OBJECTIVE: How outside factors affect physician decision making remains an open question of vital importance. We sought to investigate the importance of various influences on physician decision making when clinical guidelines differ from patient preference. -/- METHODS: An online survey asking 469 primary care providers (PCPs) across four practice sites whether they would order magnetic resonance imaging for a patient with uncomplicated back pain. Participants were randomized to one of four scenarios: a patient's preference for imaging (control), a patient's preference (...) plus a colleague's opinion against imaging (colleague), a patient's preference plus a professional society's recommendation against imaging (profession), or a patient's preference plus an accountable care organization's quality metric that measures physician use of imaging (ACO). Demographic information and the reasoning behind participants' decisions also were obtained. -/- RESULTS: A total of 168 PCPs completed the survey, yielding a 36% completion rate. A majority chose not to pursue imaging: control 68%, colleague 85%, profession 87%, and ACO 78%. Multivariate logistic regression revealed that participants were more likely not to order advanced imaging only when reminded of a professional society recommendation (P = 0.017). Regression also suggested that practice site exerted an effect on the primary outcome. Evidence-based medicine and clinical judgment were the most cited reasons for the decision. -/- CONCLUSIONS: Our results reinforce the potential to leverage professional societies to advance evidence-based medicine and reduce unnecessary testing. At the same time, practice site appeared to exert influence, suggesting that these recommendations must be part of local institutional culture to be effective. (shrink)

Soluble components of Notch signalling can be applied to manipulate a central pathway essential for the development of metazoans and often deregulated in illnesses such as stroke, cancer or cardiovascular diseases. Commonly, the Notch cascade is inhibited by small compound inhibitors, which either block the proteolysis of Notch receptors by γ‐secretases or interfere with the transcriptional activity of the Notch intracellular domain. Specific antibodies can also be used to inhibit ligand‐induced activation of Notch receptors. Alternatively, naturally occurring endogenous inhibitors of (...) Notch signalling might offer a specific way to block receptor activation. Examples are the soluble variants of the canonical Notch ligand Jagged1 and the non‐canonical Notch ligand Dlk1, both deprived of their transmembrane regions upon ectodomain shedding, or the bona fide secreted molecule EGFL7. We present frequently used methods to decrease Notch signalling, and we discuss how soluble Notch inhibitors may be used to treat diseases. (shrink)

Work requirements are the centerpiece of HHS's Trump Administration strategy to undo the ACA expansion for low income working age adults. This article examines the June 29, 2018 trial court opinion in Stewart v. Azar which held that HHS's approval of Kentucky's Section 1115 work demonstration was “arbitrary and capricious.” The purpose of Medicaid is to provide health coverage and HHS may not ignore the loss of coverage that will result from a work requirement.

Der zweite Band der DSKE enthält Kierkegaards Journale und Aufzeichnungen aus den Jahren 1836-1846. Examensvorbereitungen, aber auch Materialien zum Frühwerk bilden die Kernstücke dieses Bandes. Von herausragender Bedeutung ist Journal JJ, das als Diskussionsforum und literarische Werkstatt parallel zum pseudonymen Werk angesehen werden kann; hinzu kommen Kierkegaards Reflexionen zur gescheiterten Verlobung mit Regine Olsen. DSKE 2 basiert auf der historisch-kritischen dänischen Neuausgabe und bietet die Übersetzung der Journale und Aufzeichnungen sowie die Kommentare in einem Band. Pluspunkte: die erste kritische deutsche (...) Edition der Journale Kierkegaards erste Komplettedition der Journale in Deutschland mit detaillierten Kommentaren. (shrink)

Hastings Center Report, Volume 52, Issue 1, Page 21-28, January/February 2022.

