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When used clinically, psychedelics may appear unusual or even unique when compared to more familiar or long-standing medical interventions, prompting some to suggest that the ethical issues raised may likewise be exceptional. If that is correct, then perhaps psychedelics should be treated differently from other medical substances: for example, by being subjected to different ethical or evidentiary standards. Alternatively, it may be that psychedelics have more in common with various existing medical interventions than first meets the eye. We argue in favor of the latter position, drawing on parallels from earlier debates around genetic exceptionalism in bioethics. We suggest there are risks to adopting a stance of "psychedelic ethical exceptionalism," and propose that consistent ethical rules and evidentiary standards should be applied across all relevant areas of clinical medicine. Importantly, this does not preclude the possibility that changes to existing standards should be made; but if so, this should not be justified by appealing to the alleged uniqueness of psychedelics. [ABSTRACT FROM AUTHOR]

We develop an abstract theory of flows of geometric 퐻-structures, i.e., flows of tensor fields defining 퐻-reductions of the frame bundle, for a closed and connected subgroup H ⊂ SO ⁢ (n) , on any connected and oriented 푛-manifold with sufficient topology to admit such structures. The first part of the article sets up a unifying theoretical framework for deformations of 퐻-structures, by way of the natural infinitesimal action of GL ⁢ (n , R) on tensors combined with various bundle decompositions induced by 퐻-structures. We compute evolution equations for the intrinsic torsion under general flows of 퐻-structures and, as applications, we obtain general Bianchi-type identities for 퐻-structures, and, for closed manifolds, a general first variation formula for the L 2 -Dirichlet energy functional ℰ on the space of 퐻-structures. We then specialise the theory to the negative gradient flow of ℰ over isometric 퐻-structures, i.e., their harmonic flow. The core result is an almost-monotonocity formula along the flow for a scale-invariant localised energy, similar to the classical formulas by Chen–Struwe [M. Struwe, On the evolution of harmonic maps in higher dimensions, J. Differential Geom.28 (1988), 3, 485–502; Y. M. Chen and M. Struwe, Existence and partial regularity results for the heat flow for harmonic maps, Math. Z.201 (1989), 1, 83–103] for the harmonic map heat flow. This yields an 휀-regularity theorem and an energy gap result for harmonic structures, as well as long-time existence for the flow under small initial energy, relative to the L ∞ -norm of initial torsion, in the spirit of Chen–Ding [Y. M. Chen and W. Y. Ding, Blow-up and global existence for heat flows of harmonic maps, Invent. Math.99 (1990), 3, 567–578]. Moreover, below a certain energy level, the absence of a torsion-free isometric 퐻-structure in the initial homotopy class imposes the formation of finite-time singularities. These seemingly contrasting statements are illustrated by examples on flat 푛-tori, so long as the set [ S n , SO ⁢ (n) / H ] of homotopy classes of maps S n → SO ⁢ (n) / H contains more than one element and the universal cover of SO ⁢ (n) / H is a sphere, e.g. when n = 7 and H = G 2 , or n = 8 and H = Spin ⁢ (7) . [ABSTRACT FROM AUTHOR]

In this paper, we suggest that personalized LLMs trained on information written by or otherwise pertaining to an individual could serve as artificial moral advisors (AMAs) that account for the dynamic nature of personal morality. These LLM-based AMAs would harness users’ past and present data to infer and make explicit their sometimes-shifting values and preferences, thereby fostering self-knowledge. Further, these systems may also assist in processes of self-creation, by helping users reflect on the kind of person they want to be and the actions and goals necessary for so becoming. The feasibility of LLMs providing such personalized moral insights remains uncertain pending further technical development. Nevertheless, we argue that this approach addresses limitations in existing AMA proposals reliant on either predetermined values or introspective self-knowledge. [ABSTRACT FROM AUTHOR]

The number of quantitative systems pharmacology (QSP) submissions to the U.S. Food and Drug Administration has continued to increase over the past decade. This report summarizes the landscape of QSP submissions as of December 2023. QSP was used to inform drug development across various therapeutic areas and throughout the drug development process of small molecular drugs and biologics and has facilitated dose finding, dose ranging, and dose optimization studies. Though the majority of QSP submissions (>66%) focused on drug effectiveness, QSP was also utilized to simulate drug safety including liver toxicity, risk of cytokine release syndrome (CRS), bone density, and others. This report also includes individual contexts of use from a handful of new drug applications (NDAs) and biologics license applications where QSP modeling was used to demonstrate the utility of QSP modeling in regulatory drug development. According to the models submitted in QSP submissions, an anonymous case was utilized to illustrate how QSP informed development of a bispecific monoclonal antibody with respect to CRS risk. QSP submissions for informing pediatric drug development were summarized along with highlights of a case in inborn errors of metabolism. Furthermore, simulations of response variability with QSP were described. In summary, QSP continues to play a role in informing drug development. [ABSTRACT FROM AUTHOR]

Sacrificial dilemmas such as the trolley problem play an important role in experimental philosophy (x-phi). But it is increasingly argued that, since we are not likely to encounter runaway trolleys in our daily life, the usefulness of such thought experiments for understanding moral judgments in more ecologically valid contexts may be limited. However, similar sacrificial dilemmas are experienced in real life by animal research decision makers. As part of their job, they must make decisions about the suffering, and often the death, of many non-human animals. For this reason, a context-specific investigation of so-called "3R dilemmas" (i.e., dilemmas where there is a conflict between the principles of replacement, reduction, and refinement of the use of animals in research) is essential to improve the situation of both non-human animals and human stakeholders. An approach well suited for such investigation is experimental philosophical bioethics ("bioxphi"), which draws on methods similar to x-phi to probe more realistic, practical scenarios with an eye to informing normative debates and ethical policy. In this article, we argue for a need to investigate 3R dilemmas among professional decision-makers using the tools of bioxphi. In a first step, we define 3R dilemmas and discuss previous investigations of professionals' attitudes in such cases. In a second step, we show how bioxphi is a promising method to investigate the whys and hows of professional decision-making in 3R dilemmas. In a last step, we provide a bioxphi template for 3R dilemmas, give recommendations on its use, explore the normative relevance of data collected by such means, and discuss important limitations. [ABSTRACT FROM AUTHOR]

