Temporal Dissociation of COX-2-Dependent Arachidonic Acid and 2-Arachidonoylglycerol Metabolism in RAW264.7 Macrophages.

Cyclooxygenase-2 converts arachidonic acid (AA) to prostaglandins (PGs) and the endocannabinoid, 2-arachidonoylglycerol (2-AG), to PG glyceryl esters (PG-Gs). The physiological function of PG biosynthesis has been extensively studied, but the importance of the more recently discovered PG-G synthetic pathway remains incompletely defined. This disparity is due in part to a lack of knowledge of the physiological conditions under which PG-G biosynthesis occurs. We have discovered that RAW264.7 macrophages stimulated with Kdo2-lipid A (KLA) produce primarily PGs within the first 12 h followed by robust PG-G synthesis between 12 h and 24 h. We suggest that the amount of PG-Gs quantified is less than actually synthesized, because PG-Gs are subject to a significant level of hydrolysis during the time course of synthesis. Inhibition of cytosolic phospholipase A2 (cPLA2) by giripladib does not accelerate PG-G synthesis, suggesting the differential time course of PG and PG-G synthesis is not due to competition between AA and 2-AG. The late-phase PG-G formation is accompanied by an increase in the level of 2-AG and a concomitant decrease in 18:0-20:4 diacylglycerol (DAG). Inhibition of DAG lipases by KT-172 decreases the levels of 2-AG and PG-Gs, indicating that the DAG-lipase pathway is involved in delayed 2-AG metabolism/PG-G synthesis. These results demonstrate that physiologically significant levels of PG-Gs are produced by activated RAW264.7 macrophages well after the production of PGs plateaus.

High Prevalence of Multistep Algorithms in Diagnostic Clostridioides difficile Laboratory Testing.

CONTEXT.­: Laboratory testing practices for diagnosis of Clostridioides difficile infection (CDI) have evolved in response to published guidelines, availability of highly sensitive nucleic acid amplification tests (NAATs), perceived problems with the specificity of NAATs, and CDI reporting requirements. OBJECTIVE.­: To assess the current state of laboratory practice for diagnostic CDI testing. DESIGN.­: An optional 8-item supplemental questionnaire was distributed in December 2019 to the 1374 laboratories participating in the College of American Pathologists C difficile Detection (CDF) proficiency testing program challenge CDF-C. RESULTS.­: Of 1374 CDF-C participants, 1160 (84.4%) responded, predominantly representing laboratories based in the United States (1077 of 1160; 92.8%). The majority reported using a multistep testing algorithm (684 of 1159; 59.0%). Initial testing with a glutamate dehydrogenase and toxin A/B combination test followed by NAAT for discrepant results was the most common testing method (360 of 1146; 31.4%). NAAT alone (299 of 1146; 26.1%) was next, then NAAT followed by an assay that included toxin A/B enzyme immunoassay if NAAT is positive (258 of 1146; 22.5%). Only 5.4% (62 of 1146) reported using toxin A/B immunoassay alone. Most respondents (1093 of 1131; 96.6%) reported rejecting CDI tests on formed stool, but rejection of CDI testing in pediatric patients was uncommon (211 of 1131; 18.7%). Rejection of CDI testing in patients using laxatives was reported more often by US-based respondents (379 of 1054 [36.0%] versus 9 of 77 [11.7%], P < .001). CONCLUSIONS.­: Multistep algorithms for CDI diagnosis are widely used in line with published recommendations. Most respondents reported rejection of formed stool for CDI testing, but few reported rejection of testing in infants and patients taking laxatives, suggesting these may be areas of opportunity for laboratories to pursue in improving CDI testing practices.

HDL-C criterion of the metabolic syndrome and future diabetes and atherosclerosis in midlife women: The SWAN Study.

