An unexpected computed tomography finding in a suspected body packer.

INTRODUCTION: Computed tomography can be used to screen and diagnose the presence of drug-filled packets in the body. We present an unusual computed tomography finding in a suspected body packer. CASE SUMMARY: A traveller suspected of being a body packer was brought to the emergency department complaining of low back pain. On examination, there was an abdominal cast circumferentially encasing his abdomen, which he alleged was part of the management of his lower back pain in his own country. IMAGES: A plain computed tomogram of the abdomen and pelvis revealed that the cast was made of materials with a nodular appearance and heterogeneous density, which was different from that of a plaster of Paris cast. An investigation later confirmed the cast contained cocaine. CONCLUSION: Our case demonstrates how a body packer can traffic drugs outside their body for an alleged medical reason.

Hematopoietic stem cell niche generation and maintenance are distinguishable by an epitranscriptomic program.

The niche is typically considered as a pre-established structure sustaining stem cells. Therefore, the regulation of its formation remains largely unexplored. Whether distinct molecular mechanisms control the establishment versus maintenance of a stem cell niche is unknown. To address this, we compared perinatal and adult bone marrow mesenchymal stromal cells (MSCs), a key component of the hematopoietic stem cell (HSC) niche. MSCs exhibited enrichment in genes mediating m6A mRNA methylation at the perinatal stage and downregulated the expression of Mettl3, the m6A methyltransferase, shortly after birth. Deletion of Mettl3 from developing MSCs but not osteoblasts led to excessive osteogenic differentiation and a severe HSC niche formation defect, which was significantly rescued by deletion of Klf2, an m6A target. In contrast, deletion of Mettl3 from MSCs postnatally did not affect HSC niche. Stem cell niche generation and maintenance thus depend on divergent molecular mechanisms, which may be exploited for regenerative medicine.

Crosstalk between DNA methylation and hypoxia in acute myeloid leukaemia.

BACKGROUND: Acute myeloid leukaemia (AML) is a deadly disease characterised by the uncontrolled proliferation of immature myeloid cells within the bone marrow. Altered regulation of DNA methylation is an important epigenetic driver of AML, where the hypoxic bone marrow microenvironment can help facilitate leukaemogenesis. Thus, interactions between epigenetic regulation and hypoxia signalling will have important implications for AML development and treatment. MAIN BODY: This review summarises the importance of DNA methylation and the hypoxic bone marrow microenvironment in the development, progression, and treatment of AML. Here, we focus on the role hypoxia plays on signalling and the subsequent regulation of DNA methylation. Hypoxia is likely to influence DNA methylation through altered metabolic pathways, transcriptional control of epigenetic regulators, and direct effects on the enzymatic activity of epigenetic modifiers. DNA methylation may also prevent activation of hypoxia-responsive genes, demonstrating bidirectional crosstalk between epigenetic regulation and the hypoxic microenvironment. Finally, we consider the clinical implications of these interactions, suggesting that reduced cell cycling within the hypoxic bone marrow may decrease the efficacy of hypomethylating agents. CONCLUSION: Hypoxia is likely to influence AML progression through complex interactions with DNA methylation, where the therapeutic efficacy of hypomethylating agents may be limited within the hypoxic bone marrow. To achieve optimal outcomes for AML patients, future studies should therefore consider co-treatments that can promote cycling of AML cells within the bone marrow or encourage their dissociation from the bone marrow.

Blockade of ROS production inhibits oncogenic signaling in acute myeloid leukemia and amplifies response to precision therapies.

Mutations in the type III receptor tyrosine kinase FLT3 are frequent in patients with acute myeloid leukemia (AML) and are associated with a poor prognosis. AML is characterized by the overproduction of reactive oxygen species (ROS), which can induce cysteine oxidation in redox-sensitive signaling proteins. Here, we sought to characterize the specific pathways affected by ROS in AML by assessing oncogenic signaling in primary AML samples. The oxidation or phosphorylation of signaling proteins that mediate growth and proliferation was increased in samples from patient subtypes with FLT3 mutations. These samples also showed increases in the oxidation of proteins in the ROS-producing Rac/NADPH oxidase-2 (NOX2) complex. Inhibition of NOX2 increased the apoptosis of FLT3-mutant AML cells in response to FLT3 inhibitors. NOX2 inhibition also reduced the phosphorylation and cysteine oxidation of FLT3 in patient-derived xenograft mouse models, suggesting that decreased oxidative stress reduces the oncogenic signaling of FLT3. In mice grafted with FLT3 mutant AML cells, treatment with a NOX2 inhibitor reduced the number of circulating cancer cells, and combining FLT3 and NOX2 inhibitors increased survival to a greater extent than either treatment alone. Together, these data raise the possibility that combining NOX2 and FLT3 inhibitors could improve the treatment of FLT3 mutant AML.

