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Graft-versus-host disease (GVHD) is a serious complication of otherwise curative allogeneic haematopoietic stem cell transplants. Chronic GVHD induces pathological changes in peripheral organs as well as the brain and is a frequent cause of late morbidity and death after bone-marrow transplantation. In the periphery, bone-marrow-derived macrophages are key drivers of pathology, but recent evidence suggests that these cells also infiltrate into cGVHD-affected brains. Microglia are also persistently activated in the cGVHD-affected brain. To understand the involvement of these myeloid cell populations in the development and/or progression of cGVHD pathology, we here utilized the blood-brain-barrier permeable colony stimulating factor-1 receptor (CSF-1R) inhibitor PLX3397 (pexidartinib) at varying doses to pharmacologically deplete both cell types. We demonstrate that PLX3397 treatment during the development of cGVHD (i.e., 30 days post-transplant) improves disease symptoms, reducing both the clinical scores and histopathology of multiple cGVHD target organs, including the sequestration of T cells in cGVHD-affected skin tissue. Cognitive impairments associated with cGVHD and neuroinflammation were also attenuated by PLX3397 treatment. PLX3397 treatment prior to the onset of cGVHD (i.e., immediately post-transplant) did not change in clinical scores or histopathology. Overall, our data demonstrate significant benefits of using PLX3397 for the treatment of cGVHD and associated organ pathologies in both the periphery and brain, highlighting the therapeutic potential of pexidartinib for this condition., (© 2023. The Author(s).)

Primary care trainees must learn how to communicate effectively with patients during brief outpatient encounters, and direct observation and feedback is necessary to improve these skills. At the same time, programs are seeking more interprofessional learning opportunities for skills that transcend professions. We sought to assess the feasibility of implementing a direct observation tool, the Patient Centered Observation Form (PCOF), for communication training across three professions at the graduate level. The PCOF was introduced to trainees at an interprofessional workshop, while faculty completed PCOF training online or in person. Following use of the PCOF, we surveyed participants to determine if using the PCOF increased a) trainee-reported confidence in providing patient-centered communication, and b) faculty-reported confidence in giving feedback about patient-centered communication. The PCOF appears to be a useful adjunct to standard precepting for teaching patient-centered communication skills, extending beyond medical residents to pharmacy residents and less so, to advanced practice nursing students. In addition, PCOF training and implementation can successfully occur simultaneously across disciplines, leveraging resources and encouraging interprofessional learning.

Auditory inner hair cells (IHCs) convert sound vibrations into receptor potentials that drive synaptic transmission. For the precise encoding of sound qualities, receptor potentials are shaped by K + conductances tuning the properties of the IHC membrane. Using patch-clamp and computational modeling, we unravel this membrane specialization showing that IHCs express an exclusive repertoire of six voltage-dependent K + conductances mediated by K v 1.8, K v 7.4, K v 11.1, K v 12.1, and BK Ca channels. All channels are active at rest but are triggered differentially during sound stimulation. This enables non-saturating tuning over a far larger potential range than in IHCs expressing fewer current entities. Each conductance contributes to optimizing responses, but the combined activity of all channels synergistically improves phase locking and the dynamic range of intensities that IHCs can encode. Conversely, hypothetical simpler IHCs appear limited to encode only certain aspects (frequency or intensity). The exclusive channel repertoire of IHCs thus constitutes an evolutionary adaptation to encode complex sound through multifaceted receptor potentials., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Supporting gender equity for women working in geriatrics is important to the growth of geriatrics across disciplines and is critical in achieving our vision for a future in which we are all able to contribute to our communities and maintain our health, safety, and independence as we age. Discrimination can have a negative impact on public health, particularly with regard to those who care for the health of older Americans and other vulnerable older people. Women working in the field of geriatrics have experienced implicit and explicit discriminatory practices that mirror available data on the entire workforce. In this position article, we outline strategic objectives and accompanying practical recommendations for how geriatrics, as a field, can work together to achieve a future in which the rights of women are guaranteed and women in geriatrics have the opportunity to achieve their full potential. This article represents the official positions of the American Geriatrics Society. J Am Geriatr Soc 67:2447-2454, 2019., (© 2019 The American Geriatrics Society.)