Objective: High-density lipoprotein cholesterol (HDL-C) is one of 5 components [high blood pressure, glucose, triglycerides, waist circumference, low HDL-C], 3 of which, needed to diagnose metabolic syndrome (MetS). Evolving research shows that higher HDL-C is not necessarily cardioprotective in midlife women, supporting a need to re-evaluate HDL-C's contribution to risks related to MetS. We tested whether risk of future diabetes and higher carotid intima-media thickness (cIMT) differ by HDL-C status in midlife women diagnosed with MetS based on the other 4 components. Methods Midlife women were classified into 3 groups: 1) no MetS, 2) MetS with HDL-C ≥ 50 mg/dL (MetS hiHDL), and 3) MetS with HDL-C < 50 mg/dL (MetS loHDL). cIMT was measured 13.8 ± 0.6 years post baseline. Incident diabetes was assessed yearly. Results: Among 2773 women (1350 (48 %) of them had cIMT), 2383 (86 %) had no MetS, 117 (4 %) had MetS hiHDL, 273 (10 %) had MetS loHDL. Compared with no MetS, both MetS- hiHDL and loHDL groups had higher cIMT and diabetes risk. Risk of having high cIMT did not differ between MetS loHDL vs. hiHDL groups. Adjusting for levels of MetS criteria other than HDL-C at baseline explained the associations of each of the two MetS groups with cIMT. Conversely, after adjustment, associations of MetS hiHDL and MetS loHDL with incident diabetes persisted. Conclusions: In midlife women, HDL-C status matters for predicting risk of incident diabetes but not higher cIMT beyond other MetS components.

Deep Learning-Based Automated Measurement of Murine Bone Length in Radiographs.

Genetic mouse models of skeletal abnormalities have demonstrated promise in the identification of phenotypes relevant to human skeletal diseases. Traditionally, phenotypes are assessed by manually examining radiographs, a tedious and potentially error-prone process. In response, this study developed a deep learning-based model that streamlines the measurement of murine bone lengths from radiographs in an accurate and reproducible manner. A bone detection and measurement pipeline utilizing the Keypoint R-CNN algorithm with an EfficientNet-B3 feature extraction backbone was developed to detect murine bone positions and measure their lengths. The pipeline was developed utilizing 94 X-ray images with expert annotations on the start and end position of each murine bone. The accuracy of our pipeline was evaluated on an independent dataset test with 592 images, and further validated on a previously published dataset of 21,300 mouse radiographs. The results showed that our model performed comparably to humans in measuring tibia and femur lengths (R2 > 0.92, p-value = 0) and significantly outperformed humans in measuring pelvic lengths in terms of precision and consistency. Furthermore, the model improved the precision and consistency of genetic association mapping results, identifying significant associations between genetic mutations and skeletal phenotypes with reduced variability. This study demonstrates the feasibility and efficiency of automated murine bone length measurement in the identification of mouse models of abnormal skeletal phenotypes.

Adults With Spina Bifida Fare Worse Than Young Adults: A Systemic Vulnerability in Urinary Tract Infection-Related Hospital Care.

PURPOSE: We aim to estimate the odds of UTI-related hospital care in spina bifida (SB) patients aged 18 to 25 years as compared with patients with SB in adolescence (11-17 years) or adulthood (26-35 years). We hypothesize that patients with SB in the typical transitional age, 18 to 25 years, will have higher odds of UTI-related hospital care as compared to adolescent SB patients or adult SB patients. MATERIALS AND METHODS: Using Cerner Real-World Data, we performed a retrospective cohort analysis comparing SB patients to age- and gender-matched controls. SB cases between 2015 and 2021 were identified and compared in 3 cohorts: 11 to 17 years (adolescents), 18 to 25 years (young adults [YA]), and 26 to 35 years (adults). Logistic regression analysis was used to characterize the odds of health care utilization. RESULTS: Of the 5497 patients with SB and 77,466 controls identified, 1839 SB patients (34%) and 3275 controls (4.2%) had at least 1 UTI encounter. UTI-related encounters as a proportion of all encounters significantly increased with age in SB patients (adolescents 8%, YA 12%, adult 15%; P < .0001). Adjusting for race, sex, insurance, and comorbidities, the odds of a UTI-related encounter in YA with SB were significantly higher than for adolescents with SB (adolescent odds ratio = 0.65, 95% CI: 0.57-0.75, P < .001). YA had lower odds of a UTI-related encounter as compared with adults with SB (adult odds ratio = 1.31, 95% CI: 1.16-1.49, P < .001). CONCLUSIONS: YA with SB have higher odds of UTI-related hospital care than adolescents, but lower odds of UTI-related hospital care when compared with adults.