Single-Cell DNA Methylation Analysis in Cancer.

Morphological, transcriptomic, and genomic defects are well-explored parameters of cancer biology. In more recent years, the impact of epigenetic influences, such as DNA methylation, is becoming more appreciated. Aberrant DNA methylation has been implicated in many types of cancers, influencing cell type, state, transcriptional regulation, and genomic stability to name a few. Traditionally, large populations of cells from the tissue of interest are coalesced for analysis, producing averaged methylome data. Considering the inherent heterogeneity of cancer, analysing populations of cells as a whole denies the ability to discover novel aberrant methylation patterns, identify subpopulations, and trace cell lineages. Due to recent advancements in technology, it is now possible to obtain methylome data from single cells. This has both research and clinical implications, ranging from the identification of biomarkers to improved diagnostic tools. As with all emerging technologies, distinct experimental, bioinformatic, and practical challenges present themselves. This review begins with exploring the potential impact of single-cell sequencing on understanding cancer biology and how it could eventually benefit a clinical setting. Following this, the techniques and experimental approaches which made this technology possible are explored. Finally, the present challenges currently associated with single-cell DNA methylation sequencing are described.

Differentiating central nervous system infection from disease infiltration in hematological malignancy.

Hematological malignancies place individuals at risk of CNS involvement from their hematological disease and opportunistic intracranial infection secondary to disease-/treatment-associated immunosuppression. Differentiating CNS infection from hematological disease infiltration in these patients is valuable but often challenging. We sought to determine if statistical models might aid discrimination between these processes. Neuroradiology, clinical and laboratory data for patients with hematological malignancy at our institution between 2007 and 2017 were retrieved. MRI were deep-phenotyped across anatomical distribution, presence of pathological enhancement, diffusion restriction and hemorrhage and statistically modelled with Bayesian-directed probability networks and multivariate logistic regression. 109 patients were studied. Irrespective of a diagnosis of CNS infection or hematological disease, the commonest anatomical distributions of abnormality were multifocal-parenchymal (34.9%), focal-parenchymal (29.4%) and leptomeningeal (11.9%). Pathological enhancement was the most frequently observed abnormality (46.8%), followed by hemorrhage (22.9%) and restricted diffusion (19.3%). Logistic regression could differentiate CNS infection from hematological disease infiltration with an AUC of 0.85 where, with OR > 1 favoring CNS infection and < 1 favoring CNS hematological disease, significantly predictive imaging features were hemorrhage (OR 24.61, p = 0.02), pathological enhancement (OR 0.17, p = 0.04) and an extra-axial location (OR 0.06, p = 0.05). In conclusion, CNS infection and hematological disease are heterogeneous entities with overlapping radiological appearances but a multivariate interaction of MR imaging features may assist in distinguishing them.

Safety and Immunogenicity of an mRNA-Based Human Metapneumovirus and Parainfluenza Virus Type 3 Combined Vaccine in Healthy Adults.

Background: Human metapneumovirus (hMPV) and parainfluenza virus type 3 (PIV3) cause respiratory tract illness in children and the elderly. No licensed vaccines are available. Methods: In this phase 1, randomized, dose-ranging, first-in-human study, the safety, reactogenicity, and humoral immunogenicity of an investigational mRNA-based hMPV and PIV3 combination vaccine, mRNA-1653, were evaluated in healthy adults aged 18-49 years. Sentinel participants (n = 20) received 2 doses of mRNA-1653 (25, 75, 150, or 300 µg) in the dose escalation phase, and participants (n = 104) received 2 doses of mRNA-1653 (75, 150, or 300 µg) or placebo in the dose selection phase; injections were 28 days apart. Results: The most common solicited reactogenicity events were injection site pain, headache, fatigue, and myalgia, the majority of which were grade 1 or 2. A single mRNA-1653 dose increased neutralization titers against hMPV and PIV3 1 month after vaccination compared with baseline. No notable increases in neutralizing antibody titers were observed with escalating dose levels after mRNA-1653, although no statistical inferences were made; a second mRNA-1653 dose had little observable impact on antibody titers. Neutralizing titers through 1 year remained above baseline for hMPV and returned to baseline for PIV3. Conclusions: mRNA-1653 was well tolerated, with an acceptable safety profile and increased hMPV and PIV3 neutralization titers in healthy adults.