PURPOSE: Genomic tests, such as the Oncotype Dx 21-gene and Prosigna risk of recurrence (ROR-P) assay, are commonly used for breast cancer prognostication. Emerging data suggest variability between assays, but this has not been compared in diverse populations. MATERIALS AND METHODS: RNA sequencing was performed on 647 previously untreated stage I-III estrogen receptor–positive/human epidermal growth factor receptor 2–negative tumors in the Carolina Breast Cancer Study, which oversampled Black and younger women (age <50 years at diagnosis), using research versions of two common RNA-based prognostic assays: ROR-PR and the 21-gene recurrence score (RSR). Relative frequency differences and 95% CIs were estimated for associations with race and age, and hazards of 5-year local or distant recurrence were modeled with Cox regression. Proliferation and estrogen module scores from each assay, representing broad activity of genes in those pathways, were examined to guide interpretation of differences between tests. RESULTS: Among both younger and older individuals, Black women had higher frequency of intermediate and high ROR-PR scores than non-Black women. Race was not significantly associated with RSR in either age group. High (hazard ratio [HR], 4.67 [95% CI, 1.73 to 12.70]) and intermediate (HR, 2.12 [95% CI, 0.98 to 4.62]) ROR-PR scores were associated with greater risk of recurrence, but RSR did not predict recurrence. RSR emphasized estrogen over proliferation modules, whereas ROR-PR emphasized proliferation. Higher proliferation scores were associated with younger age and Black race in both assays. Modifications to the RSR algorithm that increased emphasis on proliferation improved prognostication in this diverse population. CONCLUSION: ROR-PR and the 21-gene RSR differentially emphasize estrogen-related and proliferative biology. The emphasis of 21-gene RS on estrogen-related biology and lower endocrine therapy initiation among Black women may contribute to poorer prognostic ability in heterogeneously treated populations. [ABSTRACT FROM AUTHOR]

Danaher and Nyholm (2024a) have recently proposed that digital duplicates—such as fine-tuned, “personalized” large language models that closely mimic a particular individual—might reduce that individual’s scarcity and thus increase the amount of instrumental value they can bring to the world. In this commentary, we introduce the notion of relational scarcity and explore how digital duplicates would affect the value of interpersonal relationships. [ABSTRACT FROM AUTHOR]

Children are treated differently to adults in liberal societies with respect to their right to bodily integrity. A commonly given justification for treating them differently is that they supposedly lack the sort of autonomy that is normally attributed to neurotypical adults. As such children fall through the cracks when it comes to protecting their bodily integrity: they are viewed as less than fully autonomous persons in philosophical, medical, and legal settings. With this editorial, we analyse current treatments of the concept of the child's right to bodily integrity and how this relates to their (developing or future) autonomy on various conceptions. [ABSTRACT FROM AUTHOR]

Generative artificial intelligence (AI) raises ethical questions concerning moral and legal responsibility—specifically, the attributions of credit and blame for AI‐generated content. For example, if a human invests minimal skill or effort to produce a beneficial output with an AI tool, can the human still take credit? How does the answer change if the AI has been personalized (i.e., fine‐tuned) on previous outputs produced without AI assistance by the same human? We conducted a preregistered experiment with representative sampling (N = 1802) repeated in four countries (United States, United Kingdom, China, and Singapore). We investigated laypeople's attributions of credit and blame to human users for producing beneficial or harmful outputs with a standard large language model (LLM), a personalized LLM, or no AI assistance (control condition). Participants generally attributed more credit to human users of personalized versus standard LLMs for beneficial outputs, whereas LLM type did not significantly affect blame attributions for harmful outputs, with a partial exception among Chinese participants. In addition, UK participants attributed more blame for using any type of LLM versus no LLM. Practical, ethical, and policy implications of these findings are discussed. [ABSTRACT FROM AUTHOR]

Introduction: This study assessed patient demographic factors associated with nonattendance for osteoporosis evaluation after being referred to our Bone Health Clinic (BHC), a hospital‐based outpatient Fracture Liaison Service (FLS), for a fragility fracture. Methods: 507 patients sustaining a fragility fracture were referred to the BHC over a 39‐month period. Retrospective chart review was conducted to capture osteoporosis evaluation attendance rates and demographic factors (age, gender, race, area deprivation index, insurance type, and fracture type). A post‐fracture follow‐up visit with either the BHC or another provider in which osteoporosis was noted in the assessment was considered attendance for osteoporosis evaluation. Nonattendance was determined at a cutoff of one year after the fracture date. Results: Of the 507 patients referred to the BHC following a fragility fracture, 177 patients attended osteoporosis evaluation with either the BHC or a primary care provider. Nonattendance was associated with older age (p = 0.0075), having private health insurance (p = 0.0434), and recent hip fracture (p < 0.0001). Attendance was associated with having government health insurance (p = 0.0103). Conclusion: Inpatient evaluation and treatment for osteoporosis should be considered in patients who are older or have sustained a hip fracture as they may have more difficulty attending post‐fracture appointments. [ABSTRACT FROM AUTHOR]

