Lipid Emulsions Inhibit Labetalol-Induced Vasodilation in the Isolated Rat Aorta.

Lipid emulsions are used as adjuvant drugs to alleviate intractable cardiovascular collapse induced by drug toxicity. We aimed to examine the effect of lipid emulsions on labetalol-induced vasodilation and the underlying mechanism in the isolated rat aorta. We studied the effects of endothelial denudation, NW-nitro-l-arginine methyl ester (l-NAME), calmidazolium, methylene blue, 1H-[1,2,4]oxadiazolo[4,3-a] quinoxalin-1-one (ODQ), and lipid emulsions on labetalol-induced vasodilation. We also evaluated the effects of lipid emulsions on cyclic guanosine monophosphate (cGMP) formation, endothelial nitric oxide synthase (eNOS) phosphorylation, and endothelial calcium levels induced by labetalol. Labetalol-induced vasodilation was higher in endothelium-intact aortas than that in endothelium-denuded aortas. l-NAME, calmidazolium, methylene blue, and ODQ inhibited labetalol-induced vasodilation in endothelium-intact aortas. Lipid emulsions inhibited labetalol-induced vasodilation in endothelium-intact and endothelium-denuded aortas. l-NAME, ODQ, and lipid emulsions inhibited labetalol-induced cGMP formation in endothelium-intact aortas. Lipid emulsions reversed the stimulatory and inhibitory eNOS (Ser1177 and Thr495) phosphorylation induced by labetalol in human umbilical vein endothelial cells and inhibited the labetalol-induced endothelial calcium increase. Moreover, it decreased labetalol concentration. These results suggest that lipid emulsions inhibit vasodilation induced by toxic doses of labetalol, which is mediated by the inhibition of endothelial nitric oxide release and reduction of labetalol concentration.

A whole-slide foundation model for digital pathology from real-world data.

Digital pathology poses unique computational challenges, as a standard gigapixel slide may comprise tens of thousands of image tiles1-3. Prior models have often resorted to subsampling a small portion of tiles for each slide, thus missing the important slide-level context4. Here we present Prov-GigaPath, a whole-slide pathology foundation model pretrained on 1.3 billion 256 × 256 pathology image tiles in 171,189 whole slides from Providence, a large US health network comprising 28 cancer centres. The slides originated from more than 30,000 patients covering 31 major tissue types. To pretrain Prov-GigaPath, we propose GigaPath, a novel vision transformer architecture for pretraining gigapixel pathology slides. To scale GigaPath for slide-level learning with tens of thousands of image tiles, GigaPath adapts the newly developed LongNet5 method to digital pathology. To evaluate Prov-GigaPath, we construct a digital pathology benchmark comprising 9 cancer subtyping tasks and 17 pathomics tasks, using both Providence and TCGA data6. With large-scale pretraining and ultra-large-context modelling, Prov-GigaPath attains state-of-the-art performance on 25 out of 26 tasks, with significant improvement over the second-best method on 18 tasks. We further demonstrate the potential of Prov-GigaPath on vision-language pretraining for pathology7,8 by incorporating the pathology reports. In sum, Prov-GigaPath is an open-weight foundation model that achieves state-of-the-art performance on various digital pathology tasks, demonstrating the importance of real-world data and whole-slide modelling.

Hypothermia Inhibits Dexmedetomidine-Induced Contractions in Isolated Rat Aortae.

