Patient Expertise and Medical Authority: Epistemic Implications for the Provider-Patient Relationship.

The provider-patient relationship is typically regarded as an expert-to-novice relationship, and with good reason. Providers have extensive education and experience that have developed in them the competence to treat conditions better and with fewer harms than anyone else. However, some researchers argue that many patients with long-term conditions (LTCs), such as arthritis and chronic pain, have become "experts" at managing their LTC. Unfortunately, there is no generally agreed-upon conception of "patient expertise" or what it implies for the provider-patient relationship. I review three prominent accounts of patient expertise and argue that all face serious objections. I contend, however, that a plausible account of patient expertise is available and that it provides a framework both for further empirical studies and for enhancing the provider-patient relationship.

The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration.

Antisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat a wide range of diseases, including neurological indications. Spinraza, an ASO that modulates splicing of SMN2 RNA, has shown profound disease modifying effects in Spinal Muscular Atrophy (SMA) patients, energizing efforts to develop ASOs for other neurological diseases. While SMA specifically affects spinal motor neurons, other neurological diseases affect different central nervous system (CNS) regions, neuronal and non-neuronal cells. Therefore, it is important to characterize ASO distribution and activity in all major CNS structures and cell types to have a better understanding of which neurological diseases are amenable to ASO therapy. Here we present for the first time the atlas of ASO distribution and activity in the CNS of mice, rats, and non-human primates (NHP), species commonly used in preclinical therapeutic development. Following central administration of an ASO to rodents, we observe widespread distribution and target RNA reduction throughout the CNS in neurons, oligodendrocytes, astrocytes and microglia. This is also the case in NHP, despite a larger CNS volume and more complex neuroarchitecture. Our results demonstrate that ASO drugs are well suited for treating a wide range of neurological diseases for which no effective treatments are available.

An Argument for Standardized Ethical Directives for Secular Healthcare Services.

We argue that the American Society for Bioethics and Humanities has endorsed a facilitation approach to clinical ethics consultation that asserts that bioethicists can offer moral recommendations that are well-grounded in bioethical consensus. We claim that the closest thing the field currently has to a citable, nationally endorsed bioethical consensus are the 22 Core References used to construct the questions for the Healthcare Ethics Consultant-Certified (HEC-C) exam. We acknowledge that the Core References reflect some important points of bioethical consensus, but note they are unwieldy, repetitive, and sometimes inconsistent on important issues faced by clinical ethicists. In this article, we draw carefully qualified inspiration from the Ethical and Religious Directives for Catholic Health Care Services (ERDs) to argue for the creation of a concise, nationally endorsed bioethical consensus document on moral issues commonly faced in clinical ethics, what we call the Standardized Ethical Guidelines for Secular Health Care Services (SEGs). We observe that such a document would better meet the expectations of stakeholders, clinical ethicists, and their trainees who desire moral recommendations grounded in a clearly articulated bioethical consensus, and we defend the SEGs from some common objections.

Responding to Fiester's Critique of a Bioethical Consensus Project.

We respond to Autumn Fiester's critique that our proposed bioethical consensus project amounts to "ethical hegemony," and evaluate her claim that ethicists should restrict themselves to "mere process" recommendations. We argue that content recommendations are an inescapable aspect of clinical ethics consultation, and our primary concern is that, without standardization of bioethical consensus, our field will vacillate among appeals to the disparate claims in the 22 "Core References," unsustainable efforts to defend value-neutral process recommendations, or become a practice of Lone Ranger clinical ethicists. We contend that a consensus document that captures the basic moral commitments of patients and careproviders is the next step in the professional evolution of our field.

Epistemic neighbors: trespassing and the range of expert authority.

The world is abuzz with experts who can help us in domains where we understand too little to help ourselves. But sometimes experts in one domain carry their privileged status into domains outside their specialization, where they give advice or otherwise presume to speak authoritatively. Ballantyne (in: Knowing our limits. Oxford University Press, New York, 2019) calls these boundary crossings "epistemic trespassing" and argues that they often violate epistemic norms. In the few cases where traveling in other domains is permissible, Ballantyne suggests there should be regulative checks ("easements") for the experts who are crossing domain boundaries. I argue that boundary crossing is warranted more often than Ballantyne allows. And while Ballantyne argues that boundary crossing is prima facie epistemically problematic, I contend that many cases of boundary crossing are not properly instances of "trespassing," and, therefore, raise no prima facie epistemic concerns. I further argue that identifying cases of what I call "epistemic neighborliness" bolsters Ballantyne's project, making it easier for novices and other experts to identify epistemic trespassing along with its epistemic problems.