Foals of mares vaccinated for Hendra virus have a suboptimal response to HeV vaccination.

Hendra virus (HeV) is lethal to horses and a zoonotic threat to humans in Australia, causing severe neurological and/or respiratory disease with high mortality. An equine vaccine has been available since 2012. Foals acquire antibodies from their dams by ingesting colostrum after parturition, therefore it is assumed that foals of mares vaccinated against HeV will have passive HeV antibodies circulating during the first several months of life until they are actively vaccinated. However, no studies have yet examined passive or active immunity against HeV in foals. Here, we investigated anti-HeV antibody levels in vaccinated mares and their foals. Testing for HeV neutralising antibodies is cumbersome due to the requirement for Biosafety level 4 (BSL-4) containment to conduct virus neutralisation tests (VNT). For this study, a subset of samples was tested for HeV G-specific antibodies by both an authentic VNT with infectious HeV and a microsphere-based immunoassay (MIA), revealing a strong correlation. An indicative neutralising level was then applied to the results of a larger sample set tested using the MIA. Mares had high levels of HeV-specific neutralising antibodies at the time of parturition. Foals acquired high levels of maternal antibodies which then waned to below predictive protective levels in most foals by 6 months old when vaccination commenced. Foals showed a suboptimal response to vaccination, suggesting maternal antibodies may interfere with active vaccination. The correlation analysis between the authentic HeV VNT and HeV MIA will enable further high throughput serological studies to inform optimal vaccination protocols for both broodmares and foals.

Glucocorticoid receptors orchestrate a convergence of host and cellular stress signals in triple negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks expression of the nuclear steroid receptors that bind estrogens (ER) and progestogens (PRs) and does not exhibit HER2 (Human epidermal growth factor 2) receptor overexpression. Even in the face of initially effective chemotherapies, TNBC patients often relapse. One primary cause for therapy-resistant tumor progression is the activation of cellular stress signaling pathways. The glucocorticoid receptor (GR), a corticosteroid-activated transcription factor most closely related to PR, is a mediator of both endocrine/host stress and local tumor microenvironment (TME)-derived and cellular stress responses. Interestingly, GR expression is associated with a good prognosis in ER+ breast cancer but predicts poor prognosis in TNBC. Classically, GR's transcriptional activity is regulated by circulating glucocorticoids. Additionally, GR is regulated by ligand-independent signaling events. Notably, the stress-activated protein kinase, p38 MAP kinase, phosphorylates GR at serine 134 (Ser134) in response to TME-derived growth factors and cytokines, including HGF and TGFß1. Phospho-Ser134-GR (p-Ser134-GR) associates with cytoplasmic and nuclear signaling molecules, including 14-3-3ζ, aryl hydrocarbon receptors (AhR), and hypoxia-inducible factors (HIFs). Phospho-GR/HIF-containing transcriptional complexes upregulate gene sets whose protein products include the components of inducible oncogenic signaling pathways (PTK6) that further promote cancer cell survival, chemoresistance, altered metabolism, and migratory/invasive behavior in TNBC. Recent studies have implicated liganded p-Ser134-GR (p-GR) in dexamethasone-mediated upregulation of genes related to TNBC cell motility and dysregulated metabolism. Herein, we review the tumor-promoting roles of GR and discuss how both ligand-dependent and ligand-independent/stress signaling-driven inputs to p-GR converge to orchestrate metastatic TNBC progression.

Associations of endogenous estrogens, plasma Alzheimer's disease biomarkers, and APOE4 carrier status on regional brain volumes in postmenopausal women.

