Targeted, Molecular Europium(III) Probes Enable Luminescence-Guided Surgery and 1 Photon Post-Surgical Luminescence Microscopy of Solid Tumors.

Discrete luminescent lanthanide complexes represent a potential alternative to organic chromophores due to their tunability of optical properties, insensitivity to photobleaching, and large pseudo-Stokes shifts. Previously, we demonstrated that the lack of depth penetration of UV excitation required to sensitize discrete terbium and europium complexes can be overcome using Cherenkov radiation emitted by clinically employed radioisotopes in situ. Here, we show that the second-generation europium complexes [Eu(III)(pcta-PEPA2)] and [Eu(III)(tacn-pic-PEPA2)] (Φ = 57% and 76%, respectively) lower the limit of detection (LoD) to 1 nmol in the presence of 10 µCi of Cherenkov emitting isotopes, 18F and 68Ga. Bifunctionalization provides access to cysteine-linked peptide conjugates with comparable brightness and LoD. The conjugate, [Eu(tacn-(pic-PSMA)-PEPA2)], displays high binding affinity to prostate-specific membrane antigen (PSMA)-expressing PC-3 prostate cancer cells in vitro and can be visualized in the membrane-bound state using confocal microscopy. Biodistribution studies with the [86Y][Y(III)(tacn-(pic-PSMA)-PEPA2)] analogue in a mouse xenograft model were employed to study pharmacokinetics. Systemic administration of the targeted Cherenkov emitter, [68Ga][Ga(III)(PSMA-617)], followed by intratumoral injection or topical application of 20 or 10 nmol [Eu(III)(tacn-(pic-PSMA)-PEPA2)], respectively, in live mice resulted in statistically significant signal enhancement using conventional small animal imaging (620 nm bandpass filter). Optical imaging informed successful tumor resection. Ex vivo imaging of the fixed tumor tissue with 1 and 2 photon excitation further reveals the accumulation of the administered Eu(III) complex in target tissues. This work represents a significant step toward the application of luminescent lanthanide complexes for optical imaging in a clinical setting.

Correction: Radiolabeling and in vivo evaluation of lanmodulin with biomedically relevant lanthanide isotopes.

[This corrects the article DOI: 10.1039/D3CB00020F.].

Moral distance, AI, and the ethics of care.

This paper investigates how the introduction of AI to decision making increases moral distance and recommends the ethics of care to augment the ethical examination of AI decision making. With AI decision making, face-to-face interactions are minimized, and decisions are part of a more opaque process that humans do not always understand. Within decision-making research, the concept of moral distance is used to explain why individuals behave unethically towards those who are not seen. Moral distance abstracts those who are impacted by the decision and leads to less ethical decisions. The goal of this paper is to identify and analyze the moral distance created by AI through both proximity distance (in space, time, and culture) and bureaucratic distance (derived from hierarchy, complex processes, and principlism). We then propose the ethics of care as a moral framework to analyze the moral implications of AI. The ethics of care brings to the forefront circumstances and context, interdependence, and vulnerability in analyzing algorithmic decision making.

Radiolabeling and in vivo evaluation of lanmodulin with biomedically relevant lanthanide isotopes.

Short-lived, radioactive lanthanides comprise an emerging class of radioisotopes attractive for biomedical imaging and therapy applications. To deliver such isotopes to target tissues, they must be appended to entities that target antigens overexpressed on the target cell's surface. However, the thermally sensitive nature of biomolecule-derived targeting vectors requires the incorporation of these isotopes without the use of denaturing temperatures or extreme pH conditions; chelating systems that can capture large radioisotopes under mild conditions are therefore highly desirable. Herein, we demonstrate the successful radiolabeling of the lanthanide-binding protein, lanmodulin (LanM), with medicinally relevant radioisotopes: 177Lu, 132/135La and 89Zr. Radiolabeling of the endogenous metal-binding sites of LanM, as well exogenous labeling of a protein-appended chelator, was successfully conducted at 25 °C and pH 7 with radiochemical yields ranging from 20-82%. The corresponding radiolabeled constructs possess good formulation stability in pH 7 MOPS buffer over 24 hours (>98%) in the presence of 2 equivalents of natLa carrier. In vivo experiments with [177Lu]-LanM, [132/135La]-LanM, and a prostate cancer targeting-vector linked conjugate, [132/135La]-LanM-PSMA, reveal that endogenously labeled constructs produce bone uptake in vivo. Exogenous, chelator-tag mediated radiolabeling to produce [89Zr]-DFO-LanM enables further study of the protein's in vivo behavior, demonstrating low bone and liver uptake, and renal clearance of the protein itself. While these results indicate that additional stabilization of LanM is required, this study establishes precedence for the radiochemical labeling of LanM with medically relevant lanthanide radioisotopes.