Hamstring strain injuries occur when localized tissue strain capacity is exceeded. Localized strain may be affected by intramuscular variation in stiffness, but research in this area is lacking. The purpose of this study was to determine the effects of intramuscular hamstring stiffness on localized muscle strain during passive hip flexion. Twenty-eight (age 25.064.9 years) healthy women (n515) and men (n513) had biceps femoris, semitendinosus, and semimembranosus stiffness measured proximally, medially, and distally during passive hip flexion and extension using shear-wave elastography. Anthropometric and stiffness measurements were entered into an anatomical model of equivalent springs to estimate localized tissue strain and differentiate between the relative contribution to passive strain from each muscular region. In shortened and stretched positions, stiffness was lowest proximally for all muscles (Cohen's d50.66-0.79, p, 0.001). In addition, relative strain contribution was greater proximally (37.5-39.4%) compared with middle (31.74-32.2%) or distal (28.6-30.3%) regions (p, 0.001), with proximal contribution to strain increasing with greater hip flexion. Our results suggest that intramuscular variations in passive hamstring stiffness contribute to inhomogeneous strain throughout the muscle during passive hip flexion. Given the prevalence of proximal stretch-pattern strain injuries, variation in intramuscular stiffness may contribute to risk for such injuries. [ABSTRACT FROM AUTHOR]

Background: De Quervain tenosynovitis of the wrist is a common pathology. The primary aim of this study is to determine the prevalence of extensor pollicis brevis and abductor pollicis longus (APL) anatomical variations in association with de Quervain tenosynovitis. The secondary aim was to compare additional patient-specific factors associated with de Quervain tenosynovitis. Methods: This retrospective study included 172 patients with de Quervain tenosynovitis who underwent first dorsal compartment release and 179 patients with thumb carpometacarpal (CMC) arthritis who underwent thumb CMC arthroplasty between August 1, 2007, and May 1, 2022. The CMC group was chosen as the control group because the study surgeons perform APL suspensionplasty as the primary procedure for thumb CMC arthritis, allowing for a comparison group without de Quervain tenosynovitis. Exclusion criteria included patients undergoing revision surgery, patients undergoing thumb CMC procedure other than APL suspensionplasty, and patients with both CMC and first dorsal compartment diagnoses. Demographics, clinical variables, and intraoperative findings were collected through retrospective chart reviews. Results: Patients in the de Quervain tenosynovitis group tended to be younger (51 years, range: 23-92 years vs 63 years, range: 28-85 years), women (86.1% vs 77.1%), and more commonly of African American or black race (15.7% vs 3.9%) and Asian race (5.2% vs 0%). There was a higher prevalence of tendon subcompartments (79.1% vs 64.2%), but fewer number of APL slips (38.3% vs 20.7% 2 or fewer slips) seen in the de Quervain tenosynovitis group. Conclusion: Anatomical variation exists between patients with and without de Quervain tenosynovitis. The presence of tendon subcompartments but not an increased number of tendon slips is associated with de Quervain tenosynovitis. [ABSTRACT FROM AUTHOR]

Psychedelics such as psilocybin reliably produce significantly altered states of consciousness with a variety of subjectively experienced effects. These include certain changes to perception, cognition, and affect,1 which we refer to here as the acute subjective effects of psychedelics. In recent years, psychedelics such as psilocybin have also shown considerable promise as therapeutic agents when combined with talk therapy, for example, in the treatment of major depression or substance use disorder.2 However, it is currently unclear whether the aforementioned acute subjective effects are necessary to bring about the observed therapeutic effects of psilocybin and other psychedelics. This uncertainty has sparked a lively—though still largely hypothetical—debate on whether psychedelics without subjective effects ("nonsubjective psychedelics" or "non-hallucinogenic psychedelics") could still have the same therapeutic impact, or whether the acute subjective effects are in fact necessary for this impact to be fully realized.3,4,5 [ABSTRACT FROM AUTHOR]

Background: Advance healthcare decision-making presumes that a prior treatment preference expressed with sufficient mental capacity ("T1 preference") should trump a contrary preference expressed after significant cognitive decline ("T2 preference"). This assumption is much debated in normative bioethics, but little is known about lay judgments in this domain. This study investigated participants' judgments about which preference should be followed, and whether these judgments differed depending on a first-person (deciding for one's future self) versus third-person (deciding for a friend or stranger) perspective. Methods: A vignette-based survey was conducted (N = 1445 US Americans; gender-balanced sample), in a 3 (relationship: self, best friend, stranger) × 2 (T1 preference: treat, do not treat) × 2 (T2 contrary preference: ambiguous, unambiguous) design. Results: Participants were more likely to defer to the incapacitated T2 preference of a third-party, while being more likely to insist on following their own T1 capacitated preference. Further, participants were more likely to conclude that others with substantial cognitive decline were still their "true selves," which correlated with increased deference to their T2 preferences. Conclusions: These findings add to the growing evidence that lay intuitions concerning the ethical entitlement to have decisions respected are not only a function of cognition, as would be expected under many traditional bioethical accounts, but also depend on the relationship of the decision to the decision-maker's true self. [ABSTRACT FROM AUTHOR]

