The immunomodulatory effect of oral NaHCO3 is mediated by the splenic nerve: multivariate impact revealed by artificial neural networks.

Stimulation of the inflammatory reflex (IR) is a promising strategy for treating systemic inflammatory disorders. Recent studies suggest oral sodium bicarbonate (NaHCO3) as a potential activator of the IR, offering a safe and cost-effective treatment approach. However, the mechanisms underlying NaHCO3-induced anti-inflammatory effects remain unclear. We investigated whether oral NaHCO3's immunomodulatory effects are mediated by the splenic nerve. Female rats received NaHCO3 or water (H2O) for four days, and splenic immune markers were assessed using flow cytometry. NaHCO3 led to a significant increase (p < 0.05, and/or partial eta squared > 0.06) in anti-inflammatory markers, including CD11bc + CD206 + (M2-like) macrophages, CD3 + CD4 + FoxP3 + cells (Tregs), and Tregs/M1-like ratio. Conversely, proinflammatory markers, such as CD11bc + CD38 + TNFα + (M1-like) macrophages, M1-like/M2-like ratio, and SSChigh/SSClow ratio of FSChighCD11bc + cells, decreased in the spleen following NaHCO3 administration. These effects were abolished in spleen-denervated rats, suggesting the necessity of the splenic nerve in mediating NaHCO3-induced immunomodulation. Artificial neural networks accurately classified NaHCO3 and H2O treatment in sham rats but failed in spleen-denervated rats, highlighting the splenic nerve's critical role. Additionally, spleen denervation independently influenced Tregs, M2-like macrophages, Tregs/M1-like ratio, and CD11bc + CD38 + cells, indicating distinct effects from both surgery and treatment. Principal component analysis (PCA) further supported the separate effects. Our findings suggest that the splenic nerve transmits oral NaHCO3-induced immunomodulatory changes to the spleen, emphasizing NaHCO3's potential as an IR activator with therapeutic implications for a wide spectrum of systemic inflammatory conditions.

Mitf regulates gene expression networks implicated in B cell homeostasis, germinal center responses, and tolerance.

Introduction: The microphthalmia transcription factor Mitf has been shown to regulate B cell activation and tolerance. However, the underlying B cell-specific mechanisms responsible, and those that distinguish Mitf from closely related Mitf/TFE (MiT) transcription factors Tfe3, Tfeb, and Tfec, remain obscure. Methods: Two complementary mouse models of Mitf and MiT deficiency were used: the Mitfmi-vga9/mi-vga9 systemic loss-of-function mutation, and B-cell specific MiT family inactivation via transgenic expression of a trans-dominant negative (TDN) protein (TDN-B). These models were employed to identify MiT family candidate target genes and pathways. Results: Both models displayed spontaneous splenomegaly coincident with elevated plasma cell numbers, autoantibody titers, and proteinuria. These abnormalities appeared dependent on T helper cells, but independent of other non-B cell intrinsic effects of systemic Mitf inactivation. MiT inactivation in B cells augmented aspects of lupus-like autoimmune disease on the C57BL/6-Faslpr/lpr background. In both models, RNAseq of ex vivo resting B cells showed transcriptional upregulation of genes that control cell cycle, germinal center responses, and plasma cell differentiation. Among the genes strongly upregulated in both models were Socs6, Isp53 (Baiap1), S1pR2, and IgG2b/c. Mitf null B cells, but not TDN-B cells, showed evidence of type I interferon dysregulation. Discussion: These studies clarify Mitf's role as 1) a key regulator of a B cell intrinsic germinal center program that influences self-tolerance through novel target genes, and 2) a regulator of systemic inflammatory processes that can impact the B cell microenvironment. This distinction of Mitf's function from that of related MiT transcription factors advances our understanding of B cell regulation and autoimmunity.

PA access to provider health programs.