Sex and Age Differences in Activity Budgets in a Population of Captive African Penguins (Spheniscus demersus).

The African penguin (Spheniscus demersus) is an endangered species that continues to experience population decline. Understanding the behavior of this species is a critical step in the conservation efforts to prevent their extinction. A comprehensive activity budget of this species has yet to be conducted in any captive population, which are critical for the Species Survival Plan (SSP) breeding programs. We performed scan sampling observations on a group of 19 penguins to construct an activity budget. We also investigated the behavioral differences between males and females, as well as between adults and juveniles. Results indicate there are minimal sex differences in time budget allocations, but there are some notable age related differences. Creating and comparing activity budgets between populations are critical for understanding animal welfare in captive settings.

N,N-Alkylation Clarifies the Role of N- and O-Protonated Intermediates in Cyclen-Based 64Cu Radiopharmaceuticals.

Radioisotopes of Cu, such as 64Cu and 67Cu, are alluring targets for imaging (e.g., positron emission tomography, PET) and radiotherapeutic applications. Cyclen-based macrocyclic polyaminocarboxylates are one of the most frequently examined bifunctional chelators in vitro and in vivo, including the FDA-approved 64Cu radiopharmaceutical, Cu(DOTATATE) (Detectnet); however, connections between the structure of plausible reactive intermediates and their stability under physiologically relevant conditions remain to be established. In this study, we share the synthesis of a cyclen-based, N,N-alkylated spirocyclic chelate, H2DO3AC4H8, which serves as a model for N-protonation. Our combined experimental (in vitro and in vivo) and computational studies unravel complex pH-dependent speciation and enable side-by-side comparison of N- and O-protonated species of relevant 64Cu radiopharmaceuticals. Our studies suggest that N-protonated species are not inherently unstable species under physiological conditions and demonstrate the potential of N,N-alkylation as a tool for the rational design of future radiopharmaceuticals.

Construction of the Bioconjugate Py-Macrodipa-PSMA and Its In Vivo Investigations with Large 132/135La3+ and Small 47Sc3+ Radiometal Ions.

To harness radiometals in clinical settings, a chelator forming a stable complex with the metal of interest and targets the desired pathological site is needed. Toward this goal, we previously reported a unique set of chelators that can stably bind to both large and small metal ions, via a conformational switch. Within this chelator class, py-macrodipa is particularly promising based on its ability to stably bind several medicinally valuable radiometals including large 132/135La3+, 213Bi3+, and small 44Sc3+. Here, we report a 10-step organic synthesis of its bifunctional analogue py-macrodipa-NCS, which contains an amine-reactive -NCS group that is amenable for bioconjugation reactions to targeting vectors. The hydrolytic stability of py-macordipa-NCS was assessed, revealing a half-life of 6.0 d in pH 9.0 aqueous buffer. This bifunctional chelator was then conjugated to a prostate-specific membrane antigen (PSMA)-binding moiety, yielding the bioconjugate py-macrodipa-PSMA, which was subsequently radiolabeled with large 132/135La3+ and small 47Sc3+, revealing efficient and quantitative complex formation. The resulting radiocomplexes were injected into mice bearing both PSMA-expressing and PSMA-non-expressing tumor xenografts to determine their biodistribution patterns, revealing delivery of both 132/135La3+ and 47Sc3+ to PSMA+ tumor sites. However, partial radiometal dissociation was observed, suggesting that py-macrodipa-PSMA needs further structural optimization.

The presentation, etiologies, pathophysiology, and treatment of pulmonary renal syndrome: A review of the literature.