Nearly 90 % of allegations of biomedical research misconduct in the United States are dismissed by responsible institutions without any faculty assessment or auditable record. Recently, members of the U.S. Congress have complained that the penalties for those against whom findings of research misconduct are made are too light and that too few grant funds associated with research misconduct have been recovered for use by other researchers and taxpayers. Here we discuss the laws that empower federal agencies that can oversee (...) investigations of biomedical research misconduct: the Office of Research Integrity and the Office of the Inspector General, both located within the Department of Health and Human Services. Research misconduct investigations pertaining to U.S. physical sciences funded through the National Science Foundation are overseen by the NSF’s OIG. While OIGs may provide some improvement over the ORI in the handling of research misconduct, we have found that a much more serious flaw exists which undermines an ability to conduct performance audits of the effectiveness by which allegations of research misconduct are handled in the United States. Specifically, sufficient data do not need to be retained by U.S. research institutions funded by HHS or NSF to allow effective audit of why allegations of research misconduct are dismissed before being seen by faculty inquiry or investigative committees. U.S. federal Generally Accepted Government Auditing Standards, if applied to the research misconduct oversight process, would allow a determination of whether the handling of allegations of biomedical research misconduct actually functions adequately, and if not, how it might be improved. In particular, we propose that independent, external peer review under GAGAS audit standards should be instituted without delay in assessing the performance of ORI, or any other similarly tasked federal agency, in handling allegations of research misconduct. (shrink)

Hedgehog (Hh) signaling is a widely studied signaling pathway because of its critical roles during development and in cell homeostasis. Vertebrate canonical and non‐canonical Hh signaling are typically assumed to be distinct and occur in different cellular compartments. While research has primarily focused on the canonical form of Hh signaling and its dependency on primary cilia – microtubule‐based signaling hubs – an extensive list of crucial functions mediated by non‐canonical Hh signaling has emerged. Moreover, amounting evidence indicates that canonical and (...) non‐canonical modes of Hh signaling are interlinked, and that they can overlap spatially, and in many cases interact functionally. Here, we discuss some of the many cellular effects of non‐canonical signaling and discuss new evidence indicating inter‐relationships with canonical signaling. We discuss how Smoothened (Smo), a key component of the Hh pathway, might coordinate such diverse downstream effects. Collectively, pursuit of questions such as those proposed here will aid in elucidating the full extent of Smo function in development and advance its use as a target for cancer therapeutics. (shrink)

Hedgehog (HH) signaling is a conserved pathway that drives developmental growth and is essential for the formation of most organs. The expression of HH target genes is regulated by a dual switch mechanism where GLI proteins function as bifunctional transcriptional activators (in the presence of HH signaling) and transcriptional repressors (in the absence of HH signaling). This results in a tight control of GLI target gene expression during rapidly changing levels of pathway activity. It has long been presumed that GLI (...) proteins also repress target genes prior to the initial expression of HH in a given tissue. This idea forms the basis for the limb bud pre‐patterning model for regulating digit number. Recent findings indicate that GLI repressor proteins are indeed present prior to HH signaling but contrary to this model, GLI proteins are inert as they do not regulate transcriptional responses or enhancer chromatin modifications at this time. These findings suggest that GLI transcriptional repressor activity is not a default state as assumed, but is itself regulated in an unknown fashion. We discuss these findings and their implications for understanding pre‐patterning, digit regulation, and HH‐driven disease. (shrink)

The Hodgkin–Huxley (HH) model of the action potential is a theoretical pillar of modern neurobiology. In a number of recent publications, Carl Craver ([2006], [2007], [2008]) has argued that the model is explanatorily deficient because it does not reveal enough about underlying molecular mechanisms. I offer an alternative picture of the HH model, according to which it deliberately abstracts from molecular specifics. By doing so, the model explains whole-cell behaviour as the product of a mass of underlying low-level events. The (...) issue goes beyond cellular neurobiology, for the strategy of abstraction exhibited in the HH case is found in a range of biological contexts. I discuss why it has been largely neglected by advocates of the mechanist approach to explanation. 1 Introduction2 A Primer on the HH Model2.1 The basic qualitative picture2.2 The quantitative model3 Interlude: What Did Hodgkin and Huxley Think?4 Craver’s View4.1 Mechanistic explanation4.2 Sketches4.3 Craver's view: The HH model as a mechanism sketch5 An Alternative View of the HH Model5.1 Another look at the equations5.2 The discrete-gating picture5.3 The road paved by Hodgkin and Huxley5.4 Summary and comparison to Craver6 Conclusion: The HH Model and Mechanistic Explanation6.1 Sketches and abstractions6.2 Why has aggregative abstraction been overlooked? (shrink)