Introduction: Fungi biosynthesize chemically diverse secondary metabolites with a wide range of biological activities. Natural product scientists have increasingly turned towards bioinformatics approaches, combining metabolomics and genomics to target secondary metabolites and their biosynthetic machinery. We recently applied an integrated metabologenomics workflow to 110 fungi and identified more than 230 high-confidence linkages between metabolites and their biosynthetic pathways. Objectives: To prioritize the discovery of bioactive natural products and their biosynthetic pathways from these hundreds of high-confidence linkages, we developed a bioactivity-driven metabologenomics workflow combining quantitative chemical information, antiproliferative bioactivity data, and genome sequences. Methods: The 110 fungi from our metabologenomics study were tested against multiple cancer cell lines to identify which strains produced antiproliferative natural products. Three strains were selected for further study, fractionated using flash chromatography, and subjected to an additional round of bioactivity testing and mass spectral analysis. Data were overlaid using biochemometrics analysis to predict active constituents early in the fractionation process following which their biosynthetic pathways were identified using metabologenomics. Results: We isolated three new-to-nature stemphone analogs, 19-acetylstemphones G (1), B (2) and E (3), that demonstrated antiproliferative activity ranging from 3 to 5 µM against human melanoma (MDA-MB-435) and ovarian cancer (OVACR3) cells. We proposed a rational biosynthetic pathway for these compounds, highlighting the potential of using bioactivity as a filter for the analysis of integrated—Omics datasets. Conclusions: This work demonstrates how the incorporation of biochemometrics as a third dimension into the metabologenomics workflow can identify bioactive metabolites and link them to their biosynthetic machinery. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to determine the perioperative complication rate of surgical fasciectomy following previous treatment with collagenase clostridium histolyticum (CCH) treatment in patients with Dupuytren disease. Methods: A retrospective review of all patients at a large health system undergoing CCH treatment and subsequent limited surgical fasciectomy for recurrence on the same digit between 2010 and 2020 was performed. Fifty-two patients with 62 affected digits met inclusion criteria, and cases were reviewed for preoperative demographics, treatment characteristics, clinical outcomes, and perioperative complications. Results: Fifty-five digits in 48 patients were treated with CCH and underwent subsequent limited surgical fasciectomy. Of all digits in the present study, 3 (6.3%) had a documented surgical complication following open surgical fasciectomy. There were zero postoperative infections, vascular injuries, or tendon injuries. The rate of nerve injury was 2.1%. The rate of postoperative skin necrosis was 4.2%. These rates were comparable or lower than those of historical published data. Conclusions: The rate of perioperative complications in patients undergoing limited surgical fasciectomy after previous CCH treatment is low. The findings of this study will aid the counseling of Dupuytren patients in deciding whether to pursue treatment with CCH versus open surgical fasciectomy. [ABSTRACT FROM AUTHOR]

Simulation has been shown to improve communication and psychometric skills in advanced practice nursing students. Little is known about the impact of a simulation educational intervention with a faculty-facilitated debriefing on the preparation of novice nurse practitioner students for their first clinical practicum. This article describes the development of an educational intervention to accomplish this. The simulation education intervention was implemented with preclinical nurse practitioner students designed to improve their preparation for their first precepted clinical experience. Students were surveyed preintervention and postintervention to explore their self-perception of confidence and preparation for clinicals looking at six domains: health history, physical examination, diagnostics, differentials, final diagnosis, and plan of care. Quantitative results were statistically significant for each domain. Qualitative findings gave deeper insight into the students' perceptions of how the intervention prepared them for clinicals. Advanced practice educators can use educational interventions such as this to prepare students for their first clinical practicums. [ABSTRACT FROM AUTHOR]

The use of additive manufacturing to rapidly test and evaluate solutions to engineering problems has been demonstrated. Selective laser sintering (SLS) is a subset of additive manufacturing that is particularly well suited to producing structural thin wall models and end use parts which can improve the ability to prototype and manufacture certain designs at a substantially lower cost and time compared to current methods. However, a more comprehensive understanding of the material properties of these parts is warranted. The presented research investigates the influence of print orientation and sample thickness on the material properties of printed SLS parts. This novel work involves holding a hatch pattern constant across SLS prints using polyamide 12 material to isolate the anisotropic effects of orientation and thickness. An evaluation of ultimate tensile strength, modulus of elasticity, strain at failure, yield strength, and Poisson's ratio, and scanning electron microscope fractography are conducted. Transverse strain and Poisson's ratio are a key aspect that provide insight into the feasibility of building numerical orthotropic models. These data are used to calculate the degree of anisotropy due to both thickness and orientation. The results support the future use of SLS printing and modeling of thin-walled structures, such as scaled structural ship modeling. The presented data provide guidance on the impact of print orientation and thickness that will aid in manufacturing structural parts with intentionally tuned material properties. [ABSTRACT FROM AUTHOR]

Simple Summary: Ewing sarcoma family tumors are the second most common bone cancer affecting adolescents and young adults. Outcomes are poor in patients with metastatic or relapsed disease, and new treatments are urgently needed. MERTK is a protein found in leukemia, melanoma, lung cancer, and other cancer types where it promotes cancer cell survival and resistance to therapies. MRX-2843 is a new drug that targets MERTK and is currently in clinical trials. We show that MERTK is present on Ewing sarcoma cells and that MRX-2843 has therapeutic activity against these cells. MRX-2843 is even more effective against Ewing sarcoma cells when combined with other drugs, venetoclax or navitoclax, that target a protein called BCL-2. These results suggest that MRX-2843 could be useful to treat Ewing sarcoma in patients. Outcomes are poor in patients with advanced or relapsed Ewing sarcoma (EWS) and current treatments have significant short- and long-term side effects. New, less toxic and more effective treatments are urgently needed. MER proto-oncogene tyrosine kinase (MERTK) promotes tumor cell survival, metastasis, and resistance to cytotoxic and targeted therapies in a variety of cancers. MERTK was ubiquitously expressed in five EWS cell lines and five patient samples. Moreover, data from CRISPR-based library screens indicated that EWS cell lines are particularly dependent on MERTK. Treatment with MRX-2843, a first-in-class, MERTK-selective tyrosine kinase inhibitor currently in clinical trials, decreased the phosphorylation of MERTK and downstream signaling in a dose-dependent manner in A673 and TC106 cells and provided potent anti-tumor activity against all five EWS cell lines, with IC50 values ranging from 178 to 297 nM. Inhibition of MERTK correlated with anti-tumor activity, suggesting MERTK inhibition as a therapeutic mechanism of MRX-2843. Combined treatment with MRX-2843 and BCL-2 inhibitors venetoclax or navitoclax provided enhanced therapeutic activity compared to single agents. These data highlight MERTK as a promising therapeutic target in EWS and provide rationale for the development of MRX-2843 for the treatment of EWS, especially in combination with BCL-2 inhibitors. [ABSTRACT FROM AUTHOR]