Dexmedetomidine is widely used to induce sedation in the perioperative period. This study examined the effect of hypothermia (33 and 25 °C) on dexmedetomidine-induced contraction in an endothelium-intact aorta with or without the nitric oxide synthase inhibitor NW-nitro-L-arginine methyl ester (L-NAME). In addition, the effect of hypothermia on the contraction induced by dexmedetomidine in an endothelium-denuded aorta with or without a calcium-free Krebs solution was examined. The effects of hypothermia on the protein kinase C (PKC), myosin light chain (MLC20) phosphorylation, and Rho-kinase membrane translocation induced by dexmedetomidine were examined. Hypothermia inhibited dexmedetomidine-induced contraction in the endothelium-intact aorta with L-NAME or endothelium-denuded aorta. Hypothermia had almost no effect on the dexmedetomidine-induced contraction in the endothelium-denuded aorta with the calcium-free Krebs solution; however, the subsequent contraction induced by the addition of calcium was inhibited by hypothermia. Conversely, the transition from profound hypothermia back to normothermia reversed the hypothermia-induced inhibition of subsequent calcium-induced contractions. Hypothermia inhibited any contraction induced by KCl, PDBu, and NaF, as well as PKC and MLC20 phosphorylation and Rho-kinase membrane translocation induced by dexmedetomidine. These results suggest that hypothermia inhibits dexmedetomidine-induced contraction, which is mediated mainly by the impediment of calcium influx and partially by the attenuation of pathways involving PKC and Rho-kinase activation.

Theophylline-induced endothelium-dependent vasodilation is mediated by increased nitric oxide release and phosphodiesterase inhibition in rat aorta.

This study aimed to examine the endothelial dependence of vasodilation induced by the phosphodiesterase inhibitor theophylline in isolated rat thoracic aortas and elucidate the underlying mechanism, with emphasis on endothelial nitric oxide (NO). The effects of various inhibitors and endothelial denudation on theophylline-induced vasodilation, and the effect of theophylline on vasodilation induced by NO donor sodium nitroprusside, cyclic guanosine monophosphate (cGMP) analog bromo-cGMP, and ß-agonist isoproterenol in endothelium-denuded aorta were examined. The effects of theophylline and sodium nitroprusside on cGMP formation were also examined. We examined the effect of theophylline on endothelial nitric oxide synthase (eNOS) phosphorylation and intracellular calcium levels. Theophylline-induced vasodilation was greater in endothelium-intact aortas than that in endothelium-denuded aortas. The NOS inhibitor, NW-nitro-L-arginine methyl ester; non-specific guanylate cyclase (GC) inhibitor, methylene blue; and NO-sensitive GC inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a] quinoxalin-1-one inhibited theophylline-induced vasodilation in endothelium-intact aortas. Theophylline increased the vasodilation induced by sodium nitroprusside, bromo-cGMP, and isoproterenol. Theophylline increased cGMP formation in endothelium-intact aortas, and sodium nitroprusside-induced cGMP formation in endothelium-denuded aortas. Moreover, theophylline increased stimulatory eNOS (Ser1177) phosphorylation and endothelial calcium levels, but decreased the phosphorylation of inhibitory eNOS (Thr495). These results suggested that theophylline-induced endothelium-dependent vasodilation was mediated by increased endothelial NO release and phosphodiesterase inhibition.

Toward structuring real-world data: Deep learning for extracting oncology information from clinical text with patient-level supervision.

Most detailed patient information in real-world data (RWD) is only consistently available in free-text clinical documents. Manual curation is expensive and time consuming. Developing natural language processing (NLP) methods for structuring RWD is thus essential for scaling real-world evidence generation. We propose leveraging patient-level supervision from medical registries, which are often readily available and capture key patient information, for general RWD applications. We conduct an extensive study on 135,107 patients from the cancer registry of a large integrated delivery network (IDN) comprising healthcare systems in five western US states. Our deep-learning methods attain test area under the receiver operating characteristic curve (AUROC) values of 94%-99% for key tumor attributes and comparable performance on held-out data from separate health systems and states. Ablation results demonstrate the superiority of these advanced deep-learning methods. Error analysis shows that our NLP system sometimes even corrects errors in registrar labels.

Advanced Practice Nurses' Experiences on Patient Safety Culture in Hospital-Based Home Healthcare: A Qualitative Descriptive Study.