Cleavage of amyloid precursor protein (APP) by β-secretase BACE1 initiates the production and accumulation of neurotoxic amyloid-β peptides, which is widely considered an essential pathogenic mechanism in Alzheimer's disease (AD). Here, we report that BACE1 is essential for normal auditory function. Compared with wild-type littermates, BACE1 -/- mice of either sex exhibit significant hearing deficits, as indicated by increased thresholds and reduced amplitudes in auditory brainstem responses (ABRs) and decreased distortion product otoacoustic emissions (DPOAEs). Immunohistochemistry revealed aberrant synaptic organization in the cochlea and hypomyelination of auditory nerve fibers as predominant neuropathological substrates of hearing loss in BACE1 -/- mice. In particular, we found that fibers of spiral ganglion neurons (SGN) close to the organ of Corti are disorganized and abnormally swollen. BACE1 deficiency also engenders organization defects in the postsynaptic compartment of SGN fibers with ectopic overexpression of PSD95 far outside the synaptic region. During postnatal development, auditory fiber myelination in BACE1 -/- mice lags behind dramatically and remains incomplete into adulthood. We relate the marked hypomyelination to the impaired processing of Neuregulin-1 when BACE1 is absent. To determine whether the cochlea of adult wild-type mice is susceptible to AD treatment-like suppression of BACE1, we administered the established BACE1 inhibitor NB-360 for 6 weeks. The drug suppressed BACE1 activity in the brain, but did not impair hearing performance and, upon neuropathological examination, did not produce the characteristic cochlear abnormalities of BACE1 -/- mice. Together, these data strongly suggest that the hearing loss of BACE1 knock-out mice represents a developmental phenotype. SIGNIFICANCE STATEMENT Given its crucial role in the pathogenesis of Alzheimer's disease (AD), BACE1 is a prime pharmacological target for AD prevention and therapy. However, the safe and long-term administration of BACE1-inhibitors as envisioned in AD requires a comprehensive understanding of the various physiological functions of BACE1. Here, we report that BACE1 is essential for the processing of auditory signals in the inner ear, as BACE1-deficient mice exhibit significant hearing loss. We relate this deficit to impaired myelination and aberrant synapse formation in the cochlea, which manifest during postnatal development. By contrast, prolonged pharmacological suppression of BACE1 activity in adult wild-type mice did not reproduce the hearing deficit or the cochlear abnormalities of BACE1 null mice., (Copyright © 2019 the authors.)