OBJECTIVE: This study assessed the availability of provider health programs (PHPs) for physician associates/assistants (PAs), as well as the accessibility of information about these resources through state licensing boards and PA constituent organizations. METHODS: Data were collected through audits of the websites of the PA licensing board and state/district constituent group for each state and the District of Columbia from October to November 2022. RESULTS: Every state except Massachusetts has a PHP that serves PAs. Review of the 51 respective state licensing board websites revealed that 23 states (45.1%) list PHP information; only 9 states (17.6%) have PHP information listed on state PA constituent organization websites. CONCLUSIONS: The results of this study indicate that PHPs for PAs are widely available. Unfortunately, the broad availability of PHPs may be limited by the lack of accessible information about these programs in many states.

Foundational Skill-Building in a Novel Well-being Curriculum.

INTRODUCTION: Mental illness and decreased well-being are pervasive throughout physician assistant (PA) training, and the accreditation standards require a wellness curriculum. The purpose of this study was to determine if a mandatory, multifaceted virtual wellness curriculum can mitigate the decline in well-being experienced by first-year PA students. METHODS: First-year PA students from 5 programs (n = 259) participated in a 16-week asynchronous virtual course. The course integrated evidence-based content on vulnerability and stigma, mindfulness and decentering, and reflective writing. Total weekly content averaged 30-60 minutes and was presented in multiple formats including recorded lectures and panels, readings, and discussion forums. Students completed anonymous pre- and postsurveys, and ordinary least squares (OLS) regression with a fixed effect for each school was used for data analysis. RESULTS: In total, 157 of 259 (60.6%) students completed both surveys with matching unique identifiers. The majority of students (73.6%; 134/182) thought this course had a positive impact on their training as a PA student. Baseline scores were significantly predictive of end-point scores for the PHLMS, OMS-HC-15, SSOSH, RPQ, and UCLA-3 (see Methods section for full names of surveys). Race was significantly predictive of PHLMS and OMS-HC-15 scores; age was significantly predictive of SSOSH scores; and gender was significantly predictive of RPQ scores. DISCUSSION: For a student with low baseline well-being who is entering a PA program, dedicated curricula focusing on foundational wellness skills can be successful in improving well-being. Future work is needed to more fully characterize the scope and extent of this program's impact on PA learners. Additional efforts are also necessary to optimize the delivery and provide access to PA students nationwide.

A Gift You Give Yourself: A Preemptive Intervention for Student Mental Health.

INTRODUCTION: Burnout, stress, and compromised mental health are known issues for clinical trainees. Various interventions have shown efficacy, but they are generally training-based and therefore not practical for "just in time" use when a student is struggling. Stigma surrounding mental health is another challenge to this aspect of wellness. METHODS: At the beginning of their training, physician assistant (PA) students from 3 cohorts at Butler University wrote short reflections on resiliency and their motivation for training. This, along with an encouraging note from a faculty member, was placed in a box and wrapped. Students then kept the box to open during a time of stress or self-doubt. An anonymous survey about this intervention was sent to these students in April 2021. RESULTS: Almost all survey respondents remembered the activity and had a positive impression of it. Nearly half opened the gift box during their training, with a majority opening it during the didactic phase rather than the clinical phase. Most of those who opened the gift box viewed it favorably. Participants reported high levels of self-stigma regarding mental health and help-seeking. DISCUSSION: The gift box intervention was well-received and used by many students. This is a "just in time" intervention to support struggling learners when they need it most, as opposed to most interventions that are more structured in their delivery and use. The high level of self-stigma for mental health help-seeking is a concern and warrants continued investigation.

Can a basic solution activate the inflammatory reflex? A review of potential mechanisms, opportunities, and challenges.

Stimulation of the inflammatory reflex (IR) is a promising strategy to treat systemic inflammatory disorders. However, this strategy is hindered by the cost and side effects of traditional IR activators. Recently, oral intake of sodium bicarbonate (NaHCO3) has been suggested to activate the IR, providing a safe and inexpensive alternative. Critically, the mechanisms whereby NaHCO3 might achieve this effect and more broadly the pathways underlying the IR remain poorly understood. Here, we argue that the recognition of NaHCO3 as a potential IR activator presents exciting clinical and research opportunities. To aid this quest, we provide an integrative review of our current knowledge of the neural and cellular pathways mediating the IR and discuss the status of physiological models of IR activation. From this vantage point, we derive testable hypotheses on potential mechanisms whereby NaHCO3 might stimulate the IR and compare NaHCO3 with classic IR activators. Elucidation of these mechanisms will help determine the therapeutic value of NaHCO3 as an IR activator and provide new insights into the IR circuitry.