PURPOSE: Genomic tests, such as the Oncotype Dx 21-gene and Prosigna risk of recurrence (ROR-P) assay, are commonly used for breast cancer prognostication. Emerging data suggest variability between assays, but this has not been compared in diverse populations. MATERIALS AND METHODS: RNA sequencing was performed on 647 previously untreated stage I-III estrogen receptor–positive/human epidermal growth factor receptor 2–negative tumors in the Carolina Breast Cancer Study, which oversampled Black and younger women (age <50 years at diagnosis), using research versions of two common RNA-based prognostic assays: ROR-PR and the 21-gene recurrence score (RSR). Relative frequency differences and 95% CIs were estimated for associations with race and age, and hazards of 5-year local or distant recurrence were modeled with Cox regression. Proliferation and estrogen module scores from each assay, representing broad activity of genes in those pathways, were examined to guide interpretation of differences between tests. RESULTS: Among both younger and older individuals, Black women had higher frequency of intermediate and high ROR-PR scores than non-Black women. Race was not significantly associated with RSR in either age group. High (hazard ratio [HR], 4.67 [95% CI, 1.73 to 12.70]) and intermediate (HR, 2.12 [95% CI, 0.98 to 4.62]) ROR-PR scores were associated with greater risk of recurrence, but RSR did not predict recurrence. RSR emphasized estrogen over proliferation modules, whereas ROR-PR emphasized proliferation. Higher proliferation scores were associated with younger age and Black race in both assays. Modifications to the RSR algorithm that increased emphasis on proliferation improved prognostication in this diverse population. CONCLUSION: ROR-PR and the 21-gene RSR differentially emphasize estrogen-related and proliferative biology. The emphasis of 21-gene RS on estrogen-related biology and lower endocrine therapy initiation among Black women may contribute to poorer prognostic ability in heterogeneously treated populations. Prognostic value of breast cancer recurrence scores may vary by endocrine therapy adherence [ABSTRACT FROM AUTHOR]

In this issue honoring the contributions of Greg Lemke, the Earp and Graham lab teams discuss several threads in the discovery, action, signaling, and translational/clinical potential of MERTK, originally called c-mer, a member of the TYRO3, AXL, and MERTK (TAM) family of receptor tyrosine kinases. The 30-year history of the TAM RTK family began slowly as all three members were orphan RTKs without known ligands and/or functions when discovered by three distinct alternate molecular cloning strategies in the pre-genome sequencing era. The pace of understanding their physiologic and pathophysiologic roles has accelerated over the last decade. The activation of ligands bridging externalized phosphatidylserine (PtdSer) has placed these RTKs in a myriad of processes including neurodevelopment, cancer, and autoimmunity. The field is ripe for further advancement and this article hopefully sets the stage for further understanding and therapeutic intervention. Our review will focus on progress made through the collaborations of the Earp and Graham labs over the past 30 years. [ABSTRACT FROM AUTHOR]

The application of model‐informed drug development (MIDD) has revolutionized drug development and regulatory decision making, transforming the process into one that is more efficient, effective, and patient centered. A critical application of MIDD is to facilitate dose selection and optimization, which play a pivotal role in improving efficacy, safety, and tolerability profiles of a candidate drug. With the surge of interest in small interfering RNA (siRNA) drugs as a promising class of therapeutics, their applications in various disease areas have been extensively studied preclinically. However, dosing selection and optimization experience for siRNA in humans is limited. Unique challenges exist for the dose evaluation of siRNA due to the temporal discordance between pharmacokinetic and pharmacodynamic profiles, as well as limited available clinical experience and considerable interindividual variability. This review highlights the pivotal role of MIDD in facilitating dose selection and optimization for siRNA therapeutics. Based on past experiences with approved siRNA products, MIDD has demonstrated its ability to aid in dose selection for clinical trials and enabling optimal dosing for the general patient population. In addition, MIDD presents an opportunity for dose individualization based on patient characteristics, enhancing the precision and effectiveness of siRNA therapeutics. In conclusion, the integration of MIDD offers substantial advantages in navigating the complex challenges of dose selection and optimization in siRNA drug development, which in turn accelerates the development process, supports regulatory decision making, and ultimately improves the clinical outcomes of siRNA‐based therapies, fostering advancements in precision medicine across a diverse range of diseases. [ABSTRACT FROM AUTHOR]

Widely varying prevalence of vitamin D deficiency has been reported in patients presenting for total knee arthroplasty (TKA). The primary aim of this study was to determine vitamin D levels in TKA patients and to compare to patients already routinely evaluated for vitamin D levels, patients with fragility fractures of the distal radius (DRF). There is significant overlap between patients presenting for TKA and with DRF, both in terms of medical comorbidities and overall health status, making these populations suitable comparative cohorts. Wefound that all patients presenting for TKA consultation had vitamin D insufficiency and 33% had vitamin D deficiency, compared to only 37% and 14% in the DRF cohort, a patient population routinely evaluated for vitamin D due to the high risk of deficiency. Furthermore, patients with DRF had higher levels of vitamin D before (38 ± 16 vs. 23 ± 5) and after vitamin D supplementation (39 ± 17 vs. 33 ± 10), suggesting that patients presenting for TKA are at even higher risk of vitamin D insufficiency than patients presenting with DRF. Reassuringly, supplementation successfully corrected 39.0% and 55.8% of patients in the DRF and TKA cohorts, respectively. [ABSTRACT FROM AUTHOR]

Background: Humeral nonunions have devastating negative effects on patients' upper extremity function and health-related quality of life. The objective of this study was to identify factors independently associated with 30-day complication, hospital readmission, and reoperation after surgical treatment of humeral nonunions. Materials and Methods: A retrospective case-control study was performed using the American College of Surgeons National Surgical Quality Improvement Program database by querying the Current Procedural Terminology codes for patients who underwent humeral nonunion repair from 2011 to 2020. The study outcomes were 30-day complication, hospital readmission, and reoperation. Results: Of the 1306 patients in our cohort, 135 patients (10%) developed a complication, 66 patients (5%) were readmitted to the hospital, and 44 patients (3%) underwent reoperation during the 30-day postoperative period. Multivariable logistic regression analysis showed that older age, longer operative time, partially dependent functional status, congestive heart failure, bleeding disorder, and contaminated wound classification were associated with 30-day complication after humeral nonunion repair. Older age and disseminated cancer were associated with 30-day reoperation after humeral nonunion repair. Disseminated cancer was associated with 30-day readmission after humeral nonunion repair. Conclusion: Using a large database over a recent 10-year period, we identified demographic and comorbid factors independently associated with episode of care adverse events after humeral nonunion repair. Patients 50 years or older had approximately three times the incidence of complications, readmissions, and reoperations in the first month after humeral nonunion repair compared with patients younger than 50 years. Our findings are relevant for preoperative risk stratification and counseling. [Orthopedics. 2024;47(4):e181–e187.] [ABSTRACT FROM AUTHOR]