Background and Purpose: The ether-à-go-go (Eag) K v superfamily comprises closely related K v 10, K v 11, and K v 12 subunits. K v 11.1 (termed hERG in humans) gained much attention, as drug-induced inhibition of these channels is a frequent cause of sudden death in humans. The exclusive drug sensitivity of K v 11.1 can be explained by central drug-binding pockets that are absent in most other channels. Currently, it is unknown whether K v 12 channels are equipped with an analogous drug-binding pocket and whether drug-binding properties are conserved in all Eag superfamily members., Experimental Approach: We analysed sensitivity of recombinant K v 12.1 channels to quinine, a substituted quinoline that blocks K v 10.1 and K v 11.1 at low micromolar concentrations., Key Results: Quinine inhibited K v 12.1, but its affinity was 10-fold lower than for K v 11.1. Contrary to K v 11.1, quinine inhibited K v 12.1 in a largely voltage-independent manner and induced channel opening at more depolarised potentials. Low sensitivity of K v 12.1 and characteristics of quinine-dependent inhibition were determined by histidine 462, as site-directed mutagenesis of this residue into the homologous tyrosine of K v 11.1 conferred K v 11.1-like quinine block to K v 12.1(H462Y). Molecular modelling demonstrated that the low affinity of K v 12.1 was determined by only weak interactions of residues in the central cavity with quinine. In contrast, more favourable interactions can explain the higher quinine sensitivity of K v 12.1(H462Y) and K v 11.1 channels., Conclusions and Implications: The quinoline-binding "motif" is not conserved within the Eag superfamily, although the overall architecture of these channels is apparently similar. Our findings highlight functional and pharmacological diversity in this group of evolutionary-conserved channels., (© 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Introduction: Team-based, interprofessional approaches to outpatient care are critical to high-quality patient care. However, few specific educational interventions promoting these skills in graduate level health care trainees have been described to date., Methods: University of Minnesota faculty from the Schools of Medicine, Pharmacy, and Nursing created an interprofessional workshop experience exploring core concepts in outpatient care for graduate level trainees in pediatrics, family medicine, medicine-pediatrics, internal medicine, graduate-level nursing, and pharmacy. We focused on four key content areas: teamwork, systems thinking, the patient-centered health care home, and patient-centered communication. The workshop included brief didactics, role-plays, team-based experiences, and interactive skill practice. Participants completed an end-of-day survey reflecting on knowledge and attitude., Results: From 2014-2017, nine workshops reached 305 trainees. Survey results from the 2015-2016 academic year are representative of our overall results and revealed that learners found the content high yield, and that they valued the opportunity to learn with their interprofessional colleagues. Improvements in perceived knowledge were noted in all domains. Trainees also reported increased skills, with 81% reporting both increased confidence in working within the interprofessional team, and change in attitude, and 90% reporting increased interest in working with their interprofessional colleagues after the workshop., Discussion: Creating an opportunity for postgraduate level trainees from a variety of disciplines and professions to convene and focus on interprofessional team-based skills can fill a gap in interprofessional learning as they enter practice. Trainees were able to draw on their everyday experiences and find common ground with their interprofessional colleagues., Competing Interests: None to report.

Background and Objectives: For years, family medicine has taught patient-centered communication through observations and observation checklists. We explored the utility of one checklist, the Patient-Centered Observation Form (PCOF), to teach and evaluate patient-centered communication in our family medicine residencies., Methods: We conducted a mixed-method study of five University of Minnesota Family Medicine Residencies' seven years of experience teaching and evaluating residents' patient-centered communication skills. All programs have a behavioral health (BH) faculty-led observation curriculum that uses the PCOF to assess resident skills and give feedback. We conducted a BH faculty focus group and interviews, generated themes from the BH responses, and then queried family medicine (FM) faculty regarding these themes through an online survey., Results: Ten BH faculty participated in the focus group/interviews, and 71% (25/35) of FM faculty completed the survey about themes derived from the BH interviews. The residencies complete between 1 to 11 observations per resident per year. Since implementation, four programs have continuously used the PCOF due to its versatility, design as a formative rather than summative feedback tool, and relative ease of use. BH faculty believe longitudinal observations with the PCOF resulted in improved resident patient-centered communication. Most importantly, all faculty described a shift in family medicine culture toward patient-centered communication. Time for observations and feedback is the primary curricular barrier., Conclusions: Our findings support the utility of the PCOF for teaching and evaluating patient-centered communication in family medicine training.

The three members of the ether-à-go-go-gene -like (Elk; K v 12.1-K v 12.3) family of voltage-gated K + channels are predominantly expressed in neurons, but only little information is available on their physiological relevance. It was shown that K v 12.2 channels modulate excitability of hippocampal neurons, but no native current could be attributed to K v 12.1 and K v 12.3 subunits yet. This may appear somewhat surprising, given high expression of their mRNA transcripts in several brain areas. Native K v 12 currents may have been overlooked so far due to limited knowledge on their biophysical properties and lack of specific pharmacology. Except for K v 12.2, appropriate genetically modified mouse models have not been described; therefore, identification of K v 12-mediated currents in native cell types must rely on characterization of unique properties of the channels. We focused on recombinant human K v 12.1 to identify distinct properties of these channels. We found that K v 12.1 channels exhibited significant mode shift of activation, i.e., stabilization of the voltage sensor domain in a "relaxed" open state after prolonged channel activation. This mode shift manifested by a slowing of deactivation and, most prominently, a significant shift of voltage dependence to hyperpolarized potentials. In contrast to related K v 11.1, mode shift was not sensitive to extracellular Na + , which allowed for discrimination between these isoforms. Sensitivity of K v 12.1 and K v 11.1 to the broad-spectrum K + antagonist 4-aminopyridine was similar. However, 4-AP strongly activated K v 12.1 channels, but it was an inhibitor of K v 11 channels. Interestingly, the agonist of K v 11 channels NS1643 also differentially modulated the activity of these channels, i.e., NS1643 activated K v 11.1, but strongly inhibited K v 12.1 channels. Thus, these closely related channels are distinguished by inverse pharmacological profiles. In summary, we identified unique biophysical and pharmacological properties of K v 12.1 channels and established straightforward experimental protocols to characterize K v 12.1-mediated currents. Identification of currents in native cell types with mode shift that are activated through 4-AP and inhibited by NS1643 can provide strong evidence for contribution of K v 12.1 to whole cell currents.

