Cdc14 phosphatases use an intramolecular pseudosubstrate motif to stimulate and regulate catalysis.

Cdc14 phosphatases are related structurally and mechanistically to protein tyrosine phosphatases (PTPs) but evolved a unique specificity for phosphoSer-Pro-X-Lys/Arg sites primarily deposited by cyclin-dependent kinases. This specialization is widely conserved in eukaryotes. The evolutionary reconfiguration of the Cdc14 active site to selectively accommodate phosphoSer-Pro likely required modification to the canonical PTP catalytic cycle. While studying Saccharomyces cerevisiae Cdc14, we discovered a short sequence in the disordered C terminus, distal to the catalytic domain, which mimics an optimal substrate. Kinetic analyses demonstrated this pseudosubstrate binds the active site and strongly stimulates rate-limiting phosphoenzyme hydrolysis, and we named it "substrate-like catalytic enhancer" (SLiCE). The SLiCE motif is found in all Dikarya fungal Cdc14 orthologs and contains an invariant glutamine, which we propose is positioned via substrate-like contacts to assist orientation of the hydrolytic water, similar to a conserved active site glutamine in other PTPs that Cdc14 lacks. AlphaFold2 predictions revealed vertebrate Cdc14 orthologs contain a conserved C-terminal alpha helix bound to the active site. Although apparently unrelated to the fungal sequence, this motif also makes substrate-like contacts and has an invariant glutamine in the catalytic pocket. Altering these residues in human Cdc14A and Cdc14B demonstrated that it functions by the same mechanism as the fungal motif. However, the fungal and vertebrate SLiCE motifs were not functionally interchangeable, illuminating potential active site differences during catalysis. Finally, we show that the fungal SLiCE motif is a target for phosphoregulation of Cdc14 activity. Our study uncovered evolution of an unusual stimulatory pseudosubstrate motif in Cdc14 phosphatases.

ß-hydroxybutyric acid attenuates oxidative stress and improves markers of mitochondrial function in the HT-22 hippocampal cell line.

Ketone bodies have been the topic of research for their possible therapeutic neurotropic effects in various neurological diseases such as Parkinson's disease, dementia, and seizures. However, continuing research on ketone bodies as a prophylactic agent for decreasing the risk for various neurodegenerative diseases is currently required. In this paper, hippocampal HT-22 cells were treated with ß-hydroxybutyric acid at different doses to elucidate the neurotropic effects. In addition, markers of oxidative stress, mitochondrial function, and apoptosis were investigated. As a result, the ketone body (ß-hydroxybutyric acid) showed a significant increase in hippocampal neuronal viability at a moderate dose. Results show that ß-hydroxybutyric acid exhibited antioxidant effect by decreasing prooxidant oxidative stress markers such as reactive oxygen species, nitrite content, and increasing glutathione content leading to decreased lipid peroxidation. Results show that ß-hydroxybutyric acid improved mitochondrial functions by increasing Complex-I and Complex-IV activities and showing that ß-hydroxybutyric acid significantly reduces caspase-1 and caspase-3 activities. Finally, using computational pharmacokinetics and molecular modeling software, we validated the pharmacokinetic effects and pharmacodynamic (N-Methyl-D-aspartic acid and acetylcholinesterase) interactions of ß-hydroxybutyric acid. The computational studies demonstrate that ß-hydroxybutyric acid can interact with N-Methyl-D-aspartic acid receptor and cholinesterase enzyme (the prime pharmacodynamic targets for cognitive impairment) and further validates its oral absorption, distribution into the central nervous system. Therefore, this work highlights the neuroprotective potential of ketone bodies in cognitive-related neurodegenerative diseases.

How Hospital Leaders and Risk Managers Can Nurture Ethics-Driven Lawyering.

How hospital lawyers assess legal risk in clinically and ethically complex cases can shape risk management operations, influence clinicians' morale, and affect the care patients receive. This article suggests that many disagreements, particularly those involving key ethical and legal questions arising from a patient's care, should launch a process that might include family meetings, early palliative care integration, and ethics consultation or committee review of clinical teams' and surrogates' reasons and perspectives. This article also explains why exploration of these perspectives can motivate fuller understanding of the sources of clinical and ethical disagreements and inform the approach to legal advice that hospital executives and risk managers should foster.