Prph2 initiates outer segment morphogenesis but maturation requires Prph2/Rom1 oligomerization.

The retinal disease gene peripherin 2 (PRPH2) is essential for the formation of photoreceptor outer segments (OSs), where it functions in oligomers with and without its homologue ROM1. However, the precise role of these proteins in OS morphogenesis is not understood. By utilizing a knock-in mouse expressing a chimeric protein comprised of the body of Rom1 and the C-terminus of Prph2 (termed RRCT), we find that the Prph2 C-terminus is necessary and sufficient for the initiation of OSs, while OS maturation requires the body of Prph2 and associated large oligomers. Importantly, dominant-negative physiological and biochemical defects in RRCT heterozygous rods are rescued by removing Rom1, suggesting Rom1 is a regulator for OS formation. Our experiments evaluating Prph2 trafficking show that Rom1 is a key determinant of whether Prph2 complexes utilize conventional versus unconventional (Golgi bypass) secretory pathways to reach the OS. These findings significantly advance our understanding of the molecular underpinnings of OS morphogenesis and particularly the role of Rom1.

The Advent of the Professional Ethicist: Moral Expertise and Health-Care Ethics Certification.

With the Healthcare Ethics Consultant Certification (HEC-C) offered through the American Society for Bioethics and Humanities (ASBH), the practice of clinical ethics has taken a decisive step into professionalization. But without an unambiguous sense of what clinical ethicists can contribute to the clinical environment, it is unclear what the HEC-C ensures clinical ethicists can do. Though the ASBH enumerates a set of core competencies, many disagree over what role those competencies empower ethicists to serve. Two recent publications are notable for advocating conflicting positions on the question of ethicists' competence: "Ethics Expertise: What It Is, How to Get It, and What to Do with It" by Christopher Meyers (2018) and Rethinking Health Care Ethics by Stephen Scher and Kasia Kozlowska (2018). In response to Scher and Kozlowska's argument that the primary role of ethicists is to create space to engage clinician's moral intuitions, this analysis follows Meyers in contending that ethicists can also contribute a kind of moral expertise. However, acquiring moral expertise is no easy task, and it is unlikely to be substantiated by a certification exam. This analysis draws on research from the psychology of expertise to outline the sort of training needed to cultivate and enhance moral expertise.

Rom1 converts Y141C-Prph2-associated pattern dystrophy to retinitis pigmentosa.

Mutations in peripherin 2 (PRPH2), also known as retinal degeneration slow/RDS, lead to various retinal degenerations including retinitis pigmentosa (RP) and macular/pattern dystrophy (MD/PD). PRPH2-associated disease is often characterized by a phenotypic variability even within families carrying the same mutation, raising interest in potential modifiers. PRPH2 oligomerizes with its homologue rod outer segment (OS) membrane protein 1 (ROM1), and non-pathogenic PRPH2/ROM1 mutations, when present together, lead to digenic RP. We asked whether ROM1 could modify the phenotype of a PRPH2 mutation associated with a high degree of intrafamilial phenotypic heterogeneity: Y141C. In vitro, Y141C-Prph2 showed signs of retention in the endoplasmic reticulum (ER), however co-expression with Rom1 rescued this phenotype. In the heterozygous Y141C knockin mouse model (Prph2Y/+), Y141C-Prph2 and Rom1 formed abnormal complexes but were present at normal levels. Abnormal complexes were eliminated in the absence of Rom1 (Prph2Y/+/Rom1-/-) and total Prph2 levels were reduced to those found in the haploinsufficient Prph2+/- RP model. The biochemical changes had functional and structural consequences; while Prph2Y/+ animals exhibited a cone-rod electroretinogram defect, Prph2Y/+/Rom1-/- animals displayed a rod-dominant phenotype and OSs similar to those seen in the Prph2+/-. These data show that ablation of Rom1 results in the conversion of an MD/PD phenotype characterized by cone functional defects and the formation of abnormal Prph2/Rom1 complexes to an RP phenotype characterized by rod-dominant functional defects and reductions in total Prph2 protein. Thus one method by which ROM1 may act as a disease modifier is by contributing to the large variability in PRPH2-associated disease phenotypes.

RNA-Seq analysis in an avian model of maternal phenylketonuria.

