADS ≤2) or indeterminate (PIRADS 3) mpMRI. 4Kscore values were categorized into ranges of 1-7, 8-19, 20-32 and greater than 32. We evaluated the proportion of men with grade group 2 or higher (GG2+) cancer in groups defined by PIRADS and 4Kscore. We also evaluated the number of biopsies avoided and GG2+ cancer missed in each group reported depend on 4Kscore cutoff points. Results: Among 1111 men who had an mpMRI, 4Kscore and biopsy, 625 of them had PIRADS ≤3 on mpMRI: 374 negative (PIRADS ≤2) and 251 indeterminate (PIRADS 3). In men with a negative mpMRI, we found a 4Kscore cut-point of 33 resulted in an increased risk of GG2+ cancer on biopsy. In patients with an equivocal lesion on mpMRI, men with a 4Kscore cutoff ≥8 had a greater risk of GG2+ cancer on biopsy. Decision curve analysis supported the proposed cut-points in each mpMRI group. Conclusions: In men with negative and indeterminate mpMRI, we found the best 4Kscore threshold to determine the need for biopsy to be 33 and 8 respectively. Future prospective studies in independent populations are needed to confirm these findings.

Incidence and predictors of deep incisional and organ/space surgical site infection following radical cystectomy.

OBJECTIVE: To investigate clinical risk factors associated with postoperative deep incisional or organ/space surgical site infections (SSI) following radical cystectomy (RC) in a well characterized and large contemporary cohort. METHODS: We used the American College of Surgeons National Surgical Quality Improvement Program database to identify adult patients who underwent RC for bladder cancer between 2015 and 2020 (n = 13,081). We conducted multivariable-adjusted logistic regression and Cox adjusted proportional hazards regression analysis to identify clinical predictors of deep incisional or organ/space SSI in the 30-day postoperative-period following RC. RESULTS: Deep incisional or organ/space SSI risk increased with continent urinary diversion (HR = 1.61, 95% CI: 1.38-1.88; P < 0.001), obesity (HR = 1.60, 95% CI: 1.35-1.90; P < 0.001), diabetes mellitus (HR = 1.30, 95% CI: 1.13-1.51; P < 0.001), and being functionally dependent before surgery (HR = 2.09, 95% CI: 1.44-3.03; P < 0.001). CONCLUSIONS: Postoperative deep incisional or organ/space SSIs following RC occur more frequently in patients who were obese, diabetic, functionally dependent before surgery, and those who underwent continent urinary diversion. These findings may assist urologists in preoperative counseling, medical optimization, and choice of urinary diversion approach, as well as improved patient monitoring and identification of candidates for intervention postoperatively.

Two Affordable, High-Fidelity Central Venous Models for Ultrasound-Guided Interventional Training.

INTRODUCTION: Ultrasound-guided vascular access is an increasingly popular technique due to its reduced complication and higher success rates. Commercially bought training phantoms allow providers to develop tactile skills in a low-risk setting, but are also expensive and poorly accessible. This study analyzes the efficacy of homemade, low-cost, gelatin-based central line vascular models to teach vascular anatomy and intravascular access techniques in training physicians. METHODS: A gelatin mold was created using a mixture of unflavored gelatin, hot water, psyllium husk powder, and rubbing alcohol. Latex tubing, balloons, precooked hot dog, and tofu were inserted to simulate arteries, veins, nerves, and the sternocleidomastoid muscle, respectively. Medical students from a single institution participated in a 90-minute workshop led by interventional radiology residents. Participants completed presurveys and postsurveys that assessed knowledge acquisition and confidence levels related to acquiring central access. All images were obtained using a USB-C Butterfly iQ probe. RESULTS: Twenty medical students were analyzed after the workshop. There was a statistically significant increase in self-reported confidence in basic ultrasound use (adjusting gain, depth, probe manipulation), localizing major anatomical structures, using ultrasound for vessel access, and reported ease in identifying muscle, nerves, and major blood vessels under ultrasound. There was also a significant increase in correctly identified anatomical landmarks after the workshop, including the sternocleidomastoid muscle, internal jugular vein, carotid artery, femoral nerve, femoral artery, and femoral vein. CONCLUSIONS: Our findings suggest that our homemade, low-cost, gelatin-based models were effective in teaching vascular anatomy and ultrasound-guided vascular access techniques to training physicians.