Purpose: Despite the increasing interest in patient safety, most research have been conducted in hospital settings, thereby demonstrating an overall lack of research regarding patient safety culture in home healthcare. South Korea has three types of home healthcare services based on hospitals, public health centers, and long-term care insurance. Home healthcare nurses in hospitals require a master's degree and advanced nursing skills. They play important roles in ensuring patients' safe transition into home health care. This study aimed to explore the experience of patient safety culture among South Korean advanced practice nurses in hospital-based home healthcare. Methods: This qualitative descriptive study was conducted through purposive sampling, whereby twenty advanced practice nurses involved in home healthcare were recruited from twelve hospitals located in three different cities throughout South Korea. Face-to-face semi-structured interviews were conducted, and the collected data were analyzed through inductive and deductive content analyses. Results: Three main categories were finally confirmed: (a) teamwork climate, (b) safety climate, and (c) working condition. The sub-categories of the teamwork climate included the collaboration between patients, caregivers, and nurses, collaboration within medical institutions, and collaboration among the individuals involved in community partnerships. The sub-categories of the safety climate included nurses' commitment to patient safety, the associated institutions' commitment to patient safety, and the government's commitment to patient safety. The sub-categories of the working condition included the frontline working environments and the associated institutions' support aimed at ensuring effective working environments. Conclusion: Cultivating patient safety culture is crucial for ensuring the safe transition of patients from acute care hospitals to home healthcare. This study revealed significant aspects of patient safety culture in hospital-based home healthcare, allowing for the continuum of care among the associated patients. Such aspects include communicating with caregivers, building community partnerships, understanding unexpected home environments, and enhancing the safety of nurses.

Fulminant Giant Cell Myocarditis following Heterologous Vaccination of ChAdOx1 nCoV-19 and Pfizer-BioNTech COVID-19.

A 48-year-old female patient underwent a heart transplantation for acute fulminant myocarditis, following heterologous vaccination with the ChAdOx1 nCoV-19 and Pfizer-BioNTech COVID-19. She had no history of severe acute respiratory syndrome coronavirus-2 infection. She did not exhibit clinical signs or have laboratory findings of concomitant infection before or after vaccination. Heart transplantation was performed because her heart failed to recover with venoarterial extracorporeal oxygenation support. Organ autopsy revealed giant cell myocarditis, possibly related to the vaccines. Clinicians may have to consider the possibility of the development of giant cell myocarditis, especially in patients with rapidly deteriorating cardiac function and myocarditis symptoms after COVID-19 vaccination.

Enhanced Physical Activity Improves Selected Outcomes in Children With ADHD: Systematic Review.

This review examines associations between physical activity (PA) and cognitive, behavioral, and physiological outcomes in children with attention-deficit/hyperactivity disorder (ADHD). We reviewed studies on participants ≤18 years old, published in English between January 1998 and December 2014, in PubMed, CINAHL, PsycINFO, and Cochrane Reviews. Twenty-six studies were grouped into two categories: those that did and did not account for effects of ADHD medications. The first category showed lower levels of PA and improved cognitive and behavioral outcomes in youth whose ADHD was treated with medications. The second category showed a positive association between PA levels and cognitive and behavioral outcomes in youth whose ADHD was not treated with medications. For both categories of studies, results were inconclusive regarding physiological outcomes. Randomized controlled trials are needed to better clarify the relationship between PA and outcomes in youth with ADHD, and particularly to understand the impact of ADHD medications on that relationship.

A Systematic Review of the Unintended Consequences of Clinical Interventions to Reduce Adverse Outcomes.