In the rapidly evolving digital landscape, cybersecurity education for children is paramount. The SuperCyberKids project, funded under the EU Erasmus+ programme, aims to address this need by developing a comprehensive educational ecosystem for children aged 8 to 13 and their teachers. Central to this initiative is the SuperCyberKids Learning Framework (SCKLF), which incorporates a game-based approach to enhance engagement and motivation through a bespoke digital learning platform and broader ecosystem. This paper focuses on the second pillar of SCKLF, a detailed survey of 65 cybersecurity education initiatives, offering a practical perspective on the current state of cybersecurity education. The survey covered initiatives within and beyond the European Union, emphasizing the target age group. The analysis of these initiatives provides invaluable insights into the practical application of cybersecurity education and played a crucial role in shaping the SCKLF. By highlighting the diversity of approaches and strategies in cybersecurity education, this research contributes to a more holistic and applied perspective, ensuring the framework’s relevance and effectiveness in fostering digital resilience among young learners. [ABSTRACT FROM AUTHOR]

An editorial is presented on the consensus statement from the Hopkins-Oxford Psychedelics Ethics (HOPE) Working Group. Topics include the recognition of the ethical complexities and social justice issues related to the use of psychedelics, the importance of diverse perspectives in ethical discussions, and the need for continued research on both benefits and potential harms associated with psychedelics.

When making substituted judgments for incapacitated patients, surrogates often struggle to guess what the patient would want if they had capacity. Surrogates may also agonize over having the (sole) responsibility of making such a determination. To address such concerns, a Patient Preference Predictor (PPP) has been proposed that would use an algorithm to infer the treatment preferences of individual patients from population-level data about the known preferences of people with similar demographic characteristics. However, critics have suggested that even if such a PPP were more accurate, on average, than human surrogates in identifying patient preferences, the proposed algorithm would nevertheless fail to respect the patient's (former) autonomy since it draws on the 'wrong' kind of data: namely, data that are not specific to the individual patient and which therefore may not reflect their actual values, or their reasons for having the preferences they do. Taking such criticisms on board, we here propose a new approach: the Personalized Patient Preference Predictor (P4). The P4 is based on recent advances in machine learning, which allow technologies including large language models to be more cheaply and efficiently 'fine-tuned' on person-specific data. The P4, unlike the PPP, would be able to infer an individual patient's preferences from material (e.g., prior treatment decisions) that is in fact specific to them. Thus, we argue, in addition to being potentially more accurate at the individual level than the previously proposed PPP, the predictions of a P4 would also more directly reflect each patient's own reasons and values. In this article, we review recent discoveries in artificial intelligence research that suggest a P4 is technically feasible, and argue that, if it is developed and appropriately deployed, it should assuage some of the main autonomy-based concerns of critics of the original PPP. We then consider various objections to our proposal and offer some tentative replies. [ABSTRACT FROM AUTHOR]

Ewing sarcoma is a pediatric bone and soft tissue tumor treated with chemotherapy, radiation, and surgery. Despite intensive multimodality therapy, ~50% patients eventually relapse and die of the disease due to chemoresistance. Here, using phospho-profiling, we find Ewing sarcoma cells treated with chemotherapeutic agents activate TAM (TYRO3, AXL, MERTK) kinases to augment Akt and ERK signaling facilitating chemoresistance. Mechanistically, chemotherapy-induced JAK1-SQ phosphorylation releases JAK1 pseudokinase domain inhibition allowing for JAK1 activation. This alternative JAK1 activation mechanism leads to STAT6 nuclear translocation triggering transcription and secretion of the TAM kinase ligand GAS6 with autocrine/paracrine consequences. Importantly, pharmacological inhibition of either JAK1 by filgotinib or TAM kinases by UNC2025 sensitizes Ewing sarcoma to chemotherapy in vitro and in vivo. Excitingly, the TAM kinase inhibitor MRX-2843 currently in human clinical trials to treat AML and advanced solid tumors, enhances chemotherapy efficacy to further suppress Ewing sarcoma tumor growth in vivo. Our findings reveal an Ewing sarcoma chemoresistance mechanism with an immediate translational value. Due to limited therapeutic options, patients with Ewing sarcoma typically receive intensive chemotherapy which limits quality of life and often resistance develops. Here, the authors identify a chemotherapy-induced JAK-STAT-GAS6-TAM kinase signaling cascade in Ewing sarcoma and therapeutically target this axis with TAM kinase inhibition. [ABSTRACT FROM AUTHOR]

We formulate the gradient Dirichlet flow of Sp (2) Sp (1) -structures on 8-manifolds, as the first systematic study of a geometric quaternion-Kähler (QK) flow. Its critical condition of harmonicity is especially relevant in the QK setting, since torsion-free structures are often topologically obstructed. We show that the conformally parallel property implies harmonicity, extending a result of Grigorian in the G 2 case. We also draw several comparisons with Spin (7) -structures. Analysing the QK harmonic flow, we prove an almost-monotonicity formula, which implies to long-time existence under small initial energy, via ϵ -regularity.We set up a theory of harmonic QK solitons, constructing a non-trivial steady example. We produce explicit long-time solutions: one, converging to a torsion-free limit on the hyperbolic plane; and another, converging to a limit which is harmonic but not torsion-free, on the manifold SU (3) . We also study compactness and the formation of singularities. [ABSTRACT FROM AUTHOR]