Book I of HH would seem to announce the end of Nietzsche's concern with the philosophical pessimism that shapes BT and figures prominently in HL. In BT he endorses the pessimistic thesis that the best thing for a human being is to die soon, while he announces in HH that the even the words "optimism" and "pessimism" are outdated since they play a role in a theological discourse that is gradually dying out. This change is connected with another, namely Nietzsche's (...) growing intolerance of metaphysical speculation of any sort. In place of the wild metaphysics of BT, which postulates Apollinian and Dionysian drives as ultimate constituents of reality and associates the latter with a primal... (shrink)

Sounds like h-nmm, hh-aaaah, hn-hn, unkay, nyeah, ummum, uuh, um-hm-uh-hm, um and uh-huh occur frequently in American English conversation but have thus far escaped systematic study. This article reports a study of both the forms and functions of such tokens in a corpus of American English conversations. These sounds appear not to be lexical, in that they are productively generated rather than finite in number, and in that the sound–meaning mapping is compositional rather than arbitrary. This implies that English bears (...) within it a small specialized sub-language which follows different rules from the language as a whole. The functions supported by this sub-language complement those of main-channel English; they include low-overhead control of turn-taking, negotiation of agreement, signaling of recognition and comprehension, management of interpersonal relations such as control and affiliation, and the expression of emotion, attitude, and affect. (shrink)

Sounds like h-nmm, hh-aaaah, hn-hn, unkay, nyeah, ummum, uuh, um-hm-uh-hm, um and uh-huh occur frequently in American English conversation but have thus far escaped systematic study. This article reports a study of both the forms and functions of such tokens in a corpus of American English conversations. These sounds appear not to be lexical, in that they are productively generated rather than finite in number, and in that the sound¿meaning mapping is compositional rather than arbitrary. This implies that English bears (...) within it a small specialized sub-language which follows different rules from the language as a whole. The functions supported by this sub-language complement those of main-channel English; they include low-overhead control of turn-taking, negotiation of agreement, signaling of recognition and comprehension, management of interpersonal relations such as control and affiliation, and the expression of emotion, attitude, and affect. (shrink)

The availability of willing providers of medical assistance in dying in Canada has been an issue since a Canadian Supreme Court decision and the subsequent passing of federal legislation, Bill C14, decriminalised MAiD in 2016. Following this legislation, Hamilton Health Sciences in Ontario, Canada, created a team to support access to MAiD for patients. This research used a qualitative, mixed methods approach to data collection, obtaining the narratives of providers and supporters of MAiD practice at HHS. This study occurred at (...) the outset of MAiD practice in 2016, and 1 year later, once MAiD practice was established. Our study reveals that professional identity and values, personal identity and values, experience with death and dying, and organisation context are the most significant contributors to conscientious participation for MAiD providers and supporters. The stories of study participants were used to create a model that provides a framework for values clarification around MAiD practice, and can be used to explore beliefs and reasoning around participation in MAiD across the moral spectrum. This research addresses a significant gap in the literature by advancing our understanding of factors that influence participation in taboo clinical practices. It may be applied practically to help promote reflective practice regarding complex and controversial areas of medicine, to improve interprofessional engagement in MAiD practice and promote the conditions necessary to support moral diversity in our institutions. (shrink)

The Obama administration’s HHS mandate to force Catholic and other religious organizations to provide insurance coverage for morally objectionable practices has been the source of a great deal of controversy. While the religious liberty question has received the most attention, the mandate reveals a yet deeper problem in the mainstream acceptance of contraception and even abortion as a normal part of medical practice. The author argues that these practices constitute a deep corruption of medicine itself, away from its original meaning (...) as a kind of restorative justice grounded in a substantive understanding of the human good and towards a formalist emphasis on preference satisfaction and patient autonomy. (shrink)

