Abnormalities in the ability of cells to properly degrade proteins have been identified in many neurodegenerative diseases. Recent work has implicated synaptojanin 1 (SynJ1) in Alzheimer's disease and Parkinson's disease, although the role of this polyphosphoinositide phosphatase in protein degradation has not been thoroughly described. Here, we dissected in vivo the role of SynJ1 in endolysosomal trafficking in zebrafish cone photoreceptors using a SynJ1‐deficient zebrafish mutant, nrca14. We found that loss of SynJ1 leads to specific accumulation of late endosomes and (...) autophagosomes early in photoreceptor development. An analysis of autophagic flux revealed that autophagosomes accumulate because of a defect in maturation. In addition we found an increase in vesicles that are highly enriched for PI(3)P, but negative for an early endosome marker in nrca14 cones. A mutational analysis of SynJ1 enzymatic domains found that activity of the 5'phosphatase, but not the Sac1 domain, is required to rescue both aberrant late endosomes and autophagosomes. Finally, modulating activity of the PI(4,5)P2 regulator, Arf6, rescued the disrupted trafficking pathways in nrca14 cones. Our study describes a specific role for SynJ1 in autophagosomal and endosomal trafficking and provides evidence that PI(4,5)P2 participates in autophagy in a neuronal cell type. -/- . (shrink)

Health care reform is a perennial issue in elections — partly because of the challenges facing health care and especially because health care is an important issue for the swing voters. Making reform happen is harder. There are deep divisions within each of the parties — not apparent during elections. Bipartisan support — and the willingness to accept the best legislation that can be passed as “good enough”— will be key.

We are well into the political season that guarantees the election of a new president. Actually, this season, the election cycle began in November 2006, as soon as the off-year election ended. Not surprisingly, health care and reforming health care are major issues for the election — although somewhat less important than they were before late 2007.I use the phrase “not surprisingly” because there are easily understandable reasons why health care tends to be an election issue whenever we are electing (...) a new president. One obvious reason is that, for several decades, we have been plagued by sizeable numbers of people without health insurance and even more importantly, by unsustainable increases in health care spending and substantial numbers of people experiencing patient safety and clinical appropriateness problems. I regard the unsustainable spending and safety and quality problems as especially important because they affect all of us — not just the 15% of the population that is without health insurance. (shrink)

Finding “common ground” to fix some of the policy problems with the ACA was never expected to be easy. How challenging depends on the election outcome. With split government or even same party control of the Congress and White House but without a supermajority in the Senate, fixing identifiable problems requires remedies that might garner bipartisan cooperation. Some potential strategies that might meet this requirement are described.

In popular image, Jesus as friend is sentimentalized, but not so in the Fourth Gospel. Jesus gave his life in love for others and always spoke and acted boldly—marks of friendship in the cultural world of the New Testament.

The cyclical nature of the church's timekeeping means that the sacred story begins anew at Advent, inviting the church to place the coming of the Christ child in a cosmic context in which even time is redefined by God's anticipated in-breaking into the world. Advent is the season of new beginnings and new hopes in its anticipation of the dawning of God's new age.

The sounds that result from our movement and that mark the outcome of our actions typically convey useful information concerning the state of our body and its movement, as well as providing pertinent information about the stimuli with which we are interacting. Here we review the rapidly growing literature investigating the influence of non-veridical auditory cues (i.e., inaccurate in terms of their context, timing, and/or spectral distribution) on multisensory body and action perception, and on motor behavior. Inaccurate auditory cues provide (...) a unique opportunity to study cross-modal processes: the ability to detect the impact of each sense when they provide a slightly different message is greater. Additionally, given that similar cross-modal processes likely occur regardless of the accuracy or inaccuracy of sensory input, studying incongruent interactions are likely to also help us predict interactions between congruent inputs. The available research convincingly demonstrates that perceptions of the body, of movement, and of surface contact features (e.g., roughness) are influenced by the addition of non-veridical auditory cues. Moreover, auditory cues impact both motor behavior and emotional valence, the latter showing that sounds that are highly incongruent with the performed movement induce feelings of unpleasantness (perhaps associated with lower processing fluency). Such findings are relevant to the design of auditory cues associated with product interaction, and the use of auditory cues in sport performance and therapeutic situations given the impact on motor behavior. (shrink)