This is a systematic review of the literature on unintended consequences of clinical interventions to reduce falls, catheter-related urinary tract infection, and vascular catheter-related infections in hospitalized patients. A systematic search of the literature was conducted in CINAHL and PubMed. We developed a screening tool and a two-stage screening process to identify relevant articles. Nine articles met inclusion criteria, and of those, 8 reported on interventions to reduce patient falls. Four studies reported a positive, unexpected benefit; 3 studies reported a negative, unexpected detriment; and 4 reported a perverse effect (different from what was expected). Three studies reported both positive and perverse effects arising from the intervention. In 4 of the studies, despite fall prevention interventions, patients fell while trying to get to the bathroom, suggesting that interventions to reduce one adverse outcome (i.e., CAUTI) may be associated with another outcome (i.e., patient falls). In some cases, there were positive outcomes for those who implemented and/or evaluated interventions. We encourage colleagues to collect and report data on possible unintended consequences of their interventions to allow a fuller picture of the relationship between intervention and all outcomes to emerge.

A concept analysis of 'Meaning in work' and its implications for nursing.

AIM: To report an analysis of the concept of 'meaning in work'. BACKGROUND: Associated with initiatives to improve the quality of working life and the emerging movement of positive organizations, 'meaning in work' has been studied as a positive individual-level state. 'Meaning in work' has potential benefits that will improve the nursing workforce if this concept is embraced in nursing. However, the concept is not clearly defined because it has been approached from diverse theoretical perspectives and used interchangeably with analogous terms. DESIGN: A concept analysis. DATA SOURCES: Three key terms (using 'work', 'meaning' or 'meaningful', 'meaning of work', 'logotherapy') were searched in the CINAHL, PsycINFO, Business Source Complete and ABI/INFORM Global online databases from January 1940-March 2015. Among 346 articles retrieved, 28 studies were included for this concept analysis. METHODS: The procedure of concept analysis developed by Walker and Avant (2011) was used. RESULTS: Four critical attributes are identified: (1) experienced positive emotion at work; (2) meaning from work itself; (3) meaningful purpose and goals of work; and (4) work as a part of life that contributes towards meaningful existence. The identified antecedent of 'meaning in work' was a cognitive shift and the identified consequences were positive personal experience and positive impact on peers and organizations. CONCLUSION: This article provides a clear definition of 'meaning in work'. The resulting coherent definition will facilitate the use of 'meaning in work' in nursing research.

Giant axon formation in mice lacking Kell, XK, or Kell and XK: animal models of McLeod neuroacanthocytosis syndrome.

McLeod neuroacanthocytosis syndrome (MLS) is a rare X-linked multisystem disease caused by XK gene mutations and characterized by hematological and neurological abnormalities. XK, a putative membrane transporter, is expressed ubiquitously and is covalently linked to Kell, an endothelin-3-converting enzyme (ECE-3). Absence of XK results in reduction of Kell at sites where both proteins are coexpressed. To elucidate the functional roles of XK, Kell, and the XK-Kell complex associated with pathogenesis in MLS, we studied the pathology of the spinal cord, anterior roots, sciatic nerve, and skeletal muscle from knockout mouse models, using Kel(-/-), Xk(-/-), Kel(-/-)Xk(-/-), and wild-type mice aged 6 to 18 months. A striking finding was that giant axons were frequently associated with paranodal demyelination. The pathology suggests probable anterograde progression from the spinal cord to the sciatic nerve. The neuropathological abnormalities were found in all three genotypes, but were more marked in the double-knockout Kel(-/-)Xk(-/-) mice than in either Kel(-/-) or Xk(-/-) mice. Skeletal muscles from Xk(-/-) and Kel(-/-)Xk(-/-) mice showed mild abnormalities, but those from Kel(-/-) mice were similar to the wild type. The more marked neuropathological abnormalities in Kel(-/-)Xk(-/-) mice suggest a possible functional association between XK and Kell in nonerythroid tissues.

Outcomes of inpatient mobilization: a literature review.