Cardiac malformations (CVMs) are a leading cause of infant morbidity and mortality. CVMs are particularly prevalent when the developing fetus is exposed to high levels of phenylalanine in-utero in mothers with Phenylketonuria. Yet, elucidating the underlying molecular mechanism leading to CVMs has proven difficult. In this study we used RNA-Seq to investigate an avian model of MPKU and establish differential gene expression (DEG) characteristics of the early developmental stages HH10, 12, and 14. In total, we identified 633 significantly differentially expressed genes across stages HH10, 12, and 14. As expected, functional annotation of significant DEGs identified associations seen in clinical phenotypes of MPKU including CVMs, congenital heart defects, craniofacial anomalies, central nervous system defects, and growth anomalies. Additionally, there was an overrepresentation of genes involved in cardiac muscle contraction, adrenergic signaling in cardiomyocytes, migration, proliferation, metabolism, and cell survival. Strikingly, we identified significant changes in expression with multiple genes involved in Retinoic Acid (RA) metabolism and downstream targets. Using qRTPCR, we validated these findings and identified a total of 42 genes within the RA pathway that are differentially expressed. Here, we report the first elucidation of the molecular mechanisms of cardiovascular malformations in MPKU conducted at early developmental timepoints. We provide evidence suggesting a link between PHE exposure and the alteration of RA pathway. These results are promising and offer novel findings associated with congenital heart defects in MPKU.

Health Literacy Evaluation of Opioid Patient Education Materials for Orthopaedic Surgery.

Increased opioid use in the United States has resulted in greater incidence of misuse. Orthopaedic patients are more likely to be prescribed opioids for pain. Low health literacy is related to opioid misuse; therefore, orthopaedic patient education tools on use of opioids must be easy to read, understand, and use for patients of all skill levels to be effective. This project aimed to review a broad array of opioid patient education tools and evaluate them from a health literacy perspective. Content evaluation revealed that not all tools expressed the same essential messaging. The mean readability score of the tools assessed was 9.5 grade; higher than the national and recommended 8th-grade reading level. Therefore, many opioid patient education tools may be difficult for patients to read and understand. Improvements in readability and other health literacy best practices are recommended to improve reading, comprehension, and use of opioid patient education tools. (Journal of Surgical Orthopaedic Advances 28(3):232-236, 2019).

Talking the Talk: Enhancing Clinical Ethics with Health Literacy Best Practices.

A significant proportion of the U.S. population exhibits low health literacy. Evidence suggests that low health literacy is correlated with higher medical costs and poorer health outcomes. Even more concerning, evidence suggests that low health literacy threatens patients' and families' autonomy and exacerbates injustices in patients who are already vulnerable to difficulties navigating the health care system. There is also, however, increasing evidence that health literacy interventions-including initiatives such as plain language practices and teach-back-improve comprehension and usefulness of health care information. I show how health literacy best practices can enhance the work of clinical ethicists in their primary roles of policy, consultation, and education. In the final section, I suggest ways health literacy initiatives may be enhanced with insights from clinical ethicists.

An initial phase of JNK activation inhibits cell death early in the endoplasmic reticulum stress response.

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR). In mammalian cells, UPR signals generated by several ER-membrane-resident proteins, including the bifunctional protein kinase endoribonuclease IRE1α, control cell survival and the decision to execute apoptosis. Processing of XBP1 mRNA by the RNase domain of IRE1α promotes survival of ER stress, whereas activation of the mitogen-activated protein kinase JNK family by IRE1α late in the ER stress response promotes apoptosis. Here, we show that activation of JNK in the ER stress response precedes activation of XBP1. This activation of JNK is dependent on IRE1α and TRAF2 and coincides with JNK-dependent induction of expression of several antiapoptotic genes, including cIap1 (also known as Birc2), cIap2 (also known as Birc3), Xiap and Birc6 ER-stressed Jnk1(-/-) Jnk2(-/-) (Mapk8(-/-) Mapk9(-/-)) mouse embryonic fibroblasts (MEFs) display more pronounced mitochondrial permeability transition and increased caspase 3/7 activity compared to wild-type MEFs. Caspase 3/7 activity is also elevated in ER-stressed cIap1(-/-) cIap2(-/-) and Xiap(-/-) MEFs. These observations suggest that JNK-dependent transcriptional induction of several inhibitors of apoptosis contributes to inhibiting apoptosis early in the ER stress response.

Optimizing Non-viral Gene Therapy Vectors for Delivery to Photoreceptors and Retinal Pigment Epithelial Cells.

Considerable progress has been made in the design and delivery of non-viral gene therapy vectors, but, like their viral counterparts, therapeutic levels of transgenes have not met the requirements for successful clinical applications so far. The biggest advantage of polymer-based nanoparticle vectors is the ease with which they can be modified to increase their ability to penetrate the cell membrane and target specific cells by simply changing the formulation of the nanoparticle compaction. We took advantage of this characteristic to improve transfection rates of our particles to meet the transgene levels which will be needed for future treatment of patients. For this study, we successfully investigated the possibility of our established pegylated polylysine particles to be administered via intravitreal rather than subretinal route to ease the damage during injection. We also demonstrated that our particles are flexible enough to sustain changes in the formulation to accommodate additional targeting sequences without losing their efficiency in transfecting neuronal cells in the retina. Together, these results give us the opportunity to even further improve our particles.