Background: Women carrying the APOE4 allele are at greater risk of developing Alzheimer's disease (AD) from ages 65-75 years compared to men. To better understand the elevated risk conferred by APOE4 carrier status among midlife women, we investigated the separate and interactive associations of endogenous estrogens, plasma AD biomarkers, and APOE4 carrier status on regional brain volumes in a sample of late midlife postmenopausal women. Methods: Participants were enrolled in MsBrain, a cohort study of postmenopausal women (n = 171, mean age = 59.4 years, mean MoCA score = 26.9; race = 83.2% white, APOE4 carriers = 40). Serum estrone (E1) and estradiol (E2) levels were assessed using liquid chromatography-tandem mass spectrometry. APOE genotype was determined using TaqMan SNP genotyping assays. Plasma AD biomarkers were measured using single molecule array technology. Cortical volume was measured and segmented by FreeSurfer software using individual T1w MPRAGE images. Multiple linear regression models were conducted to determine whether separate and interactive associations between endogenous estrogen levels, plasma AD biomarkers (Aß42/Aß40, Aß42/p-tau181), and APOE4 carrier status predict regional brain volume (21 regions per hemisphere, selected a priori); and, whether significant interactive associations between estrogens and AD biomarkers on brain volume differed by APOE4 carrier status. Results: There was no main effect of APOE4 carrier status on regional brain volumes, endogenous estrogen levels, or plasma AD biomarkers. Estrogens did not associate with regional brain volumes, except for positive associations with left caudal middle frontal gyrus and fusiform volumes. The interactive association of estrogens and APOE4 carrier status on brain volume was not significant for any region. The interactive association of estrogens and plasma AD biomarkers predicted brain volume of several regions. Higher E1 and E2 were more strongly associated with greater regional brain volumes among women with a poorer AD biomarker profile (lower Aß42/40, lower Aß42/p-tau181 ratios). In APOE4-stratified analyses, these interactions were driven by non-APOE4 carriers. Conclusion: We demonstrate that the brain volumes of postmenopausal women with poorer AD biomarker profiles benefit most from higher endogenous estrogen levels. These findings are driven by non-APOE4 carriers, suggesting that APOE4 carriers may be insensitive to the favorable effects of estrogens on brain volume in the postmenopause.

Gyrification across psychotic disorders: A bipolar-schizophrenia network of intermediate phenotypes study.

BACKGROUND: The profiles of cortical gyrification across schizophrenia, bipolar I disorder, and schizoaffective disorder have been studied to a limited extent, report discordant findings, and are rarely compared in the same study. Here we assess gyrification in a large dataset of psychotic disorder probands, categorized according to the DSM-IV. Furthermore, we explore gyrification changes with age across healthy controls and probands. METHODS: Participants were recruited within the Bipolar-Schizophrenia Network of Intermediate Phenotypes study and received T1-MPRAGE and clinical assessment. Gyrification was measured using FreeSurfer 7.1.0. Pairwise t-tests were conducted in R, and age-related gyrification changes were analyzed in MATLAB. P values <0.05 after false discovery rate correction were considered significant. RESULTS: Significant hypogyria in schizophrenia, bipolar disorder, and schizoaffective disorder probands compared to controls was found, with a significant difference bilaterally in the frontal lobe between schizophrenia and bipolar disorder probands. Verbal memory was associated with gyrification in the right frontal and right cingulate cortex in schizophrenia. Age-fitted gyrification curves differed significantly among psychotic disorders and controls. CONCLUSIONS: Findings indicate hypogyria in DSM-IV psychotic disorders compared to controls and suggest differential patterns of gyrification across the different diagnoses. The study extends age related models of gyrification to psychotic disorder probands and supports that age-related differences in gyrification may differ across diagnoses. Fitted gyrification curves among probands categorized by DSM-IV significantly deviate from controls, with the model capturing early hypergyria and later hypogyria in schizophrenia compared to controls; this suggests unique disease and age-related changes in gyrification across psychotic disorders.

Developing a phenotype risk score for tic disorders in a large, clinical biobank.