Passive hamstring stiffness varies proximo‐distally, resulting in inhomogeneous tissue strain during stretching that may affect localized adaptations and risk of muscle injuries. The purpose of the present study was to determine the acute and chronic effects of static stretching (SS) on intramuscular hamstring stiffness. Thirty healthy active participants had acute changes in passive biceps femoris (BF), semimembranosus (SM), and semitendinosus (ST) stiffness measured at 25% (proximal), 50% (middle), and 75% (distal) muscle length, using shear‐wave elastography, immediately after SS. Participants then completed 4 weeks of either a SS intervention (n = 15) or no intervention (CON, n = 15) with stiffness measured before and after the interventions. The acute and chronic effects of SS were compared between anatomical regions and between regions on the basis of their relative stiffness pre‐intervention. Acutely, SS decreased stiffness throughout the BF and SM (p ≤ 0.05) but not the ST (p = 0.326). However, a regional effect of stretching was observed for SM and ST with greater reduction in stiffness occurring in stiffer muscular regions (p = 0.001–0.013). Chronically, SS increased BF and ST (p < 0.05), but not SM (p = 0.422) stiffness compared with CON, but no regional effect of stretching was observed in any muscle (p = 0.361–0.833). SS resulted in contrasting acute and chronic effects, acutely decreasing stiffness in stiffer regions while chronically increasing stiffness. These results indicate that the acute effects of SS vary along the muscle's length on the basis of the relative stiffness of the muscle and that acute changes in stiffness from SS are unrelated to chronic adaptations. [ABSTRACT FROM AUTHOR]

The development of Tifgreen bermudagrass, and the subsequent mutations of this cultivar, has revolutionized the game of golf in the southern United States as superintendents have access to high‐quality putting surface capable of withstanding hot summers. However, the lack of genetic diversity may make them vulnerable to various pests and the low tolerance to freeze temperatures may make them susceptible to winterkill. In recent years, Oklahoma State University and other universities have begun to create new interspecific F1 hybrids between common (Cynodon dactylon) and African bermudagrasses (C. transvaalensis) for putting greens. The objectives of this study were to investigate the genetic diversity and variation among 14 experimental genotypes and two standard cultivars (TifEagle and Tifdwarf). Simple sequence repeat (SSR) markers and morphological characteristics were used to evaluate the genetic relationships and variation among the 16 genotypes. Results showed significant variation for 11 vegetative traits and two reproductive traits. The phenotypic coefficient of variation was greatest for the third internode length and the least for the first leaf angle for both the field and greenhouse trials. The morphological cluster analysis also showed variation between the two trial environments. The SSR marker cluster analysis showed the 16 genotypes were grouped into four major groups, with a similarity coefficient ranging from 0.44 to 1. The highest similarity was found among the two commercial standards and an experimental ultradwarf from Florida. Several new genotypes (OKC3920, 5 × 23, 11 × 2, 19 × 19, and 34 × 20) were also grouped with the ultradwarf genotypes in the morphological cluster analysis, showing the possibility of achieving similar morphological traits with new genetics. Further field evaluations are needed to determine the performance of these genotypes under low mowing heights. Core Ideas: Substantial DNA diversity of greens‐type bermudagrasses was introduced via crosses as compared to ultradwarf cultivars.Significant morphological variation existed among ultradwarf cultivars and experimental selections.Select genotypes displayed similar morphology to ultradwarf cultivars. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "How social relationships shape moral wrongness judgments" published in Nature Communications. The correction addresses errors in the original article, including misused terms, reporting errors, and incorrect calculations. The corrections have been made in the PDF and HTML versions of the article, and a script with all the corrected results has been provided. The errors do not affect the conclusions of the study. The document provides corrections to various tables and sections in the research article, ensuring the accuracy of the data presented. [Extracted from the article]

The article argues for the inclusion of large language models (LLMs) as co-reasoners in medical decision-making, extending the "human in the loop" concept to incorporate artificial intelligence (AI). Topics discussed include the role of patient participation, the ethical implications of integrating AI reasoning, and the potential of LLMs to contribute valuable reasons in medical contexts.

A commentary on the 2024 article "Affect, Values and Problems Assessing Decision-Making Capacity," by Jennifer Hawkins is presented. Topics include the set of studies into factors that influence ordinary people's judgments about medical decision-making, how ordinary people may not share Hawkins' view that cognitive capacity is necessary for a medical decision to be entitled to respect and why Hawkins'view requires a theory of why certain factors are relevant in some cases but not others.

Marine kelp forests cover 1/3 of our world's coastlines, are heralded as a nature-based solution to address socio-environmental issues, connect hundreds of millions of people with the ocean, and support a rich web of biodiversity throughout our oceans. But they are increasingly threatened with some areas reporting over 90% declines in kelp forest cover in living memory. Despite their importance and the threats they face, kelp forests are entirely absent from the international conservation dialogue. No international laws, policies, or targets focus on kelp forests and very few countries consider them in their national policy. The Kelp Forest Challenge addresses that gap. Together with 252 kelp experts, professionals, and citizens from 25 countries, the Kelp Forest Challenge was developed as a grassroots vision of what the world can achieve for kelp forest conservation. It is a global call to restore 1 million and protect 3 million hectares of kelp forests by 2040. This is a monumental challenge, that will require coordination across multiple levels of society and the mobilization of immense resources. Pledges may therefore include area for protection or restoration, enabling pledges which assist in conservation (funding, equipment, professional expertise, capacity building), or awareness-based pledges which increase awareness or education about kelp forests. Correspondingly, participants may be from government, scientific institutions, private sector, NGOs, community groups, or individuals. This challenge is the beginning of a 17-year mission to save our kelp forests and anyone and any organisation is invited to participate. [ABSTRACT FROM AUTHOR]