Maternal SMCHD1 controls both imprinted Xist expression and imprinted X chromosome inactivation.

Embryonic development is dependent on the maternal supply of proteins through the oocyte, including factors setting up the adequate epigenetic patterning of the zygotic genome. We previously reported that one such factor is the epigenetic repressor SMCHD1, whose maternal supply controls autosomal imprinted expression in mouse preimplantation embryos and mid-gestation placenta. In mouse preimplantation embryos, X chromosome inactivation is also an imprinted process. Combining genomics and imaging, we show that maternal SMCHD1 is required not only for the imprinted expression of Xist in preimplantation embryos, but also for the efficient silencing of the inactive X in both the preimplantation embryo and mid-gestation placenta. These results expand the role of SMCHD1 in enforcing the silencing of Polycomb targets. The inability of zygotic SMCHD1 to fully restore imprinted X inactivation further points to maternal SMCHD1's role in setting up the appropriate chromatin environment during preimplantation development, a critical window of epigenetic remodelling.

The Promise of Single-cell Technology in Providing New Insights Into the Molecular Heterogeneity and Management of Acute Lymphoblastic Leukemia.

Drug resistance and treatment failure in pediatric acute lymphoblastic leukemia (ALL) are in part driven by tumor heterogeneity and clonal evolution. Although bulk tumor genomic analyses have provided some insight into these processes, single-cell sequencing has emerged as a powerful technique to profile individual cells in unprecedented detail. Since the introduction of single-cell RNA sequencing, we now have the capability to capture not only transcriptomic, but also genomic, epigenetic, and proteomic variation between single cells separately and in combination. This rapidly evolving field has the potential to transform our understanding of the fundamental biology of pediatric ALL and guide the management of ALL patients to improve their clinical outcome. Here, we discuss the impact single-cell sequencing has had on our understanding of tumor heterogeneity and clonal evolution in ALL and provide examples of how single-cell technology can be integrated into the clinic to inform treatment decisions for children with high-risk disease.

scTEM-seq: Single-cell analysis of transposable element methylation to link global epigenetic heterogeneity with transcriptional programs.

Global changes in DNA methylation are observed in development and disease, and single-cell analyses are highlighting the heterogeneous regulation of these processes. However, technical challenges associated with single-cell analysis of DNA methylation limit these studies. We present single-cell transposable element methylation sequencing (scTEM-seq) for cost-effective estimation of average DNA methylation levels. By targeting high-copy SINE Alu elements, we achieve amplicon bisulphite sequencing with thousands of loci covered in each scTEM-seq library. Parallel transcriptome analysis is also performed to link global DNA methylation estimates with gene expression. We apply scTEM-seq to KG1a acute myeloid leukaemia (AML) cells, and primary AML cells. Our method reveals global DNA methylation heterogeneity induced by decitabine treatment of KG1a cells associated with altered expression of immune process genes. We also compare global DNA methylation estimates to expression of transposable elements and find a predominance of negative correlations. Finally, we observe co-ordinated upregulation of many transposable elements in a sub-set of decitabine treated cells. By linking global DNA methylation heterogeneity with transcription, scTEM-seq will refine our understanding of epigenetic regulation in cancer and beyond.

Informed substitution of hazardous chemicals through the lens of California's Safer Consumer Products Alternatives Analysis: Best practices, challenges, and opportunities.