AIMS AND OBJECTIVES: To review current research evidence on the outcomes of mobilising hospitalised adults. BACKGROUND: Although immobility is known to cause functional decline or complications, inpatient ambulation emerged as the most often missed element of nursing care. This study is designed to review research studies that give evidence as to the consequences of mobilising or not mobilising hospitalised adult patients. DESIGN: A literature review of published peer-reviewed empirical research was undertaken. METHODS: The electronic databases of MEDLINE (Ovid), CINAHL, and PubMed were accessed to search for relevant empirical articles, supplemented by a search of reference lists contained in retrieved articles and citation tracking. RESULTS: Thirty-six studies were identified for inclusion in the review. Four areas (study design, sample size, measurement and statistical analysis) were evaluated for methodological quality, and most studies showed strong quality. A synthesis of the findings generated four themes of the effects of inpatient mobilisation: (1) physical outcomes included pain, deep vein thrombosis, fatigue, etc.; (2) psychological outcomes included anxiety, depressive mood, distress, comfort and satisfaction; (3) social outcomes included quality of life and independence; and (4) organisational outcomes included length of stay, mortality and cost. CONCLUSION: Mobilising hospitalised adults brings benefits for not only physical functioning, but also their emotional and social well-being. Moreover, ambulation yields important organisational benefits. These benefits of mobilisation on four areas required viewing the patient in a holistic manner. Even though each study approached different types of patients, illnesses and procedures, this review showed that most inpatients would benefit from mobilisation and would experience optimal functions. RELEVANCE TO CLINICAL PRACTICE: The importance of mobilisation for positive patient outcomes highlights the need to develop methods to ensure that this nursing action is completed on a systematic basis.

Molecular basis of two novel and related high-prevalence antigens in the Kell blood group system, KUCI and KANT, and their serologic and spatial association with K11 and KETI.

BACKGROUND: The numerous antigens in the Kell blood group system result from missense nucleotide changes in KEL. Antibodies to antigens in this system can be clinically important. We describe six probands whose plasma contained antibodies to high-prevalence Kell antigens and discuss their relationship. STUDY DESIGN AND METHODS: Polymerase chain reaction amplification, direct sequencing, restriction fragment length polymorphism assays, hemagglutination, flow cytometry, and protein modeling were performed by standard methods. RESULTS: Proband 1 (KUCI) and her serologically compatible sister were heterozygous for a nucleotide change in Exon 11 (KEL*1271C/T; Ala424Val). Proband 2 (KANT) was heterozygous for KEL*1283G/T (Arg428Leu) and KEL*1216C/T (Arg406Stop) in Exon 11. Red blood cells (RBCs) from Proband 1 and her sister were not agglutinated by plasma from Proband 2; however, RBCs from Proband 2 were agglutinated by plasma from Proband 1. Probands 3, 4, 5, and 6 had the KEL*1391C>T change associated with the previously reported KETI- phenotype. Proband 5 was also homozygous for KEL*905T>C encoding the K11-K17+ phenotype. Hemagglutination studies revealed an association between KUCI, KANT, KETI, and K11. Protein modeling indicated that whereas Ala424 and Arg428 are clustered, Val302 and Thr464 are not. CONCLUSION: Ala424 in the Kell glycoprotein is associated with the high-prevalence Kell antigen, KUCI (ISBT 006032), which is detected by the antibody of Proband 1. Arg428 is associated with the high-prevalence Kell antigen, KANT (ISBT 006033). The association between KUCI, KANT, KETI, and K11 and the results of protein modeling are discussed.

Ablation of the Kell/Xk complex alters erythrocyte divalent cation homeostasis.

XK is a putative transporter of unknown function that is ubiquitously expressed and linked through disulfide bonds to Kell protein, an endothelin-3 (ET-3)-converting enzyme. We generated three knockout (KO) mice that lacked either Xk, Kell or both proteins and characterized erythrocyte cation levels, transport and hematological parameters. Absence of Xk or Kell was accompanied by changes in erythrocyte K(+), Mg(2+), Na(+) and Ca(2+) transport that were associated with changes in mean cellular volume and corpuscular hemoglobin concentration mean. Baseline Ca(2+)-ATPase activity was undetected in erythrocytes from all three mouse types but was restored upon pre-incubation with ET-3. Consistent with these alterations in Ca(2+) handling, we observed increased Gardos channel activity in Kel and Xk KO mice. In addition Kel deletion was associated with increased Mg(2+) permeability while Xk deletion blocked Na/Mg exchanger activity. Our results provide evidence that cellular divalent cation regulation is functionally coupled to the Kell/XK system in erythrocytes and loss of this complex may contribute to acanthocytosis formation in McLeod syndrome.