Didactic Physician Assistant Students' Perceptions of Evidence-Based Medicine Resources: A Preliminary Investigation.

Evidence-Based Medicine (EBM) instruction is required for physician Assistant (PA) students. This pilot study surveyed didactic PA students at three geographically diverse PA programs at the end of their didactic EBM course to understand which attributes of EBM resources they find most and least useful, and their self-efficacy in searching and appraising medical literature. Thematic analysis identified the most important student-reported attributes of a resource. PA students in this sample preferred UpToDate and PubMed as their top EBM tools based on attribute ratings. However, each database included in this pilot study received positive feedback, despite a low usage rate across institutions. The most important attributes were ease of use/search, information presentation, and conclusion/critical appraisal skill. After one EBM course, on average, students rated their self-efficacy searching the literature and appraising the literature as "moderately confident." This suggests that instructors and librarians have an opportunity to expose students to more tools as well as encourage "the right tool for the right job."

A MACS protocol for purification of untouched germinal center B cells from unimmunized or germinal center-induced mice.

Highly enriched germinal center (GC) B cell populations are essential for studying humoral immunity. Current MACS protocols that isolate untouched GC B cells require GC induction and typically require further FACS purification with direct antibody labeling to achieve sufficiently high purities. We present a MACS protocol with progressive and repeated negative selections that yields highly purified untouched GC B cells from both unimmunized and GC-induced mice and allows further FACS isolation of unlabeled GC B cells from remaining debris by scatter.

Attitudes Towards Mental Health Among Physician Assistant Students with Shared Living Experiences Through Synchronous Videoconferencing.

PURPOSE: We tested the hypothesis that physician assistant (PA) students can benefit from exposure to senior PAs who share their living experiences with mental illness. METHODS: First-year students from 5 PA programs were asked to participate in this mixed methods study. After completing a pre-activity survey, students from 3 programs participated in an intervention consisting of senior PA faculty sharing their mental health experiences, including treatment and recovery. A facilitated discussion followed, and students not exposed to the intervention served as controls. The qualitative component of the study was based on transcripts from 3 focus groups of students in the exposed group. RESULTS: We recruited 167 students from 5 PA training programs, 112 of whom (67%) completed baseline and endpoint assessments (37 in the exposed group, 75 in the control). The intervention resulted in significant improvements on the Opening Minds to Stigma (OMS-HC, p = 0.002, Cohen's d = 0.38) and Self-Stigma of Seeking Help (SSOSH, p = 0.006, d = 0.31) scales. Change in the OMS-HC was driven by its social distance (p = 0.003) and disclosure (p = 0.02) subscales. No comparable changes were found in the control group. We identified 3 overarching themes: 1) active elements of the intervention; 2) mutuality; and 3) peer relationships. CONCLUSIONS: Senior PAs sharing their lived experiences with mental illness proved to be an effective anti-stigma intervention for PA students. A candid, intimate, and confidential virtual learning space was feasible through synchronized videoconferencing. Our findings can inform programmatic interventions to address stigma, self-stigma, help-seeking behaviors, and the overall mental health of PA students.

PA licensure questions, the Americans with Disabilities Act, and seeking medical care.

OBJECTIVE: This study built on a recent publication to explore physician assistant (PA) licensure renewal applications, as well as PA likelihood to seek help for physical or mental health conditions. METHODS: We were able to obtain licensure renewal applications from 47 states. A national survey was then conducted to explore the connection between licensure questions and help-seeking behavior. RESULTS: Only 18 states were consistent with the Americans with Disabilities Act (ADA) in their approach to initial and renewal applications. Thirty-five percent of PAs expressed reluctance to seek help for a mental health issue due to concerns about licensure repercussions. States with applications that were inconsistent with the ADA were significantly more likely to express these concerns. CONCLUSIONS: Considerable stigma exists among PAs regarding seeking help for mental health issues. Problematic licensure questions increase this reluctance. Advocacy is needed to reduce stigma of mental health and substance use, and to modernize licensure applications.