Pocketful of Justice: Will Digital Medicine Be Available to the Poor?

Digital medicine -- a drug delivered with an ingestion sensor and related data collection system -- has potential clinical value, especially for people whose lives are made more disorganized by poverty-related stress. It would be unjust if poor people were effectively barred from this treatment modality. Yet, unless a concerted effort is made to enable access through provision of smartphones to those who cannot afford them, this injustice will aggravate the digital divide in clinical care.

Too Many Patients A Framework to Guide Statewide Allocation of Scarce Mechanical Ventilation During Disasters.

The threat of a catastrophic public health emergency causing life-threatening illness or injury on a massive scale has prompted extensive federal, state, and local preparedness efforts. Modeling studies suggest that an influenza pandemic similar to that of 1918 would require ICU and mechanical ventilation capacity that is significantly greater than what is available. Several groups have published recommendations for allocating life-support measures during a public health emergency. Because there are multiple ethically permissible approaches to allocating scarce life-sustaining resources and because the public will bear the consequences of these decisions, knowledge of public perspectives and moral points of reference on these issues is critical. Here we describe a critical care disaster resource allocation framework developed following a statewide community engagement process in Maryland. It is intended to assist hospitals and public health agencies in their independent and coordinated response to an officially declared catastrophic health emergency in which demand for mechanical ventilators exceeds the capabilities of all surge response efforts and in which there has been an executive order to implement scarce resource allocation procedures. The framework, built on a basic scoring system with modifications for specific considerations, also creates an opportunity for the legal community to review existing laws and liability protections in light of a specific disaster response process.

The Ethics of Smart Pills and Self-Acting Devices: Autonomy, Truth-Telling, and Trust at the Dawn of Digital Medicine.

Digital medicine is a medical treatment that combines technology with drug delivery. The promises of this combination are continuous and remote monitoring, better disease management, self-tracking, self-management of diseases, and improved treatment adherence. These devices pose ethical challenges for patients, providers, and the social practice of medicine. For patients, having both informed consent and a user agreement raises questions of understanding for autonomy and informed consent, therapeutic misconception, external influences on decision making, confidentiality and privacy, and device dependability. For providers, digital medicine changes the relationship where trust can be verified, clinicians can be monitored, expectations must be managed, and new liability risks may be assumed. Other ethical questions include direct third-party monitoring of health treatment, affordability, and planning for adverse events in the case of device malfunction. This article seeks to lay out the ethical landscape for the implementation of such devices in patient care.

STOPPING DECEPTIVE HEALTH CLAIMS: THE NEED FOR A PRIVATE RIGHT OF ACTION UNDER FEDERAL LAW.

This Article offers a thorough analysis of an important public health issue, namely how to confront the growing problem of deceptive claims regarding foods and dietary supplements, including increasingly prevalent but unverifiable claims. The authors call for the creation of a limited private right of action under the Federal Trade Commission (FTC) Act for deceptive health-related claims for these products. The proposal responds to the growing market for these products and the inadequacy of current laws and enforcement actions to prevent such claims. In crafting the limited private right of action, the authors attempt to enhance consumer protection without undermining federal agency primacy in enforcement. The Article ends with an appendix setting forth proposed language for a statutory amendment to the FTC Act incorporating the authors' proposal.

Analysis: A Legal Perspective.

This commentary summarizes the uncertain state of the law regarding consent for posthumous gamete retrieval. The emergence of a legal framework will be aided by the kind of ethical analysis prompted by this family's request for removal and preservation of a deceased patient's ovaries.

Probiotics: achieving a better regulatory fit.

The development and marketing of new probiotic products, substances containing live microorganisms that have a beneficial effect on the human body, have dramatically increased over the last few years. This article examines how the Food and Drug Administration and Federal Trade Commission currently regulate probiotics and makes recommendations as to changes that might be made to ensure that probiotic products are made available to the general public in a way that is both safe and effective.

A legislatively mandated council: a model for palliative care policy integration.