Tics are a common feature of early-onset neurodevelopmental disorders, characterized by involuntary and repetitive movements or sounds. Despite affecting up to 2% of children and having a genetic contribution, the underlying causes remain poorly understood. In this study, we leverage dense phenotype information to identify features (i.e., symptoms and comorbid diagnoses) of tic disorders within the context of a clinical biobank. Using de-identified electronic health records (EHRs), we identified individuals with tic disorder diagnosis codes. We performed a phenome-wide association study (PheWAS) to identify the EHR features enriched in tic cases versus controls (n = 1406 and 7030; respectively) and found highly comorbid neuropsychiatric phenotypes, including: obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorder, and anxiety (p < 7.396 × 10-5). These features (among others) were then used to generate a phenotype risk score (PheRS) for tic disorder, which was applied across an independent set of 90,051 individuals. A gold standard set of tic disorder cases identified by an EHR algorithm and confirmed by clinician chart review was then used to validate the tic disorder PheRS; the tic disorder PheRS was significantly higher among clinician-validated tic cases versus non-cases (p = 4.787 × 10-151; ß = 1.68; SE = 0.06). Our findings provide support for the use of large-scale medical databases to better understand phenotypically complex and underdiagnosed conditions, such as tic disorders.

A systematic umbrella review and meta-meta-analysis of eHealth and mHealth interventions for improving lifestyle behaviours.

The aim of this meta-meta-analysis was to systematically review randomised controlled trial (RCT) evidence examining the effectiveness of e- and m-Health interventions designed to improve physical activity, sedentary behaviour, healthy eating and sleep. Nine electronic databases were searched for eligible studies published from inception to 1 June 2023. Systematic reviews with meta-analyses of RCTs that evaluate e- and m-Health interventions designed to improve physical activity, sedentary behaviour, sleep and healthy eating in any adult population were included. Forty-seven meta-analyses were included, comprising of 507 RCTs and 206,873 participants. Interventions involved mobile apps, web-based and SMS interventions, with 14 focused on physical activity, 3 for diet, 4 for sleep and 26 evaluating multiple behaviours. Meta-meta-analyses showed that e- and m-Health interventions resulted in improvements in steps/day (mean difference, MD = 1329 [95% CI = 593.9, 2065.7] steps/day), moderate-to-vigorous physical activity (MD = 55.1 [95% CI = 13.8, 96.4] min/week), total physical activity (MD = 44.8 [95% CI = 21.6, 67.9] min/week), sedentary behaviour (MD = -426.3 [95% CI = -850.2, -2.3] min/week), fruit and vegetable consumption (MD = 0.57 [95% CI = 0.11, 1.02] servings/day), energy intake (MD = -102.9 kcals/day), saturated fat consumption (MD = -5.5 grams/day), and bodyweight (MD = -1.89 [95% CI = -2.42, -1.36] kg). Analyses based on standardised mean differences (SMD) showed improvements in sleep quality (SMD = 0.56, 95% CI = 0.40, 0.72) and insomnia severity (SMD = -0.90, 95% CI = -1.14, -0.65). Most subgroup analyses were not significant, suggesting that a variety of e- and m-Health interventions are effective across diverse age and health populations. These interventions offer scalable and accessible approaches to help individuals adopt and sustain healthier behaviours, with implications for broader public health and healthcare challenges.

Endogenous estrogens and brain activation during verbal memory encoding and recognition in the postmenopause.

OBJECTIVE: Determine associations of endogenous estrogens with memory systems in the postmenopausal brain and evaluate clinical significance. STUDY DESIGN: In the MsBrain cohort (n=199, mean age 59.3+3.9 years, 83.9% white), we examined the cross-sectional association of serum estradiol and estrone, measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS), during a functional magnetic resonance imaging (fMRI) task of word encoding and recognition. To characterize the clinical significance of those associations, we examined the magnitude of activation in relation to a neuropsychological measures of memory and affect. RESULTS: Endogenous estradiol was positively associated with activation in temporal and frontal cortices during encoding and negatively associated with one prefrontal region during recognition (p<.05). Activation in the left inferior frontal gyrus was associated with memory performance (ß(SE)= 0.004(0.002), p<.05), and anxiety (ß(SE)= -0.100(0.050), p<.05). The left middle frontal gyrus was associated with memory performance (ß(SE)= 0.006(0.002), p<.01), depression, and anxiety. The left superior temporal gyrus (STG) was associated with depression (ß(SE)= -0.083(0.036), p<.05) and anxiety (ß(SE)= -0.134(0.058), p<.05). Estrone was positively associated with activation in a range of brain areas including bilateral STG and right superior frontal gyrus during encoding (p<.05). Activation of the left insula an precental gyrus were associated with symptoms of depression and anxiety. None related to memory. CONCLUSION: The function of brain areas critical to memory performance varies with estrogen levels in the postmenopause, even though those levels are low. Higher levels of estradiol may facilitate memory performance through enhanced function of temporal and frontal cortices during encoding of verbal material.