The psychedelic psilocybin has shown promise both as treatment for psychiatric conditions and as a means of improving well-being in healthy individuals. In some jurisdictions (e.g., Oregon, USA), psilocybin use for both purposes is or will soon be allowed and yet, public attitudes toward this shift are understudied. We asked a nationally representative sample of 795 US Americans to evaluate the moral status of psilocybin use in an appropriately licensed setting for either treatment of a psychiatric condition or well-being enhancement. Showing strong bipartisan support, participants rated the individual's decision as morally positive in both contexts. These results can inform effective policy-making decisions around supervised psilocybin use, given robust public attitudes as elicited in the context of an innovative regulatory model. We did not explore attitudes to psilocybin use in unsupervised or non-licensed community or social settings. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to assess the impact of implementation of an outpatient fracture liaison service (FLS) on completion rates of dual-energy x-ray absorptiometry (DXA) and screening labs including 25-OH vitamin D and parathyroid hormone (PTH) in patients with upper extremity (UE) fragility fractures. Methods: At our institution, 367 patients were treated in 2014-2015 for UE fragility fractures of the distal radius and proximal humerus before implementation of our outpatient FLS and 395 patients in 2017-2018 after implementation. Retrospective chart review was conducted to identify completed DXA scans within 2 years of fracture treatment and completed 25-OH vitamin D and PTH labs within 1 year of fracture treatment. Results: There were no statistical differences in the demographics of patients treated for distal radial and proximal humeral fragility fractures during the 2014-2015 and 2017-2018 time periods. Implementation of the FLS resulted in a 9.9% increase (P value =.021) in completed DXA scans within 2 years of fracture treatment. Completed 25-OH vitamin D and PTH labs saw a significant increase of 17.1% and 23.8%, respectively (P values <.001). Conclusions: Implementation of an outpatient FLS can help to improve osteoporosis evaluation with completed DXA scans and 25-OH vitamin D and PTH labs. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to identify factors that influence preoperative patient preferences toward anesthesia in patients in a hand and upper extremity clinic. Methods: A survey was administered to consecutive patients in a hand and upper extremity orthopedic clinic at an urban tertiary academic institution. The survey addressed presenting clinical complaint, anesthesia preference for minor soft tissue hand and wrist procedures, factors influencing anesthesia preference, and patient history of anesthesia and surgical treatment. The primary outcome measure was anesthesia preference: local-only or local with sedation. Results: Surveys were completed by 219 patients over a 1-month period with a mean patient age of 55 years. Most patients presented with a hand/wrist complaint (56%). One hundred fifty-two patients (71%) preferred local anesthesia with sedation and 61 patients (29%) preferred local-only anesthesia. Patients who preferred local-only anesthesia reported being more likely to be influenced by surgeon preference and cost, and also were more likely to have had prior experience with local-only anesthesia. In contrast, patients who preferred local anesthesia with sedation were more likely to be concerned about pain or were nervous about surgery. Prior surgical experience did not influence preference for anesthesia. Conclusion: Patient preferences for local-only anesthesia versus local anesthesia with sedation for ambulatory hand surgery are mixed, with most patients preferring sedation. Understanding patient preferences for anesthesia can better inform preoperative discussions and shared decision-making in anesthesia choice. [ABSTRACT FROM AUTHOR]

(1) Background: This observational cohort study describes the frequency, content, and satisfaction with advance care planning (ACP) conversations with healthcare providers (HCPs), as reported by patients with advanced colorectal cancer. (2) Methods: The patients were recruited from two tertiary cancer centers in Alberta, Canada. Using the My Conversations survey with previously validated questions, the patients were asked about specific ACP elements discussed, with which HCPs these elements were discussed, their satisfaction with these conversations, and whether they had a goals of care designation (GCD) order. We surveyed and analyzed data from the following four time points: enrollment, months 1, 2, and 3. (3) Results: In total, 131 patients were recruited. At enrollment, 24% of patients reported discussing at least one ACP topic. From enrollment to month 3, patients reported a high frequency of discussions (80.2% discussed fears, 71.0% discussed prognosis, 54.2% discussed treatment preferences at least once); however, only 44.3% of patients reported discussing what is important to them in considering health care preferences. Patients reported having ACP conversations most often with their oncologists (84.7%) and cancer clinic nurses (61.8%). Patients reported a high level of satisfaction with their ACP conversations, with over 80% of patients reported feeling heard and understood. From enrollment to month 3, there was an increase in the number of patients with a GCD order from 53% to 74%. (4) Conclusions: Patients reported more frequent conversations compared to the literature and clinical documentation. While the satisfaction with these conversations is high, there is room for quality improvement, particularly in eliciting patients' personal goals for their treatment. [ABSTRACT FROM AUTHOR]

The article focuses on addressing ethical concerns related to the potential use of personalized large language models (LLMs) for academic idea and prose generation. Concerns raised include issues of bias, conformity, lowered standards, and the potential negative effects on academic publishing. It authors advocate for a co-creation model where humans play a role in crafting, curating, and communicating the material generated by LLMs to ensure responsible use.

One of the goals of the Accelerating Rare Disease Cures (ARC) program in the Center for Drug Evaluation and Research (CDER) at the US Food and Drug Administration (FDA) is the development and use of regulatory and scientific tools, including drug/disease modeling, dose selection, and translational medicine tools. To facilitate achieving this goal, the FDA in collaboration with the University of Maryland Center of Excellence in Regulatory Science and Innovation (M‐CERSI) hosted a virtual public workshop on May 11, 2023, entitled "Creating a Roadmap to Quantitative Systems Pharmacology–Informed Rare Disease Drug Development." This workshop engaged scientists from pharmaceutical companies, academic institutes, and the FDA to discuss the potential utility of quantitative systems pharmacology (QSP) in rare disease drug development and identify potential challenges and solutions to facilitate its use. Here, we report the main findings from this workshop, highlight the key takeaways, and propose a roadmap to facilitate the use of QSP in rare disease drug development. [ABSTRACT FROM AUTHOR]