Large-scale sequencing tests, including whole-exome and whole-genome sequencing, are rapidly moving into clinical use. Sequencing is already being used clinically to identify therapeutic opportunities for cancer patients who have run out of conventional treatment options, to help diagnose children with puzzling neurodevelopmental conditions, and to clarify appropriate drug choices and dosing in individuals. To evaluate and support clinical applications of these technologies, the National Human Genome Research Institute and National Cancer Institute have funded studies on clinical and research sequencing under (...) the Clinical Sequencing Exploratory Research program as well as studies on return of results. Most of these studies use sequencing in real-world clinical settings and collect data on both the application of sequencing and the impact of receiving genomic findings on study participants. They are occurring in the context of controversy over how to obtain consent for exome and genome sequencing. (shrink)

This paper analyses the activities of five organizations shaping the debate over the global governance of genome editing in order to assess current approaches to public engagement (PE). We compare the recommendations of each group with its own practices. All recommend broad engagement with the general public, but their practices vary from expert-driven models dominated by scientists, experts, and civil society groups to citizen deliberation-driven models that feature bidirectional consultation with local citizens, as well as hybrid models that combine elements (...) of both approaches. Only one group practices PE that seeks community perspectives to advance equity. In most cases, PE does little more than record already well-known views held by the most vocal groups, and thus is unlikely to produce more just or equitable processes or policy outcomes. Our exploration of the strengths, weaknesses, and possibilities of current forms of PE suggests a need to rethink both “public” and “engagement.”. (shrink)

Confidentiality is a cornerstone of the physician-patient relationship. Breaches of confidentiality in the context of genetic testing are of particular concern for a number of reasons. First, genetic testing reveals information not only about a particular patient, but also about his or her family members. Second,genetic testing can label healthy people as “at risk,” subjecting them to possible stigmatization or discrimination by third parties. Third, as genetic testing becomes more widespread and is incorporated into primary care, breaches of confidentiality might (...) inadvertently occur more frequently because primary care providers may not be trained to understand the uniqueness of genetic information. Until now, genetic services have been provided primarily by medical geneticists and genetic counselors. However, with the proliferation of new genetic presymptomatic and carrier tests, primary care physicians are going to become increasingly involved in genetic testing. Currently, little is known about physicians’ attitudes toward disclosure of confidential genetic information to third parties. (shrink)

Confidentiality is a cornerstone of the physician-patient relationship. Breaches of confidentiality in the context of genetic testing are of particular concern for a number of reasons. First, genetic testing reveals information not only about a particular patient, but also about his or her family members. Second,genetic testing can label healthy people as “at risk,” subjecting them to possible stigmatization or discrimination by third parties. Third, as genetic testing becomes more widespread and is incorporated into primary care, breaches of confidentiality might (...) inadvertently occur more frequently because primary care providers may not be trained to understand the uniqueness of genetic information. Until now, genetic services have been provided primarily by medical geneticists and genetic counselors. However, with the proliferation of new genetic presymptomatic and carrier tests, primary care physicians are going to become increasingly involved in genetic testing. Currently, little is known about physicians’ attitudes toward disclosure of confidential genetic information to third parties. (shrink)

The Covid‐19 pandemic has concentrated bioethics attention on the “lifeboat ethics” of rationing and fair allocation of scarce medical resources, such as testing, intensive care unit beds, and ventilators. This focus drives ethics resources away from persistent and systemic problems—in particular, the structural injustices that give rise to health disparities affecting disadvantaged communities of color. Bioethics, long allied with academic medicine and highly attentive to individual decision‐making, has largely neglected its responsibility to address these difficult “upstream” issues. It is time (...) to broaden our teaching, research, and practice to match the breadth of the field in order to help address these significant societal inequities and unmet health needs. (shrink)

This paper focuses on two problems connected with our sources for Athenian politics between 510/09 and 488/7 B.C.: In the Athenaion Politeia attributed to Aristotle, ostracism is included in the laws of Cleisthenes. But later the author of the Ath. dates the first ostracism to the year 488/7. Depending on the date of Cleisthenes' laws, this leaves a gap of thirteen to twenty years between the institution of ostracism and its first use. Yet the very nature of the law suggests (...) that it was passed for immediate use. Cleisthenes' rival, Isagoras, is described in Ath. 20.1 as φίλος τῶν τυράννων. This label conflicts with two details in the political struggle. It involves Cleomenes, who had recently expelled the tyrants from Athens, in an astounding volte-face in supporting one who is known as φίλος τῶν τνράννων. Secondly, Isagoras had had the opportunity of imposing by force the kind of government he wanted—but it was an oligarchy, not a tyranny. How did the inappropriate label originate?The reaction of most scholars to the first problem has been to reject the ascription of ostracism to Cleisthenes in Ath. 22.1 and 22.4 and date the institution of ostracism to shortly before the first recorded ostracism. (shrink)