California adopted the Safer Consumer Products (SCP) regulations in 2013, which mandate that companies that manufacture specific products containing designated chemicals of concern complete an Alternatives Analysis. Alternatives Analysis is a process to avoid regrettable substitution by identifying, comparing, and selecting safer alternatives based on technical functions, hazards, exposure pathways, life-cycle multimedia impacts, and economic impacts. The SCP Alternatives Analysis builds upon and expands existing frameworks for alternatives assessments (AAs). The aim of this study was to identify practices from AA that facilitate the robust assessment of alternatives and that align with SCP requirements and identify gaps in the practice. We evaluated completed AAs for methods regarding transparency and careful documentation of information sources, data gaps, uncertainty, criteria, and justification for decision-making. The AAs in this review demonstrate some of the challenges in the field. Most AAs have a constrained scope and only consider chemical substitutes rather than a broad array of functional alternatives. Their scopes were also limited in the hazard endpoints that were evaluated. This was most noted with ecotoxicity endpoints, which were generally confined to aquatic toxicity. The majority of AAs do not explicitly explain their decision-making methods or adequately discuss tradeoffs across the adverse impacts. The AAs also lack the analysis in the exposure, life-cycle impacts, and economic impacts that are required in the SCP Alternatives Analysis process. Further, we recommend strategies and research opportunities to address these challenges and strengthen the practice of AAs. Integr Environ Assess Manag 2022;18:1007-1019. © 2021 SETAC.

Substance use disorder approaches in US primary care clinics with national reputations as workforce innovators.

BACKGROUND: Over the last decade, primary care clinics in the United States have responded both to national policies encouraging clinics to support substance use disorders (SUD) service expansion and to regulations aiming to curb the opioid epidemic. OBJECTIVE: To characterize approaches to SUD service expansion in primary care clinics with national reputations as workforce innovators. METHODS: Comparative case studies were conducted to characterize different approaches among 12 primary care clinics purposively and iteratively recruited from a national registry of workforce innovators. Observational field notes and qualitative interviews from site visits were coded and analysed to identify and characterize clinic attributes. RESULTS: Codes describing clinic SUD expansion approaches emerged from our analysis. Clinics were characterized as: avoidant (n = 3), contemplative (n = 5) and responsive (n = 4). Avoidant clinics were resistant to planning SUD service expansion; had no or few on-site behavioural health staff; and lacked on-site medication treatment (previously termed medication-assisted therapy) waivered providers. Contemplative clinics were planning or had partially implemented SUD services; members expressed uncertainties about expansion; had co-located behavioural healthcare providers, but no on-site medication treatment waivered and prescribing providers. Responsive clinics had fully implemented SUD; members used non-judgmental language about SUD services; had both co-located SUD behavioural health staff trained in SUD service provision and waivered medication treatment physicians and/or a coordinated referral pathway. CONCLUSIONS: Efforts to support SUD service expansion should tailor implementation supports based on specific clinic training and capacity building needs. Future work should inform the adaption of evidence-based practices that are responsive to resource constraints to optimize SUD treatment access.

Primary care clinics in the US have been encouraged to expand addiction services to increase treatment access and respond to the opioid epidemic. This study uses structured observations and depth interviews to assess and compare how primary care clinics with innovative workforces have responded to the growing need for substance use disorder treatment. Each of the clinics studied represents a 'case.' We systematically compared cases to understand how and if addiction services were expanded. Twelve clinic 'cases' were coded and characterized based on a continuum of receptivity ranging from avoidant (i.e., resistant), contemplative (i.e., organization members plan to implement change) and responsive (i.e. expansions implemented). Our analysis characterized three clinics as avoidant to expanding addiction services reporting no plans to respond to calls to expand addiction services. Five clinics were characterized as contemplative, meaning they recognized the need but still had reservations and concerns about the expansion. Four clinics were characterized as responsive to addiction service expansion and had several organizational-wide strategies to assess, intervene and treat patients with addictions. Despite national and state-based policies to entice clinics to expand addiction services there was a diversity of approaches observed in clinics. Avoidant and contemplative clinics may need implementation support to build capacity for this type of delivery expansion.

Demographics of mental healthcare presentations in a northwest Ontario emergency department.

