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The mucosal barrier is composed of polarized epithelial cells with distinct apical and basolateral surfaces separated by tight junctions and serves as both a physical and immunological barrier to incoming pathogens. Specialized polarity proteins are critical for establishment and maintenance of polarity. Many human pathogens have evolved virulence mechanisms that target the polarity network to enhance binding, create replication niches, move through the barrier by transcytosis, or bypass the barrier by disrupting cell-cell junctions. This review summarizes recent advances and compares and contrasts how three important human pathogens that colonize mucosal surfaces, Pseudomonas aeruginosa, Helicobacter pylori, and Neisseria meningitidis, subvert the host cell polarization machinery during infection.

Pathogens can alter epithelial polarity by recruiting polarity proteins to the apical membrane, but how a change in protein localization is linked to polarity disruption is not clear. In this study, we used chemically induced dimerization to rapidly relocalize proteins from the cytosol to the apical surface. We demonstrate that forced apical localization of Par3, which is normally restricted to tight junctions, is sufficient to alter apical membrane identity through its interactions with phosphatidylinositol 3-kinase (PI3K) and the Rac1 guanine nucleotide exchange factor Tiam1. We further show that PI3K activity is required upstream of Rac1, and that simultaneously targeting PI3K and Tiam1 to the apical membrane has a synergistic effect on membrane remodeling. Thus, Par3 coordinates the action of PI3K and Tiam1 to define membrane identity, revealing a signaling mechanism that can be exploited by human mucosal pathogens.

Background Cabozantinib and gemcitabine improve tumor control in pancreatic ductal adenocarcinoma (PDAC) in preclinical models through c-Met inhibition. We sought to determine the maximum tolerated dose (MTD) of this combination in patients with advanced PDAC. Methods Patients with ≤1 prior treatment and adequate performance status were eligible. Cabozantinib was given orally once daily, beginning day (-)7 and continued with gemcitabine given intravenously on days 1, 8, and 15 every 28 days. Dose level was assigned using Time to Event Continual Reassessment Method (TITE-CRM). Primary endpoint was MTD, defined as the highest dose level at which ≤25 % of patients incurred a dose-limiting toxicity (DLT). Secondary endpoints included response rate, progression-free survival (PFS), overall survival (OS) and urinary biomarker assessment. Results Twelve patients were enrolled and treated with 10 patients evaluable for DLT. The probability of DLT was >25 % for all dose levels tested, and thus an MTD was not determined. DLTs included grade 3 ALT/AST elevations and thrombocytopenia. Three patients had partial responses, but each discontinued therapy due to toxicity. Median PFS and OS were 4.7 (95 % CI: 1.4-9.7) and 10.1 months (95 % CI: 3.6-20.6). Exploratory biomarker analysis showed correlation of c-Met and VEGF levels with response. Conclusions An MTD for the combination was not established. Cabozantinib and gemcitabine appear impractical for further development due to DLT at low doses and continuing toxicities with ongoing therapy. Acknowledging the small sample size, responses were seen suggesting further investigation of c-Met inhibition in PDAC may be warranted.

The mucosal epithelium consists of polarized cells with distinct apical and basolateral membranes that serve as functional and physical barriers to external pathogens. The apical surface of the epithelium constitutes the first point of contact between mucosal pathogens, such as Pseudomonas aeruginosa, and their host. We observed that binding of P. aeruginosa aggregates to the apical surface of polarized cells led to the striking formation of an actin-rich membrane protrusion with inverted polarity, containing basolateral lipids and membrane components. Such protrusions were associated with a spatially localized host immune response to P. aeruginosa aggregates that required bacterial flagella and a type III secretion system apparatus. Host protrusions formed de novo underneath bacterial aggregates and involved the apical recruitment of a Par3/Par6α/aPKC/Rac1 signaling module for a robust, spatially localized host NF-κB response. Our data reveal a role for spatiotemporal epithelial polarity changes in the activation of innate immune responses.

It is known that the incidence of epilepsy increases with age, but only a few studies have investigated the consequences and mechanisms of seizure and epilepsy in aged animals. Astrocytic changes are known to directly influence neuronal excitability and seizure susceptibility. However, information regarding alterations to astrocytes after seizures in aged animals is lacking in the literature. In the present study, the density and morphology of astrocytes expressing GFAP were investigated in the hippocampus of aged rats that experienced status epilepticus induced by pilocarpine. One month after seizures, astrocytes in aged rats have increased volume and present activated morphology. Despite these morphological changes, the density of astrocytes was not altered in the hippocampus of aged rats after seizures.