Pragmatic clinical trials offer important benefits, such as generating evidence that is suited to inform real-world health care decisions and increasing research efficiency. However, PCTs also present ethical challenges. One such challenge involves the management of information that emerges in a PCT that is unrelated to the primary research question, yet may have implications for the individual patients, clinicians, or health care systems from whom or within which research data were collected. We term these findings as?pragmatic clinical trial collateral findings,? (...) or?PCT-CFs?. In this article, we explore the ethical considerations associated with the identification, assessment, and management of PCT-CFs, and how these considerations may vary based upon the attributes of a specific PCT. Our purpose is to map the terrain of PCT-CFs to serve as a foundation for future scholarship as well as policy-making and to facilitate careful deliberation about actual cases as they occur in practice. (shrink)

Physicians who care for critically ill people with opioid use disorder frequently face medical, legal, and ethical questions related to the provision of life-saving medical care. We examine a complex medical case that illustrates these challenges in a person with relapsing injection drug use. We focus on a specific question: Is futility an appropriate and useful standard by which to determine provision of life-saving care to such individuals? If so, how should such determinations be made? If not, what alternative decisionmaking (...) framework exists? We determine that although futility has been historically utilized as a justification for withholding care in certain settings, it is not a useful standard to apply in cases involving people who use injection drugs for non-medical purposes. Instead, we are welladvised to explore each patient's situation in a holistic approach that includes the patient, family members, and care providers in the decision-making process. The scope of the problem illustrated demonstrates the urgent need to definitively improve outcomes in people who use injection drugs. Increasing access to high quality medication-assisted treatment and psychiatric care for individuals with opioid use disorder will help our patients achieve a sustained remission and allow us to reach this goal. (shrink)

When there have been substantial failures by institutional leadership in their oversight responsibility to protect research integrity, the public should demand that these be recognized and addressed by the institution itself, or the funding bodies. This commentary discusses a case of research failures in developing genomic predictors for cancer risk assessment and treatment at a leading university. In its review of this case, the Office of Research Integrity, an agency within the US Department of Health and Human Services, focused their (...) report entirely on one individual faculty member and made no comment on the institution’s responsibility and its failure to provide adequate oversight and investigation. These actions missed an important opportunity to emphasize the institution’s critical responsibilities in oversight of research integrity and the importance of institutional transparency and accountability. (shrink)

In this paper, we explore best practices for asynchronous discussions in graduate online bioethics education. We explain that online approaches have advantages and challenges in contrast to in-person discussions. Online challenges are lack of visual or auditory cues and technical access. Advantages include extended opportunities for specific focus, thoughtful reflection, and critical review. We found no significant review of related best practices in bioethics. Our more general literature review of graduate education and online approaches, plus experience in our own bioethics (...) graduate program, suggest provisional best practices that we detail. We reason that online graduate discussion provisionally should aim for a “community of inquiry” framework that incorporates cognitive, social, and teaching “presences,” as well as a learning presence. However, we also note unresolved concerns about whether the framework sufficiently addresses learning, is complete, and captures communicative functions. Drawing further on the literature, we also suggest best practices for instructor feedback to students about their discussion performance, including that remarks should be timely and specific. Summaries from two courses in our graduate bioethics program illustrate how we implement discussion strategies. Finally, we review assessment strategies and suggest that embedded formative assessments in discussion support and demonstrate deeper learning. Limitations in generalizability include that our review targets asynchronous and text-based online discussion, our program assessments do not necessarily detail best practices, student expectations and approaches could be rather particular to our program, and specific bioethics content in principle could alter best practices. (shrink)

Despite general agreement that altered reward sensitivity is involved in attention-deficit/hyperactivity disorder (ADHD), a wide range of different alterations has been proposed. We cite work showing abnormal sensitivity to delay of reward, together with abnormal sensitivity to individual instances of reward. We argue that at the cellular level these behavioural characteristics might indicate that dopamine timing is off in children with ADHD.

The three important target articles make a strong case for regarding racism as a public health crisis. Each calls for advocacy by the bi...