OBJECTIVES: Providing emergency mental health services for populations in remote rural areas of Canada is challenging. Program needs are distinct. We describe the emergency mental health workload and service needs at the Sioux Lookout Meno Ya Win Health Centre (SLMHC) in northwest Ontario. METHODS: Emergency department (ED) data were collected for mental health, addiction and self-harm diagnoses (MHA) in 2018/2019. Comparisons were made to similar sized provincial hospitals and EDs. Mental health admissions data from Oct 1, 2018 to Dec 31, 2019 were manually collected from hospital medical charts for demographics, suicide attempts/ideation and frequency of applications for Form 1 psychiatric assessment. RESULTS: The volume of MHA ED visits as a percentage of total ED visits was 4 times higher at SLMHC when compared to both the 67 other Ontario level C hospitals (< 100 beds) and the 15 level C hospital with a similar volume of ED visits (15,000-20,000), (15% vs 4%). Self-harm presentations were 308 at SLMHC versus an average of 42 ± 37 at the 15 level C hospitals with a similar ED volume. From Oct 1, 2019 to Dec 31, 2019, there were 49 patients requiring a Form 1, with an average wait time of 55 h before transfer to a schedule 1 facility. CONCLUSION: There is an increased level of mental health, addiction and self-harm presentations in this northern ED. Lack of alternative resources indicate the need for the development of an integrated model of mental health care service. Reliance on the ED for crisis management indicates the need for the development of more regionally relevant models of care.

RéSUMé: OBJECTIFS: Fournir des services de santé mentale d'urgence aux populations des régions rurales éloignées du Canada est un défi. Les besoins du programme sont distincts. Nous décrivons la charge de travail d'urgence en santé mentale et les besoins en services au Sioux Lookout Meno Ya Win Health Centre (SLMHC) dans le nord-ouest de l'Ontario. MéTHODES: Des données sur les urgences ont été recueillies pour les diagnostics de santé mentale, de toxicomanie et d'automutilation (MHA) en 2018/2019. Des comparaisons ont été faites avec des hôpitaux provinciaux et des services d'urgence de taille similaire. Les données sur les admissions en santé mentale du 1er octobre 2018 au 31 décembre 2019 ont été collectées manuellement à partir des dossiers médicaux des hôpitaux pour les données démographiques, les tentatives/idées de suicide et la fréquence des demandes d'évaluation psychiatrique du formulaire 1. RéSULTATS: Le volume de visites aux urgences du MHA en pourcentage du total des visites aux urgences était 4 fois plus élevé au SLMHC par rapport aux 67 autres hôpitaux de niveau C de l'Ontario (< 100 lits) et aux 15 hôpitaux de niveau C avec un volume similaire de visites aux urgences (15 000­20 000), (15% contre 4%). Les présentations d'automutilation étaient de 308 au SLMHC contre une moyenne de 42 ± 37 dans les 15 hôpitaux de niveau C avec un volume d'urgence similaire. Du 1er octobre 2019 au 31 décembre 2019, 49 patients ont nécessité un formulaire 1, avec un temps d'attente moyen de 55 heures avant le transfert vers un établissement de l'annexe 1. CONCLUSION: Le nombre de cas de santé mentale, de toxicomanie et d'automutilation est en augmentation dans cette urgence du nord. Le manque de ressources alternatives indique la nécessité de développer un modèle intégré de service de soins de santé mentale. Le recours aux services d'urgence pour la gestion des crises indique la nécessité d'élaborer des modèles de soins plus adaptés au niveau régional.

Mechanism of noncoding RNA-associated N6-methyladenosine recognition by an RNA processing complex during IgH DNA recombination.

Immunoglobulin heavy chain (IgH) locus-associated G-rich long noncoding RNA (SµGLT) is important for physiological and pathological B cell DNA recombination. We demonstrate that the METTL3 enzyme-catalyzed N6-methyladenosine (m6A) RNA modification drives recognition and 3' end processing of SµGLT by the RNA exosome, promoting class switch recombination (CSR) and suppressing chromosomal translocations. The recognition is driven by interaction of the MPP6 adaptor protein with nuclear m6A reader YTHDC1. MPP6 and YTHDC1 promote CSR by recruiting AID and the RNA exosome to actively transcribe SµGLT. Direct suppression of m6A modification of SµGLT or of m6A reader YTHDC1 reduces CSR. Moreover, METTL3, an essential gene for B cell development in the bone marrow and germinal center, suppresses IgH-associated aberrant DNA breaks and prevents genomic instability. Taken together, we propose coordinated and central roles for MPP6, m6A modification, and m6A reader proteins in controlling long noncoding RNA processing, DNA recombination, and development in B cells.

The Lived Experience of Already-Lonely Older Adults During COVID-19.