Safety of mobilizing hospitalized adults: review of the literature.

This article examines literature that provides evidence about the safety of mobilizing hospitalized adults. A search of electronic databases and hand searches yielded 24 studies that were included in the review. Evidence of mobilization safety was found in 4 clinical settings (medical, surgical, cardiac procedure, and intensive care), and the findings from these studies suggest that early mobilization of hospitalized adults is safe.

Two McLeod patients with novel mutations in XK.

McLeod syndrome (MLS) is a rare, X-linked, late-onset, disease involving hematological, brain, and neuromuscular systems, caused by mutations in XK that result in either defective XK or complete loss of XK protein. Acanthocytosis of erythrocytes is a typical feature. We report novel mutations in two patients who exhibited typical clinical characteristics of MLS. The coding and flanking intronic regions of XK were amplified by PCR, sequenced, and compared with the normal XK sequence. XK protein, and its complexed partner protein, Kell, were assessed by Western blot analysis. Patient 1 was found to have a single base insertion, 605insA at 175Ile creating a frame shift within the coding sequence of XK. Patient 2 had a single base substitution in the 3' splice sequence of intron 2 (IVS2-2a>g). In both cases mutations resulted in the absence of XK protein.

Spontaneously arising red cells with a McLeod-like phenotype in normal donors.

Very few human genes can be used to identify spontaneous inactivating somatic mutations. We hypothesized that because the XK gene is X-linked, it would be easy to identify spontaneously arising red cells with a phenotype resembling the McLeod syndrome, which results from inherited XK mutations. Here, by flow cytometry, we detect such phenotypic variants at a median frequency of 9 x 10(-6) in neonatal cord blood samples and 39 x 10(-6) in healthy adults (p=0.004). It may be possible to further investigate the relationship between aging, mutations, and cancer using this approach.

Changes in red cell ion transport, reduced intratumoral neovascularization, and some mild motor function abnormalities accompany targeted disruption of the Mouse Kell gene (Kel).

Kell (ECE-3), a highly polymorphic blood group glycoprotein, displays more than 30 antigens that produce allo-antibodies and, on red blood cells (RBCs), is complexed through a single disulfide bond with the integral membrane protein, XK. XK is a putative membrane transporter whose absence results in a late onset form of neuromuscular abnormalities known as the McLeod syndrome. Although Kell glycoprotein is known to be an endothelin-3-converting enzyme, the full extent of its physiological function is unknown. To study the functions of Kell glycoprotein, we undertook targeted disruption of the murine Kel gene by homologous recombination. RBCs from Kel(-/-) mice lacked Kell glycoprotein, Kell/XK complex, and endothelin-3-converting enzyme activity and had reduced levels of XK. XK mRNA levels in spleen, brain, and testis were unchanged. In Kel(-/-) mice RBC Gardos channel activity was increased and the normal enhancement by endothelin-3 was blunted. Analysis of the microvessels of tumors produced from LL2 cells indicated that the central portion of tumors from wild-type mice were populated with many mature blood vessels, but that vessels in tumors from Kel(-/-) mice were fewer and smaller. The absence of Kell glycoprotein mildly affected some motor activities identified by foot splay on the drop tests. The targeted disruption of Kel in mouse enabled us to identify phenotypes that would not be easily detected in humans lacking Kell glycoprotein. In this regard, the Kell knockout mouse provides a good animal model for the study of normal and/or pathophysiological functions of Kell glycoprotein.