Degradation in Binaural and Spatial Hearing and Auditory Temporal Processing Abilities as a Function of Aging.

Objectives: Sensorineural hearing loss is common with advancing age, but even when hearing is normal or near normal in older persons, performance deficits are often seen for suprathreshold listening tasks such as understanding speech in background noise or localizing the direction sounds are coming from. This suggests there is also a more central source of the problem. Objectives of this study were to examine as a function of age (young adult to septuagenarian) performance on: 1) a spatial acuity task examining lateralization ability, and a spatial speech-in-noise (SSIN) recognition task, both measured in a hemi-anechoic sound field using a circular horizontal-plane loudspeaker array, and 2) a suprathreshold auditory temporal processing task and a spectro-temporal processing task, both measured under headphones. Further, we examined any correlations between the measures. Design: Subjects were 48 adults, aged 21 to 78, with either normal hearing or only a mild sensorineural hearing loss through 4000 Hz. The lateralization task measured minimum audible angle (MAA) for 500 and 4000 Hz narrowband noise (NBN) bursts in diffuse background noise for both an on-axis (subject facing 0°) and off-axis (facing 45°) listening condition at signal-to-noise ratios (SNRs) of -3, -6, -9, and -12 dB. For 42 of the subjects, SSIN testing was also completed for key word recognition in sentences in multi-talker babble noise; specifically, the separation between speech and noise loudspeakers was adaptively varied to determine the difference needed for 40% and 80% correct performance levels. Finally, auditory temporal processing ability was examined using the Temporal Fine Structure test (44 subjects), and the Spectro-Temporal Modulation test (46 subjects). Results: Mean lateralization performances were poorer (larger MAAs) in older compared to younger subjects, particularly in the more adverse listening conditions (i.e., for 4000 Hz, off-axis, and at poorer SNRs). Performance variability was notably higher for older subjects than for young adults. The 4000 Hz NBN bursts produced larger MAAs than did 500 Hz NBN bursts. The SSIN data also showed declining mean performance with age at both criterion levels, with greater variability again found for older subjects. Spearman rho analyses revealed some low to moderate, but significant correlation coefficients for age versus MAA and for age versus SSIN results. Results from both the TFS and STM showed decreased mean performance with aging, and revealed moderate, significant correlations, with the strongest relationship shown with the TFS test. Finally, of note, extended-high-frequency (EHF) hearing loss (measured between 9000 and 16,000 Hz) was found to increase with aging, but was not seen in the young adult subjects. Conclusions: Particularly for more adverse listening conditions, age-related deficits were found on both of the spatial hearing tasks and in temporal and spectro-temporal processing abilities. It may be that deficits in temporal processing ability contribute to poorer spatial hearing performance in older subjects due to inaccurate coding of binaural/interaural timing information sent from the periphery to the brainstem. In addition, EHF hearing loss may be a coexisting factor that impacts performance in older subjects.

Signal Regulatory Protein α Expression in Systemic Vasculitis.