Mechanisms are needed to foster discussion of policy choices about end-of-life care, identify areas of general agreement, and clarify possible areas of disagreement. The Maryland State Advisory Council on Quality Care at the End of Life (MSAC), created by legislation as a permanent part of Maryland government, is one such mechanism. We describe the rationale for creating the MSAC, its operational features, and some of its successes and challenges. Given state-to-state variation in many aspects of health care organization and financing, we do not present the MSAC as a model to be adopted in every state. The MSAC's body of work over 8 years indicates that the model can be an effective catalyst for positive change in end-of-life policy making. Reformers elsewhere should consider this model, with an eye to both the MSAC's accomplishments and areas in which a different approach might be more fruitful.

Building esprit de corps: learning to better navigate between "my" patient and "our" patient.

Excellence in the care of hospital patients, particularly those in an intensive care unit, reflects esprit de corps among the care team. Esprit de corps depends on a delicate balance; each clinician must preserve a sense of personal responsibility for "my" patient and yet participate in the collaborative work essential to the care of "our" patient. A harmful imbalance occurs when a physician demands total control of the decision-making process, especially concerning end-of-life treatment options. Although emotional factors may push a physician to claim decision-making exclusivity, compounded by a legal framework that overemphasizes individual responsibility, esprit de corps can be preserved through timely communication among clinicians and a recognition that optimal care for "my" patient requires effective team practice.

Content of advance directives for individuals with advanced dementia.

OBJECTIVE: To examine how people with end-stage dementia have conveyed their wishes for end-of-life care in advance directives. METHOD: The documents of 123 residents of three Maryland nursing homes, all with end-stage dementia, were reviewed. RESULTS: More years of education and White race were significantly associated with having an advance directive. With the exceptions of comfort care and pain treatment, advance directives were used primarily to restrict, not request, many forms of care at the end of life. Decisions about care for end-stage conditions such as Alzheimer's dementia are less often addressed in these documents than for terminal conditions and persistent vegetative state. DISCUSSION: For advance directives to better reflect a person's wishes, discussions with individuals and families about advance directives should include a range of care issues in the settings of terminal illness, persistent vegetative state or end-stage illness. These documents should be reviewed periodically to make certain that they convey accurately the person's treatment preferences.

Surrogate decision making: reconciling ethical theory and clinical practice.

The care of adult patients without decision-making abilities is a routine part of medical practice. Decisions for these patients are typically made by surrogates according to a process governed by a hierarchy of 3 distinct decision-making standards: patients' known wishes, substituted judgments, and best interests. Although this framework offers some guidance, it does not readily incorporate many important considerations of patients and families and does not account for the ways in which many patients and surrogates prefer to make decisions. In this article, the authors review the research on surrogate decision making, compare it with normative standards, and offer ways in which the 2 can be reconciled for the patient's benefit.

Nutrition and involuntary weight loss: a pilot study of an educational intervention for nursing home surveyors.

OBJECTIVE: To describe the knowledge and attitudes of nursing home (NH) surveyors before and after a brief educational intervention related to nutrition and involuntary weight loss in nursing home residents. DESIGN: A questionnaire covering knowledge and attitudes about nutrition was given 1 month before and 6 months after a targeted educational intervention. PARTICIPANTS AND SETTING: State of Maryland nursing home surveyors. MEASUREMENTS: A 24-item questionnaire of NH surveyor knowledge (11 items) and attitudes (13 items) regarding issues related to nutrition and involuntary weight loss in NH residents. RESULTS: Overall surveyors' knowledge scores increased from 68% (SD, 17%) pre-intervention to 76% (SD, 18%) post-intervention (P = .11). Knowledge related to the lack of the effect of tube feeding on survival in NH residents with end-stage dementia was the only knowledge item that improved significantly with the intervention (39% correct pre-intervention and 68% correct post-intervention, P = .04). There were no changes in attitudes toward the diagnosis or treatment of nutrition after the intervention. CONCLUSION: Overall, NH surveyor knowledge related to nutrition and involuntary weight loss varied widely across topic areas. Neither knowledge nor attitudes were substantially affected by a brief educational intervention. Development of effective educational interventions for NH surveyors should be a priority for stakeholders in NH care.