Pulmonary renal syndrome (PRS) is a constellation of different disorders that cause both rapidly progressive glomerulonephritis and diffuse alveolar hemorrhage. While antineutrophil cytoplasmic antibody associated vasculitis and anti-glomerular basement membrane disease are the predominant causes of PRS, numerous other mechanisms have been shown to cause this syndrome, including thrombotic microangiopathies, drug exposures, and infections, among others. This syndrome has high morbidity and mortality, and early diagnosis and treatment is imperative to improve outcomes. Treatment generally involves glucocorticoids and immunosuppressive agents, but treatment targeted to the underlying disorder can improve outcomes and mitigate side effects. Familiarity with the wide range of possible causes of PRS can aid the clinician in workup, diagnosis and early initiation of treatment. This review provides a summary of the clinical presentation, etiologies, pathophysiology, and treatment of PRS.

The expanding role of primary care providers in care of individuals with kidney disease.

An estimated 37 million Americans have chronic kidney disease (CKD). Primary care providers (PCPs) have long played a critical role in detecting CKD and preventing disease progression, particularly in the early stages of the disease. With recent studies demonstrating substantial improvements in kidney outcomes with use of sodium glucose cotransporter 2 (SGLT2) inhibitors, PCPs have an even greater opportunity to improve care of individuals with CKD. Health disparities in nephrology have recently come to the forefront - again, PCPs will play a key role in efforts to reduce such disparities and ensure all patients receive high quality care. This review summarizes the latest guidelines for treatment of CKD and its complications, explores health disparities affecting patients with CKD, and highlights the role of the PCP in caring for this population.

Multiplex and In Vivo Optical Imaging of Discrete Luminescent Lanthanide Complexes Enabled by In Situ Cherenkov Radiation Mediated Energy Transfer.

Recently, we pioneered the application of Cherenkov radiation (CR) of radionuclides for the in situ excitation of discrete Eu(III) and Tb(III) complexes. CR is produced by isotopes decaying under emission of charged particles in dielectric media and exhibits a maximum intensity below 400 nm. We have demonstrated that luminescent lanthanide antenna complexes are ideal acceptors for Cherenkov radiation-mediated energy transfer (CRET). Here, we develop and assess peptide-functionalized Tb(III) and Eu(III) complexes in conjunction with CRET excitation by the positron emissive radioisotope 18F for simultaneous, multiplexed imaging and in vivo optical imaging. This work demonstrates, for the first time, that the detection of the luminescence emission of a discrete Eu(III) complex in vivo is feasible. Our results open possibilities for discrete luminescent lanthanide complexes to be used as diagnostic, optical tools for the intrasurgical guidance of tumor resection.

Establishing Radiolanthanum Chemistry for Targeted Nuclear Medicine Applications.

We report the first targeted nuclear medicine application of the lanthanum radionuclides 132/135 La. These isotopes represent a matched pair for diagnosis via the positron emissions of 132 La and therapy mediated by the Auger electron emissions of 135 La. We identify two effective chelators, known as DO3Apic and macropa, for these radionuclides. The 18-membered macrocycle, macropa, bound 132/135 La with better molar activity than DO3Apic under similar conditions. These chelators were conjugated to the prostate-specific membrane antigen (PSMA)-targeting agent DUPA to assess the use of radiolanthanum for in vivo imaging. The 132/135 La-labeled targeted constructs showed high uptake in tumor xenografts expressing PSMA. This study validates the use of these radioactive lanthanum isotopes for imaging applications and motivates future work to assess the therapeutic effects of the Auger electron emissions of 135 La.

Auditory neglect in children following perinatal stroke.

Auditory neglect has been found in adults with right hemisphere focal brain lesions following strokes. Visual and tactile neglect has been found in children following both left and right hemisphere lesions resulting from perinatal strokes. The present cross-sectional study assessed auditory neglect in children with early unilateral brain damage from perinatal stroke. Twenty-six children with perinatal stroke and matched controls participated. All were asked to identify the location of a pure tone presented in left or right auditory fields. We found that children who had experienced left hemisphere perinatal strokes were significantly better at localizing sounds on the left side of space than the right side of space, and that response times improved with age on a normal trajectory relative to controls in left hemispace, while they did not improve normally in right hemispace. Children with right hemisphere perinatal strokes were significantly worse at localizing sounds on the right side of space relative to typically developing controls, and did not follow control trajectories for improvement in response times on the left or the right sides of space. Our preliminary results suggest that left hemisphere perinatal strokes may result in contralateral auditory neglect, while right hemisphere perinatal strokes may result in bilateral auditory neglect. Neglect was more severe in children with parietal lobe involvement, suggesting that the parietal lobe may play a dominant role in auditory attention in the developing brain.