OBJECTIVE: Signal regulatory protein α (SIRPα) is found primarily on myeloid cells, including macrophages and neutrophils; binds to CD47; and regulates phagocytosis, antigen presentation, cellular fusion, cell proliferation, and migration. Therefore, SIRPα may be involved in the pathogenesis of autoimmune diseases, including systemic vasculitis. This study aimed to assess SIRPα expression in tissue samples from patients with vasculitis. METHODS: Immunohistochemical staining for SIRPα was performed on temporal artery (TA), kidney, and lung biopsy samples from patients with giant cell arteritis (GCA), patients with microscopic polyangiitis (MPA), patients with granulomatosis with polyangiitis (GPA), and patients without vasculitis. A score of SIRPα+ expression was calculated, derived from the percentages of monocytes, macrophages, and dendritic cells and neutrophils with different staining intensities in affected tissues. RESULTS: A total of 46 samples from patients with different vasculitides (GCA, MPA, and GPA) were included in the study. Tissue samples included TA samples from 15 patients with GCA; kidney samples from 11 and 9 patients with GPA and MPA, respectively; and lung samples from 11 patients with GPA. Most tissue samples from patients with active vasculitis (15 of 15 TA samples, 17 of 20 kidney samples, and 9 of 11 lung samples) showed SIRPα staining. SIRPα staining intensity was less in kidney samples compared to TA and lung samples. CONCLUSION: This study demonstrates high-level expression of SIRPα in macrophages and monocytes in affected tissue in systemic vasculitis. These findings provide a foundation for further studies exploring the role of the SIRPα-CD47 pathway in the pathogenesis of systemic vasculitis and the potential for the blockade of SIRPα and/or the depletion of SIRPα+ cells as treatment of systemic vasculitis.

Feedback and observational learning differ in effectiveness during category learning in early school aged children and adults.

When learning new categories, do children benefit from the same types of training as adults? We compared the effects of feedback-based training with observational training in young adults (ages 18-25) and early school aged children (ages 6-7) across two different multimodal category learning tasks: conjunctive rule based and information integration. We used multimodal stimuli that varied across a visual feature (rotation speed of the "planet" stimulus) and an auditory feature (pitch frequency of a pure tone stimulus). We found an interaction between age and training type for the rule-based category task, such that adults performed better in feedback training than in observational training, whereas training type had no significant effect on children's category learning performance. Overall adults performed better than children in learning both the rule based and information integration category structures. In information integration category learning, feedback versus observational training did not have a significant effect on either adults' or children's category learning. Computational modelling revealed that children defaulted to univariate rules in both tasks. The finding that children do not benefit from feedback training and can learn successfully via observational learning has implications for the design of educational interventions appropriate for children.

Outcomes in solid organ transplant recipients receiving organs from a donor with Fusarium solani species complex meningitis.

BACKGROUND: Five organs (heart, right lung, liver, right, and left kidneys) from a deceased patient were transplanted into five recipients in four US states; the deceased patient was identified as part of a healthcare-associated fungal meningitis outbreak among patients who underwent epidural anesthesia in Matamoros, Mexico. METHODS: After transplant surgeries occurred, Fusarium solani species complex, a fungal pathogen with a high case-mortality rate, was identified in cerebrospinal fluid from the organ donor by metagenomic next-generation sequencing (mNGS) and fungal-specific polymerase chain reaction and in plasma by mNGS. RESULTS: Four of five transplant recipients received recommended voriconazole prophylaxis; four were monitored weekly by serum (1-3)-ß-d-glucan testing. All five were monitored for signs of infection for at least 3 months following transplantation. The liver recipient had graft failure, which was attributed to an etiology unrelated to fungal infection. No fungal DNA was identified in sections of the explanted liver, suggesting that F. solani species complex did not contribute to graft failure. The remaining recipients experienced no signs or symptoms suggestive of fusariosis. CONCLUSION: Antifungal prophylaxis may be useful in preventing donor-derived infections in recipients of organs from donors that are found to have Fusarium meningitis.

Oral Lipid Nanocrystal Amphotericin B (MAT2203) for the Treatment of Invasive Fungal Infections.

Amphotericin B (AmB) has broad fungicidal activity against many fungi, but the high incidence of adverse events, particularly nephrotoxicity, and the need for intravenous administration restrict its use for many patients. MAT2203, an investigational oral AmB formulation available under a compassionate use program, uses a lipid nanocrystal bilayer structure to deliver AmB with lower toxicity. We present a synopsis of clinical characteristics, treatment course, and outcomes for 5 patients who were treated with MAT2203. Outcomes were positive, with cure of infection noted in 4 patients and improvement in 1 patient who remains on therapy. MAT2203 was well tolerated with only modest gastrointestinal adverse effects. This new oral formulation might provide a safer treatment option for patients requiring extended courses of AmB.