Endoplasmic reticulum stress causes insulin resistance by inhibiting delivery of newly synthesized insulin receptors to the cell surface.

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes ER stress and activates a signaling network known as the unfolded protein response (UPR). Here we characterize how ER stress and the UPR inhibit insulin signaling. We find that ER stress inhibits insulin signaling by depleting the cell surface population of the insulin receptor. ER stress inhibits proteolytic maturation of insulin proreceptors by interfering with transport of newly synthesized insulin proreceptors from the ER to the plasma membrane. Activation of AKT, a major target of the insulin signaling pathway, by a cytosolic, membrane-bound chimera between the AP20187-inducible FV2E dimerization domain and the cytosolic protein tyrosine kinase domain of the insulin receptor was not affected by ER stress. Hence, signaling events in the UPR, such as activation of the JNK mitogen-activated protein (MAP) kinases or the pseudokinase TRB3 by the ER stress sensors IRE1α and PERK, do not contribute to inhibition of signal transduction in the insulin signaling pathway. Indeed, pharmacologic inhibition and genetic ablation of JNKs, as well as silencing of expression of TRB3, did not restore insulin sensitivity or rescue processing of newly synthesized insulin receptors in ER-stressed cells. [Media: see text].

DNA nanoparticles are safe and nontoxic in non-human primate eyes.

INTRODUCTION: DNA nanoparticles (NPs) comprising polylysine conjugated to polyethylene glycol efficiently target murine photoreceptors and the retinal pigment epithelium (RPE) and lead to long-term phenotypic improvement in models of retinal degeneration. Advancing this technology requires testing in a large animal model, particularly with regard to safety. So, herein we evaluate NPs in non-human primates (baboon). METHODS AND RESULTS: NPs with plasmids carrying GFP and a ubiquitous, RPE-specific, or photoreceptor-specific promoter were delivered by either subretinal or intravitreal injection. We detected GFP message and protein in the retina/RPE from eyes dosed with NPs carrying ubiquitously expressed and RPE-specific vectors, and GFP message in eyes injected with NPs carrying photoreceptor-specific vectors. Importantly, we observed NP DNA in the retina/RPE following intravitreal injection, indicating the inner limiting membrane does not prevent NP diffusion into the outer retina. We did not observe any adverse events in any baboon, and there were no NP-associated changes in retinal function. Furthermore, no systemic or local inflammatory reaction to the vectors/injections was observed, and no NP DNA was found outside the eye. CONCLUSION: Taken together with the well-established rodent safety and efficacy data, these findings suggest that DNA NPs may be a safe and potentially clinically viable nonviral ocular therapy platform for retinal diseases.

Health literacy and surgery expectations in total hip and knee arthroplasty patients.

OBJECTIVES: This study assessed patients' health literacy and expectations for total hip (THA) and total knee (TKA) replacement surgery, and compared health literacy levels of patients and their caregivers. METHODS: A convenience sample of 200 THA/TKA participants, patients and their caregivers, participated in this study. RESULTS: Results demonstrated no statistical difference in health literacy between patients and their caregivers. However, patients with lower health literacy had significantly lower expectations for walking after surgery. CONCLUSIONS: Practices should be aware that caregivers may not be any better equipped to consume and use complicated patient education materials than the patient they are assisting. Additionally, lower health literacy, rather than or in addition to race or social factors, may contribute to disparities in opting for THA/TKA because of lower expectations for walking after surgery. PRACTICE IMPLICATIONS: Healthcare practices should develop patient educational materials that are easy for all patients and caregivers to understand, especially those with low health literacy. Additional patient education and counseling may help patients with low health literacy realistically align their expectations and mitigate barriers to consenting to surgery due to low expectations.

Checks and balances: the welcomed tension between philosophy and science.

There is a tension between science and philosophy, but this tension need not engender enmity or derision. Scientists and philosophers can work together, and we argue that working together is beneficial to both, even if it is sometimes uncomfortable. We offer examples of how philosophy can autonomously and effectively inform scientific practice. Science and philosophy share certain methodological concerns and practices; therefore, scientists who disregard philosophy are vulnerable to critical conceptual mistakes. If our arguments are correct, and if it can also be shown that science informs philosophy, then, while it is possible for both disciplines to operate autonomously, each should welcome the checks and balances that each provides for one another in the investigation and explanation of reality.