BACKGROUND AND OBJECTIVES: From the outset of the coronavirus disease 2019 (COVID-19) pandemic, analysts warned that older populations, due to their age, chronic illnesses, and lack of technological facility, would suffer disproportionately from loneliness as they sheltered in place indefinitely. Several studies have recently been published on the impact of COVID-19-related loneliness among older populations, but little has been written about the experiences of already-lonely older individuals; those who had lived with persistent loneliness before the advent of COVID-19. This qualitative study sought to understand how already-lonely older individuals navigated and endured the social isolation of the pandemic. RESEARCH DESIGN AND METHODS: Twelve semistructured interviews were conducted with individuals aged 65 or older who scored a 6 or above on the 3-item UCLA Loneliness Risk screening tool. Interviews were coded using the constant comparative method. Themes and understandings of loneliness that reoccurred within and across interviews were identified and collected. RESULTS: Already-isolated older interviewees did not necessarily experience the abject loneliness hypothesized by analysts. Most interviewees used longstanding arrangements, in place to mitigate loneliness and endure social isolation, to manage the social deprivation of COVID-19. As a result, their loneliness did not compound during long bouts of mandated social isolation. To the contrary, loneliness during the pandemic appeared to carry a new valence for interviewees, as COVID-19 imbued their isolation with new meaning, rendering their loneliness necessary and responsible. DISCUSSION AND IMPLICATIONS: Exploring individuals' subjective perceptions of loneliness can help provide a deeper understanding of what it means to be isolated and alone during COVID-19 and aid in designing strategies to mitigate loneliness.

Federated deep learning for detecting COVID-19 lung abnormalities in CT: a privacy-preserving multinational validation study.

Data privacy mechanisms are essential for rapidly scaling medical training databases to capture the heterogeneity of patient data distributions toward robust and generalizable machine learning systems. In the current COVID-19 pandemic, a major focus of artificial intelligence (AI) is interpreting chest CT, which can be readily used in the assessment and management of the disease. This paper demonstrates the feasibility of a federated learning method for detecting COVID-19 related CT abnormalities with external validation on patients from a multinational study. We recruited 132 patients from seven multinational different centers, with three internal hospitals from Hong Kong for training and testing, and four external, independent datasets from Mainland China and Germany, for validating model generalizability. We also conducted case studies on longitudinal scans for automated estimation of lesion burden for hospitalized COVID-19 patients. We explore the federated learning algorithms to develop a privacy-preserving AI model for COVID-19 medical image diagnosis with good generalization capability on unseen multinational datasets. Federated learning could provide an effective mechanism during pandemics to rapidly develop clinically useful AI across institutions and countries overcoming the burden of central aggregation of large amounts of sensitive data.

Mental health nurses experience of the introduction and practice of the Safewards model: a qualitative descriptive study.

BACKGROUND: A lack of safety experienced by patients and staff in acute psychiatric units is a major concern and containment methods used to manage conflict have the potential to cause harm and upset to both staff and patients. To ensure safety for all, it is highly desirable to reduce levels of conflict and containment and the Safewards model is an evidence-based model aimed at reducing conflict and containment rates by improving nurse-patient relationships and safety. METHODS: The aim of this study was to explore mental health nurses' experience of the introduction and practice of three Safewards interventions; reassurance, soft words and discharge messages. A qualitative descriptive research design utilising a purposive sample (n = 21) of registered psychiatric nurses (n = 16) and managers (n = 5) in an acute psychiatric unit in Ireland. Following a 12-week implementation of Safewards, three focus groups were conducted, two with nursing staff and one with nurse managers. Data were analysed using Braun and Clarke thematic analysis framework which supported the identification of four themes: introducing Safewards, challenges of Safewards, impact of Safewards and working towards success. RESULTS: The findings indicate that the process of implementation was inadequate in the training and education of staff, and that poor support from management led to poor staff adherence and acceptance of the Safewards interventions. The reported impact of Safewards on nursing practice and patient experience were mixed. Overall, engagement and implementation under the right conditions are essential for success and while some participants perceived that the interventions already existed in practice, participants agreed Safewards enhanced their communication skills and relationships with patients. CONCLUSION: The implementation of Safewards requires effective leadership and support from management, mandatory training for all staff, and the involvement of staff and patients during implementation. Future research should focus on the training and education required for successful implementation of Safewards and explore the impact of Safewards on nursing practice and patient experience.