K v 12.1 K + channels are expressed in several brain areas, but no physiological function could be attributed to these subunits so far. As genetically-modified animal models are not available, identification of native K v 12.1 currents must rely on characterization of distinct channel properties. Recently, it was shown in Xenopus laevis oocytes that K v 12.1 channels were modulated by membrane PI(4,5)P 2 . However, it is not known whether these channels are also sensitive to physiologically-relevant PI(4,5)P 2 dynamics. We thus studied whether K v 12.1 channels were modulated by activation of phospholipase C β (PLCβ) and found that they were insensitive to receptor-triggered depletion of PI(4,5)P 2 . Thus, K v 12.1 channels add to the growing list of K + channels that are insensitive to PLCβ signaling, although modulated by PI(4,5)P 2 in Xenopus laevis oocytes.

Determining when advanced practice registered nurse students are safe and competent for beginning-level practice is challenging. This article describes the development and testing of a capstone objective structured clinical examination designed to evaluate the practice readiness of students enrolled in the family, adult-gerontology, women's health nurse practitioner, and nurse-midwifery tracks. Lessons learned from this process and how they were used to enhance the curricula are discussed.

Background and Purpose: Signalling through phospholipase C (PLC) controls many cellular processes. Much information on the relevance of this important pathway has been derived from pharmacological inhibition of the enzymatic activity of PLC. We found that the most frequently employed PLC inhibitor, U73122, activates endogenous ionic currents in widely used cell lines. Given the extensive use of U73122 in research, we set out to identify these U73122-sensitive ion channels., Experimental Approach: We performed detailed biophysical analysis of the U73122-induced currents in frequently used cell lines., Key Results: At concentrations required to inhibit PLC, U73122 modulated the activity of transient receptor potential melastatin (TRPM) channels through covalent modification. U73122 was shown to be a potent agonist of ubiquitously expressed TRPM4 channels and activated endogenous TRPM4 channels in CHO cells independently of PLC and of the downstream second messengers PI(4,5)P2 and Ca(2+) . U73122 also potentiated Ca(2) (+) -dependent TRPM4 currents in human Jurkat T-cells, endogenous TRPM4 in HEK293T cells and recombinant human TRPM4. In contrast to TRPM4, TRPM3 channels were inhibited whereas the closely related TRPM5 channels were insensitive to U73122, showing that U73122 exhibits high specificity within the TRPM channel family., Conclusions and Implications: Given the widespread expression of TRPM4 and TRPM3 channels, these actions of U73122 must be considered when interpreting its effects on cell function. U73122 may also be useful for identifying and characterizing TRPM channels in native tissue, thus facilitating the analysis of their physiology., (© 2016 The British Pharmacological Society.)

Team-based care is a cornerstone of primary care. However, in medical school and residency, trainees get little formal education on this as a concept and how it works in an outpatient setting. Faculty members from the University of Minnesota created a one-day workshop, "Essentials of Ambulatory Care," to help residents in primary care specialties as well as pharmacy and nursing students pursuing advanced degrees better understand the roles and responsibilities of members of the primary care team. The workshop also helped them develop new skills for doing patient-centered visits. This article describes the workshop and what we learned from those who participated in the first session.