SMS2 deficiency impairs PKCδ-regulated B cell tolerance in the germinal center.

B cell tolerance prevents autoimmunity by deleting or deactivating autoreactive B cells that otherwise may cause autoantibody-driven disorders, including systemic lupus erythematosus (lupus). Lupus is characterized by immunoglobulin Gs carrying a double-stranded (ds)-DNA autospecificity derived mainly from somatic hypermutation in the germinal center (GC), pointing to a checkpoint breach of GC B cell tolerance that leads to lupus. However, tolerance mechanisms in the GC remain poorly understood. Here, we show that upregulated sphingomyelin synthase 2 (SMS2) in anti-dsDNA GC B cells induces apoptosis by directly activating protein kinase C δ (PKCδ)'s pro-apoptotic activity. This tolerance mechanism prevents lupus autoimmunity in C57/BL6 mice and can be stimulated pharmacologically to inhibit lupus pathogenesis in lupus-prone NZBWF1 mice. Patients with lupus consistently have substantially reduced SMS2 expression in B cells and to an even greater extent in autoimmune-prone, age-associated B cells, suggesting that patients with lupus have insufficient SMS2-regulated B cell tolerance.

The Relationship between a Defined Microstructure within the Mold Surface and the Corresponding Roughness on the Part: A Systematic Study on Particle Size, Filler-, and Compatibilizer Content.

The perception of a surface and its haptic properties are significantly influenced by roughness and microstructure, respectively, whereby non-negligible parameters include friction, contact area, temperature, and humidity between the human finger and the examined surface. In particular, for a scientific investigation on haptic influences, the production of samples with a defined surface roughness is indispensable. The aim of this study is to analyze the impact of various mold insert roughnesses combined with the influences of particle size, filler-, and compatibilizer content on impression quality. An unfilled high density polyethylene was chosen as a reference for the impression quality investigations, while fillers with significantly different particle sizes and a compatibilizer were used to produce proprietary compounds. Injection molded parts were manufactured utilizing mold inserts with three different line roughness values. To support the obtained results, a multivariate analysis of variance, a simulation of the filling phase as well as a rheological material characterization were conducted. The results revealed that (i) the impression quality can be independent of the applied insert roughness based on the filler particle size that was studied, (ii) an increasing on both filler particle size and compatibilizer content raise the sample roughness as a function of the penetration ability of the filler into the insert valleys, and (iii) with a higher insert roughness, the thermoplastic moldings generally exhibit a significantly smoother topography. An assumed correlation between part roughness and melt viscosity could not be confirmed.

Assessing Trends in Physician Assistant Student Depression Risk, Suicidal Ideation, and Mental Health Help-Seeking Behavior.

PURPOSE: The purpose of this study was to assess how physician assistant (PA) student depression risk, suicidal ideation, and mental health help-seeking behaviors change during didactic training and the relationship between depression risk and demographic factors. METHODS: Data were obtained through an anonymous online survey sent to didactic students in 7 PA programs during orientation and again at midpoint of the didactic year. Descriptive statistics, independent samples t-testing, and one-way ANOVA analyses were used to assess trends in patient health questionnaire (PHQ-9) scores over the 6-month time period. The PHQ-9 is the module of the PHQ that measures severity of depression risk. RESULTS: The orientation survey response rate was 82.7% (287/347) and the midpoint survey response rate was 62% (217/350). Analysis revealed that mean PHQ-9 scores increased significantly from 2.49 to 6.42 (p < 0.001) from orientation to midpoint of the didactic year, with 18.9% of students having scores of 10 or greater at midpoint compared to 4.5% at orientation. Thoughts of self-harm and/or suicidal ideation in the past 2 weeks also increased from 3.5% to 7.4% during the same time frame. Additionally, students' likelihood of seeking mental health help decreased between orientation and midpoint despite the concurrent increases in depression risk and suicidal ideation. CONCLUSION: Rising PHQ-9 scores indicated an increased risk of major depression among didactic-year PA students. Further research on early screening methods and factors that encourage help-seeking behaviors may serve to inform programs about how to create learning environments that mitigate depression risk and promote wellbeing during professional training.