To identify risk subgroups of youth suicide decedents using demographic and clinical psychiatric and medical diagnostic profiles to inform tailored youth suicide prevention efforts. This study linked Ohio Medicaid and death certificate data for Medicaid enrolled youth aged 8–25 years who died by suicide between January 1, 2010, and December 31, 2020 (N = 511). Latent class analysis was used to identify distinct clinical risk subgroups. Three latent classes were identified. Internalizing problems were common across all classes, but especially prevalent in class 1, the High Internalizing + Multiple Comorbidities group (n = 152, 30%). A prior history of suicidal behavior was confined to class 1 decedents, who were otherwise characterized by substance misuse, and multiple psychiatric and medical comorbidities. Class 2 decedents, the Internalizing + Externalizing group (n = 176, 34%), were more often younger, male, Black, and unlikely to have a history of substance misuse. Decedents in class 3, the Internalizing + Substance Misuse group (n = 183, 36%), were more often older and likely to have a history of substance misuse, but unlikely to exhibit other externalizing problems. Internalizing psychopathology is particularly common among youth who die by suicide, with comorbid externalizing psychopathology, substance misuse, and medical problems contributing to youth suicide risk. Because less than a third of youth who die by suicide have a prior history of recognized suicidal thinking or behavior, universal screening for youth suicide risk should be considered, particularly in younger children, and efforts to integrate suicide prevention in traditional health care settings should be prioritized. [ABSTRACT FROM AUTHOR]

As osteoarthritis (OA) of the trapeziometacarpal (TMC) joint leads to a high degree of disease burden with compromises in rudimentary and fine movements of the hand, intra-articular injections may be a desirable treatment option. However, because there are no evidence-based guidelines, the choice of intra-articular injection type is left to the discretion of the individual surgeon in collaboration with the patient. The purpose of our study was to perform a systematic review and meta-analysis using level I studies to compare outcomes following corticosteroid and alternative methods of intra-articular injections for the management of TMC OA. Our hypothesis was that intra-articular corticosteroid injections were no more effective than other methods of intra-articular injections for the management of TMC OA. A systematic literature search was performed. Eligible for inclusion were randomized control trials reporting on intra-articular corticosteroid injection for the management of TMC OA. Clinical outcomes were recorded. The 10 included studies comprised 673 patients. The mean age was 57.8 ± 8.3 years, with a mean follow-up of 6.4 ± 2.7 months. There was no significant difference in visual analog scale scores, grip strength and tip pinch strength between corticosteroids and hyaluronic acid at short- and medium-term follow-up. Further, there was no difference in visual analog scale pain scores at rest at medium-term follow-up between corticosteroids and platelet-rich plasma. Despite short-term improvement with intra-articular corticosteroid injections, there was no significant difference in pain and functional outcomes following intra-articular corticosteroid injections compared to hyaluronic acid or platelet-rich plasma administration. Given the affordability, ease of administration, and efficacy associated with corticosteroids, they are a favorable option when considering the choice of intra-articular injection for the management of TMC OA. Therapeutic II. [ABSTRACT FROM AUTHOR]

In the current study, we assessed character strengths in individuals with autism spectrum disorder (ASD, n = 32) and neurotypical controls (n = 32) using the Values in Action Inventory (VIA-IS, Peterson and Seligman 2004) and explored associations with levels of satisfaction with life (SWL). The most frequently endorsed signature strengths (i.e., five top-ranked strengths within an individual's strength ranking) were "emotional" ("humour", "love") and "interpersonal strengths" ("kindness", "fairness") in the control group, the most frequently endorsed signature strengths in the ASD group were "intellectual strengths" ("open-mindedness", "creativity", "love of learning"). "Interpersonal" and "emotional strengths" had, however, the highest positive associations with SWL in the ASD group.

Objective: This study examines the psychometric properties of the revised Perceived Social Competence Scale (PSCS), a brief, user-friendly tool used to assess social competence among youth. Method: Confirmatory factor analyses (CFAs) examined the factor structure and invariance of an enhanced scale (PSCS-II), among a sample of 420 youth. Correlations between PSCS-II and self-reported social skill scores were examined. A longitudinal CFA tested the invariance of the factor structure over time with a different sample of 451 youth. Results: The revised 5-item PSCS-II demonstrated acceptable factorial validity, factorial invariance across time and gender as well as strong predictive validity. Conclusion: The PSCS-II was supported as a strengthened version of the PSCS to measure social competence in social work research and practice.

"Transition Planning for Youth with Special Health Care Needs (YSHCN)" chronicles the research and work completed by agencies in Illinois to provide examples of best practice in transition planning. Increasing numbers of YSHCN survive into adulthood creating a need for focus on the transition to adult life for these young people, including meeting health care needs. As a part of the Transitions project, the Illinois Chapter of the American Academy of Pediatrics and the University of Illinois at Chicago Division of Specialized Care for Children surveyed Illinois public high schools to identify transition planning efforts, staff training needs and used those results to develop and implement training. A natural way to organize health services is by integration with school transition services. The credentialed school nurse would be the ideal person to contribute to the development of the health care transition plans based on the student's heath care provider's medical management plan.