Endometrial carcinoma: association between mutational status, sites of metastasis, recurrence, and correlation with overall survival.

PURPOSE: To investigate the association between sites of endometrial carcinoma (EC) recurrence and metastases, mutational status, race, and overall survival (OS). METHODS: This single-center retrospective study evaluated patients with biopsy-proven EC that underwent genomic molecular testing between January 2015 and July 2021. Association between genomic profile and sites of metastases or recurrence was performed using Pearson's chi-squared or Fisher exact test. Survival curves for ethnicity and race, mutations, sites of metastases or recurrence were estimated using the Kaplan-Meier method. Univariable and multivariable Cox proportional hazard regression models were used. RESULTS: The study included 133 women [median age 64 years (IQR 57-69)]. The most common mutation was TP53 (65/105 patients, 62%). The most common site of metastasis was the peritoneum (35/43, 81%). The most common recurrence was in lymph nodes (34/75, 45%). Mutations of TP53 and PTEN were significantly associated with Black women (p = 0.048, p = 0.004, respectively). In the univariable Cox regression analyses, TP53 mutation and presence of recurrence or metastases to the peritoneum were associated with lower OS (HR 2.1; 95% CI 1.1, 4.3; p = 0.03/ HR 2.9; 95% CI 1.6, 5.4; p = 0.0004; respectively). On multivariable Cox proportional hazards model ER expression (HR 0.4; 95% CI 0.22, 0.91; p = 0.03), peritoneal recurrence or metastases (HR 3.55; 95% CI 1.67, 7.57; p = 0.001), and Black race (HR 2.2; 95% CI 1.1, 4.6; p = 0.03) were significant independent predictors of OS. CONCLUSIONS: The integration of EC mutational status and clinicopathological risk assessment demonstrated potential implications on the patterns of metastasis, recurrence, and OS.

Disease stage-dependent changes in brain levels and neuroprotective effects of neuroactive steroids in Parkinson's disease.

Neuroactive steroids are known neuroprotective agents and neurotransmitter regulators. We previously found that expression of the enzymes synthesizing 5α-dihydroprogesterone (5α-DHP), allopregnanolone (ALLO), and dehydroepiandrosterone sulfate (DHEAS) were reduced in the substantia nigra (SN) of Parkinson's Disease (PD) brain. Here, concentrations of a comprehensive panel of steroids were measured in human post-mortem brains of PD patients and controls. Gas chromatography-mass spectrometry (GC/MS) was used to measure steroid levels in SN (involved in early symptoms) and prefrontal cortex (PFC) (involved later in the disease) of five control (CTR) and nine PD donors, divided into two groups: PD4 (PD-Braak stages 1-4) and PD6 (PD-Braak stages 5-6). In SN, ALLO was increased in PD4 compared to CTR and 5α-DHP and ALLO levels were diminished in PD6 compared to PD4. The ALLO metabolite 3α5α20α-hexahydroprogesterone (3α5α20α-HHP) was higher in PD4 compared to CTR. In PFC, 3α5α20α-HHP was higher in PD4 compared to both CTR and PD6. The effects of 5α-DHP, ALLO and DHEAS were tested on human post-mortem brain slices of patients and controls in culture. RNA expression of genes involved in neuroprotection, neuroinflammation and neurotransmission was analysed after 5 days of incubation with each steroid. In PD6 slices, both 5α-DHP and ALLO induced an increase of the glutamate reuptake effector GLAST1, while 5α-DHP also increased gene expression of the neuroprotective TGFB. In CTR slices, ALLO caused reduced expression of IGF1 and GLS, while DHEAS reduced the expression of p75 and the anti-apoptotic molecule APAF1. Together these data suggest that a potentially protective upregulation of ALLO occurs at early stages of PD, followed by a downregulation of progesterone metabolites at later stages that may exacerbate the pathological changes, especially in SN. Neuroprotective effects of neurosteroids are thus dependent on the neuropathological stage of the disease.