Inhibitory Effect of 1,8-Cineol on ß-Catenin Regulation, WNT11 Expression, and Cellular Progression in HNSCC.

OBJECTIVES: Head and neck squamous cell carcinoma (HNSCC) is one of the most common tumors worldwide. The high mortality rates have not changed during the last three decades, and thus there is an enormous need for innovative therapy approaches. Several recent studies suggest an important role of the Wnt/ß-catenin signaling pathway in the tumorigenesis of HNSCC. We analyzed the effect of the monoterpene oxide 1,8-cineol on the regulation of the Wnt/ß-catenin signaling pathway and the cellular progression of different HNSCC cell lines. METHODS: Permanent HNSCC cell lines were exposed to varying concentrations and times of 1,8-cineol. Regulation and activity profiles of the Wnt/ß-catenin signaling cascade were analyzed using Western hybridization experiments, MTT assays, real-time PCR-based epithelial to mesenchymal transition array, and immunohistochemistry. RESULTS: Exposure of different cell lines to 1,8-cineol treatment resulted in a dose-dependent inhibition of proliferation and a decreased activity of the WNT/ß-catenin pathway. We can show the inhibition of glycogen synthase kinase 3 (GSK-3)α/ß (Ser-9/21) as well as a corresponding decreased endolysosomal localization, leading to a decreased ß-catenin activity. Furthermore, we can show that exposure to cineol functionally results in a reduced expression of WNT11. CONCLUSION: In this work, we demonstrate for the first time that 1,8-cineol acts as an inhibitor of the Wnt/ß-catenin activity in HNSCC via a decreased inhibition of GSK-3, which lead to reduced levels of WNT11 and a dose-dependent decrease of the cellular progression. Our data represent a new mechanism of 1,8-cineol activity, which may lead to novel molecular targets and treatment approaches of this natural drug.

Using theory and evidence to drive measurement of patient, nurse and organizational outcomes of professional nursing practice.

An evolving body of literature suggests that the implementation of evidence based clinical and professional guidelines and strategies can improve patient care. However, gaps exist in our understanding of the effect of implementation of guidelines on outcomes, particularly patient outcomes. To address this gap, a measurement framework was developed to assess the impact of an organization-wide implementation of two nursing-centric best-practice guidelines on patient, nurse and organizational level outcomes. From an implementation standpoint, we anticipate that our data will show improvements in the following: (i) patient satisfaction scores and safety outcomes; (ii) nurses ability to value and engage in evidence based practice; and (iii) organizational support for evidence-informed nursing care that results in quality patient outcomes. Our measurement framework and multifaceted methodological approach outlined in this paper might serve as a blueprint for other organizations in their efforts to evaluate the impacts associated with implementation of clinical and professional guidelines and best practices.

Quality nursing care and opportunities for improvement: insights from patients and family members.

A study was undertaken to delineate patients' and families' experiences and perceptions associated with their nurse-patient therapeutic relationships and nursing care. Data were analyzed using a directed content analysis approach. Two key themes emerged: patients and family members described primarily receiving excellent nursing care and to a lesser extent substandard care. Study findings have implications for nurse leaders to enhance nurses' therapeutic relationships with patients and family members and patient-centered care within their organizations.

A narrative approach to empirical nursing ethics research: uncovering the everyday moral knowledge of nurses

In this paper we explore the use of Margaret Urban Walker's metaethical perspective, particularly the use of narratives, to inform the development of a research approach to uncover the everyday moral knowledge of nurses. A method based on Walker's work makes it possible to analyze the power dimensions inherent in nurses' moral experience, to ground a narrative approach to nursing ethics with a robust moral epistemology, and to differentiate different types of narratives. A number of analytic questions, which have their basis in Walker's work, are presented and are used to analyze a practice narrative written to illustrate how narratives can be used to draw out the moral knowledge of nurses within the context of their actual work.

Neste artigo nós exploramos o uso da perspectiva metafísica de Margaret Urban Walker, particularmente o uso de narrativas, para informar o desenvolvimento de uma abordagem de pesquisa para revelar o conhecimento moral cotidiano de enfermeiras. Um método baseado no trabalho de Walker torna possível analisar as dimensões de poder intrínsecas na experiência moral das enfermeiras, fundamentar a abordagem narrativa à ética da enfermagem com uma moral epistemológica robusta e distinguir diferentes tipos de narrativas. Um número de questões analíticas que tem suas bases no trabalho Walker, são apresentadas e utilizadas para analisar a prática narrativa e ilustrar como as narrativas podem ser usadas para delinear o conhecimento moral de enfermeiras dentro do contexto de seu trabalho real.