On the Influence of Viscoelastic Modeling in Fluid Flow Simulations of Gum Acrylonitrile Butadiene Rubber.

Computational fluid dynamics (CFD) simulation is an important tool as it enables engineers to study different design options without a time-consuming experimental workload. However, the prediction accuracy of any CFD simulation depends upon the set boundary conditions and upon the applied rheological constitutive equation. In the present study the viscoelastic nature of an unfilled gum acrylonitrile butadiene rubber (NBR) is considered by applying the integral and time-dependent Kaye-Bernstein-Kearsley-Zapas (K-BKZ) rheological model. First, exhaustive testing is carried out in the linear viscoelastic (LVE) and non-LVE deformation range including small amplitude oscillatory shear (SAOS) as well as high pressure capillary rheometer (HPCR) tests. Next, three abrupt capillary dies and one tapered orifice die are modeled in Ansys POLYFLOW. The pressure prediction accuracy of the K-BKZ/Wagner model was found to be excellent and insensitive to the applied normal force in SAOS testing as well as to the relation of first and second normal stress differences, provided that damping parameters are fitted to steady-state rheological data. Moreover, the crucial importance of viscoelastic modeling is proven for rubber materials, as two generalized Newtonian fluid (GNF) flow models severely underestimate measured pressure data, especially in contraction flow-dominated geometries.

Temperature Profile in Rubber Injection Molding: Application of a Recently Developed Testing Method to Improve the Process Simulation and Calculation of Curing Kinetics.

Injection molding of rubber compounds is an easily conducted yet sophisticated method for rubber processing. Simulation software is used to examine the optimal process conditions, identify failure scenarios, and save resources. Due to the complexity of the entire process, various aspects have to be considered in the numerical approach. This contribution focused on a comparison of process simulations with various definitions of the material's inlet temperature, ranging from a stepwise increase, but constant temperature, to an exact axial mass temperature profile prior to injection. The latter was obtained with a specially designed, unique test stand consisting of a plasticizing cylinder equipped with pressure sensors, a throttle valve for pressure adjustments, and a measurement bar with thermocouples for the determination of the actual state of the mass temperature. For the verification of the theoretical calculations, practical experiments were conducted on a rubber injection molding machine equipped with the mold used in the simulation. The moldings, obtained at different vulcanization time, were characterized mechanically and the results were normalized to a relative degree of cure in order to enable comparison of the real process and the simulation. Considering the actual state of the mass temperature, the simulation showed an excellent correlation of the measured and calculated mass temperatures in the cold runner. Additionally, the relative degree of cure was closer to reality when the mass temperature profile after dosing was applied in the simulation.

Do PA licensure questions violate the Americans with Disabilities Act?

OBJECTIVE: Negative stigma related to mental health diagnoses is common in both clinicians and the public. Questions about physical and mental conditions on licensure applications often are overly broad and may violate the Americans with Disabilities Act (ADA). This study investigated state physician assistant (PA) licensing applications relating to physical and mental health, and their consistency with the ADA. METHODS: We collected PA state licensure applications from all 50 states and the District of Columbia. To be considered consistent with the ADA about physical conditions, an application had to only contain questions about a current (within the past year) physical health condition that impaired the applicant's ability to practice as a PA, or not include any questions about physical health. Questions that asked for speculation about possible future situations were considered inconsistent with the ADA. RESULTS: Nearly 57% of state PA licensing applications were consistent with ADA guidelines on physical conditions; 51% were consistent for mental health conditions. CONCLUSIONS: Many state PA licensing boards include questions about physical and mental health conditions that are not limited to current impairment. These licensure questions could violate the ADA, and may reduce PAs' willingness to seek help for mental health issues. Balancing public safety with clinician health is a challenge. Further research and action are needed to optimize PA licensure questions on physical and mental health.

Infectious disease considerations in immunocompromised patients.

Immunocompromised patients account for about 3% of the US population. Complications arising from infection are common in these patients and can present diagnostic and therapeutic challenges. This article describes the pathophysiology of immunosuppression in five common immunocompromised states-asplenia, HIV infection, solid organ transplant, biologic use, and cancer-as well as specific infectious risks and considerations for affected patients and how to manage them.