Uterine serous carcinoma: assessing association between genomics and patterns of metastasis.

Background: Uterine serous carcinoma (USC) is an aggressive subtype of endometrial carcinoma which has been increasing at alarming rates, particularly among Asian, Hispanic and Black women. USC has not been well characterized in terms of mutational status, pattern of metastases and survival. Objective: To investigate the association between sites of recurrence and metastases of USC, mutational status, race, and overall survival (OS). Methods: This single-center retrospective study evaluated patients with biopsy-proven USC that underwent genomic testing between January 2015 and July 2021. Association between genomic profile and sites of metastases or recurrence was performed using χ2 or Fisher's exact test. Survival curves for ethnicity and race, mutations, sites of metastasis/recurrence were estimated using the Kaplan-Meier method and compared with log-rank test. Cox proportional hazard regression models were used to examine the association between OS with age, race, ethnicity, mutational status, and sites of metastasis/recurrence. Statistical analyses were performed using SAS Software Version 9.4. Results: The study included 67 women (mean age 65.8 years, range 44-82) with 52 non-Hispanic women (78%) and 33 Black women (49%). The most common mutation was TP53 (55/58 women, 95%). The peritoneum was the most common site of metastasis (29/33, 88%) and recurrence (8/27, 30%). PR expression was more common in women with nodal metastases (p=0.02) and non-Hispanic women (p=0.01). ERBB2 alterations were more common in women with vaginal cuff recurrence (p=0.02), while PIK3CA mutation was more common in women with liver metastases (p=0.048). ARID1A mutation and presence of recurrence or metastases to the liver were associated with lower OS (Hazard Ratio (HR): 31.87; 95%CI: 3.21, 316.9; p<0.001 and HR: 5.66; 95%CI: 1.2, 26.79; p=0.01, respectively). In the bivariable Cox model, the presence of metastasis/recurrence to the liver and/or the peritoneum were both independent significant predictors of OS (HR: 9.8; 95%CI: 1.85-52.7; p=0.007 and HR: 2.7; 95%CI: 1.02-7.1; p=0.04, respectively). Conclusions: TP53 is often mutated in USC, which most commonly metastasize and recur in the peritoneum. OS was shorter in women with ARID1A mutations and with metastasis/recurrence to the liver. The presence of metastasis/recurrence to liver and/or peritoneum were independently associated with shorter OS.

Microglia Transcriptional Profiling in Major Depressive Disorder Shows Inhibition of Cortical Gray Matter Microglia.

BACKGROUND: Microglia have been implicated in the pathophysiology of major depressive disorder (MDD), but information on biological mechanisms is limited. Therefore, we investigated the gene expression profile of microglial cells in relation to neuronal regulators of microglia activity in well-characterized MDD and control autopsy brains. METHODS: Pure, intact microglia were isolated at brain autopsy from occipital cortex gray matter (GM) and corpus callosum white matter of 13 donors with MDD and 10 age-matched control donors for RNA sequencing. Top differentially expressed genes were validated using immunohistochemistry staining. Because gene expression changes were only detected in GM microglia, neuronal regulators of microglia were investigated in cortical tissue and synaptosomes from the cortex by reverse transcriptase-quantitative polymerase chain reaction and Western blot. RESULTS: Transcriptome analysis revealed 92 genes differentially expressed in microglia isolated from GM, but none in microglia from white matter in donors with MDD, compared with control donors. Of these, 81 genes were less abundantly expressed in GM in MDD, including CD163, MKI67, SPP1, CD14, FCGR1A/C, and C1QA/B/C. Accordingly, pathways related to effector mechanisms, such as the complement system and phagocytosis, were differentially regulated in GM microglia in MDD. Immunohistochemistry staining revealed significantly lower expression of CD163 protein in MDD. Whole tissue analysis showed an increase in CD200 (p = .0009) and CD47 (p = .068) messenger RNA, and CD47 protein was significantly elevated (p = .0396) in synaptic fractions of MDD cases. CONCLUSIONS: Transcriptional profiling indicates an immune-suppressed microglial phenotype in MDD that is possibly caused by neuronal regulation.