En el presente artículo exploramos el uso de la perspectiva metafísica de Margaret Urban Walter, particularmente el uso de narrativas, para informar sobre el desarrollo de un abordaje de investigación que revela el conocimiento moral cotidiano de las enfermeras. Un método basado en el trabajo de Walter permite analizar las dimensiones de poder inherentes en la experiencia moral de las enfermeras, así como fundamentar con una moral epistemológica robusta, el abordaje narrativo ético de la enfermería, y distinguir los diferentes tipos de narrativas. Un número de cuestiones analíticas basadas en el trabajo de Walker son aquí presentadas y empleadas para analizar la práctica narrativa e ilustrar cómo las narrativas pueden ser usadas para delinear el conocimiento moral de las enfermeras dentro del contexto de su trabajo real.

High rates of sustained smoking cessation in women hospitalized with cardiovascular disease: the Women's Initiative for Nonsmoking (WINS).

BACKGROUND: Although men hospitalized with cardiovascular disease (CVD) show high smoking-cessation rates, similar data for women are lacking. We tested the efficacy of smoking-cessation intervention in women hospitalized for CVD. METHODS AND RESULTS: In this randomized controlled trial conducted from 1996 to 2001, 277 women diagnosed with CVD (mean age 61+/-10 years) were randomly assigned within 1 of 12 San Francisco Bay Area hospitals to a usual-care group (UG; n=135) or intervention group (IG; n=142). Baseline histories were obtained, and interviews to ascertain self-reported smoking status occurred at 6, 12, 24, and 30 months after hospitalization. The UG received strong physician's advice, a self-help pamphlet, and a list of community resources. The IG received strong physician's advice and a nurse-managed cognitive behavioral relapse-prevention intervention at bedside, with telephone contact at intervals after discharge. The groups were similar demographically and had smoked cigarettes for a median of 38 (IG) or 40 (UG) years. Time to resumption of continuous smoking was assessed by Kaplan-Meier analysis, and risk differences between groups were determined. Time smoke-free was significantly greater for the IG than the UG (P=0.038). Point prevalence for nonsmoking at the interviews was somewhat greater for the IG than the UG (P>0.15 at all times). CONCLUSIONS: Cognitive behavioral intervention resulted in longer average times to resumption of smoking, but in these 2 groups of older women with limited social and financial resources, long-term success rates were similar. Systematic identification of smokers and even the brief intervention afforded the UG yielded a high smoking-cessation rate over time.

Women's initiative for nonsmoking (WINS) IV: description of 277 women smokers hospitalized with cardiovascular disease.

OBJECTIVES: This article describes the demographic, psychosocial, and medical characteristics and smoking patterns of women hospitalized with cardiovascular disease (CVD) enrolled in the Women's Initiative for Nonsmoking (WINS) trial. DESIGN: Study design is a randomized clinical trial with cross-sectional baseline data. SETTING: Women enrolled during a 27-month period from 10 hospitals in the San Francisco Bay Area. PARTICIPANTS: Subjects included 277 women. RESULTS: The women's ages ranged from 33 to 86 years, with a mean age of 60.7 (+/-10) years. Most (51%) were college graduates, had attended some college or had postgraduate degrees; 40% were married; 76% were white. Median income was between 30,000 dollars and 35,000, but 27% of the women had incomes less than 15,000 dollars per year. The women smoked a median of 20 cigarettes per day (range, 1-90). Median age when women began smoking was 18.6 years; average number of years smoked was 40; and 78% had made more than 2 previous attempts to quit. On a 10-point scale, 71% of the women rated their confidence to quit smoking (self-efficacy) as 5 or greater. According to the Burnam Depression Screener, 56.7% were depressed. CONCLUSIONS: This is the largest study describing the smoking patterns of women hospitalized with CVD. These women were older, white, had smoked for many years, were moderately to highly addicted to tobacco, had few financial resources, and a large proportion were depressed. These important psychosocial factors need to be taken into account when planning smoking cessation interventions for women with CVD.