This article examines Nietzsche's engagement with Stoic philosophical therapy in the free spirit trilogy. I suggest that Nietzsche first turned to Stoicism in the late 1870s in his attempt to develop a philosophical therapy that might treat the injuries human beings suffer through fate or chance without recourse to the metaphysical theodicies discredited by Enlightenment skepticism and positivism. I argue that in HH and D Nietzsche adopts a conventional form of Stoic therapy. The article then shows how Nietzsche came to (...) take a critical stance against Stoic therapy on the grounds that it entails a radical extirpation of the value judgments that underpin the emotions. For this reason, I claim that in GS he attempts to develop a rival philosophical therapy, one that aims to enable human beings to unconditionally affirm fate but without this affirmation entailing, as it does for the Stoics, the dissolution of all emotional valuations. However, despite Nietzsche's belief that he had fundamentally broken with Stoicism, I argue, first, that Nietzsche's therapy in GS is deeply indebted to a "cosmic" model of Stoicism, which consists in the loving consent to the events that happen to us, and second, that he gives us no reasonable account of how it is possible to unconditionally affirm fate without adopting some form of Stoic indifference or apatheia. (shrink)

I claim that the Hodgkin‐Huxley (HH) current equations owe a great deal of their importance to their role in bringing results from experiments on squid giant action preparations to bear on the study of the action potential in other neurons in other in vitro and in vivo environments. I consider ideas from Weber and Craver about the role of Coulomb’s and other fundamental equations in explaining the action potential and in HH’s development of their equations. Also, I offer an embellishment (...) to Schaffner’s emergent unifier conception of the HH model. †To contact the author, please write to: Department of HPS, University of Pittsburgh, 1017 Cathedral of Learning, Pittsburgh, PA 15260; e‐mail: [email protected]. (shrink)

As part of the regulatory review process, both the Food and Drug Administration and Office for Human Research Protections (U.S. Department of Health and Human Services [HHS]...

Many individuals with developmental language disorder (DLD) and individuals who are deaf or hard of hearing (D/HH) have social–emotional problems, such as social difficulties, and show signs of aggression, depression, and anxiety. These problems can be partly associated with their executive functions (EFs) and theory of mind (ToM). The difficulties of both groups in EF and ToM may in turn be related to self-directed speech (i.e., overt or covert speech that is directed at the self). Self-directed speech is thought to (...) allow for the construction of non-sensory representations (i.e., representations that do not coincide with direct observation). Such non-sensory representations allow individuals to overcome the limits set upon them by the senses. This ability is constrained by the development of word meaning structure (i.e., the way words are understood). We argue that the greater ability to construct non-sensory representations may result in more enhanced forms of EF and ToM. We conclude that difficulties in EF, ToM, and social–emotional functioning in those with hearing and language problems may be accounted for in terms of word meaning impairments. We propose that word meaning structure and self-directed speech should be considered in assigning EF and ToM treatments to individuals with DLD and those who are D/HH. (shrink)

The close link between signaling by the developmental regulators of the Hedgehog family and cholesterol biochemistry has been known for some time. The morphogen is covalently attached to cholesterol in a peculiar autocatalytic reaction and embryonal disruption of cholesterol synthesis leads to malformations that mimic Hh signaling defects. Recently, it was furthermore shown that secreted Hh could hitchhike on lipoprotein particles to establish its morphogenic gradient in the developing embryo. Additionally, there is new evidence that the Hh‐receptor Patched transmits the (...) Hh signal by modulating the secretion of an inhibitory sterol molecule from the receiving cells. Here we present some of the most recent discoveries on the Hh–sterol link and discuss their implications from a systems design perspective. We predict that a robust functioning of the Hh pathway will require the involvement of more sterol metabolites, and these should be the subject of future research. BioEssays 29:1085–1094, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Two posttranslational lipid modifications present on all Hedgehog (Hh) morphogens—an N‐terminal palmitate and a C‐terminal cholesterol—are established and essential regulators of Hh biofunction. Yet, for several decades, the question of exactly how both lipids contribute to Hh signaling remained obscure. Recently, cryogenic electron microscopy revealed different modes by which one or both lipids may contribute directly to Hh binding and signaling to its receptor Patched1 (Ptc). Some of these modes demand that the established release factor Dispatched1 (Disp) extracts dual‐lipidated Hh (...) from the cell surface, and that another known upstream signaling modulator called Scube2 chaperones the dual‐lipidated morphogen to Ptc. By mechanistically and biochemically aligning this concept with established in vivo and recent in vitro findings, this reflection identifies remaining questions in lipidated Hh transport and evaluates additional mechanisms of Disp‐ and Scube2‐regulated release of a second bioactive Hh fraction that has one or both lipids removed. (shrink)