Factors that support children and young people to express their views and to have them heard in healthcare: An inductive qualitative content analysis.

Despite development of healthcare charters supporting Article 12 of The United Nations Convention on the Rights of the Child, children and young people remain largely silenced in discussions about their healthcare. This article is based on the premise that children and young people should be able to exercise their right to express their views and be heard in all matters that affect their lives. This study examined children's and young people's experiences of expressing their views and having them heard in an Australian healthcare context. Using child-centred inquiry and 'draw, write, and tell' methods, data were collected from 20 children and young people. Five factors that supported children and young people to express their views and have their views heard were identified: time, relationships with health professionals, communication, teamwork, and family support. By paying attention to these factors, clinicians and others in health settings can better facilitate child-centred practices and support children and young people to express their views and have those views heard.

Children's and young people's experiences of expressing their views and having them heard in health care: A deductive qualitative content analysis.

AIM: To gain an understanding of children's experiences of expressing their views and having them heard in Australian healthcare settings. DESIGN: Child-centred qualitative research. A deductive qualitative content analysis was undertaken. METHODS: Data were collected from 20 Australian children and young people between the ages of 7 and 18 years old using the 'draw, write and tell' method. RESULTS: Children's experiences of 'space' and 'voice', and therefore the opportunity to express their views in health care were, in the main, positive. At the same time, their experiences of 'audience' and 'influence', the situations in which those views are given due weight, were overwhelmingly described as negative. CONCLUSION: Australian paediatric health services appear to have responded to calls to provide children with the opportunity to express their views and thus are delivering on the elements of 'space' and 'voice', whereas the realisation of 'audience' and 'influence' has some way to go. Due weight is not always given to children's views. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: The Lundy model can be used to facilitate a better understanding of the concept of voice, and the responsibility of health organisations in implementing the rights of children and young people, as articulated in Article 12. IMPACT: Children and young people have a right to express their views and have them heard in health care, but their experiences in Australian health care are unknown. While children's experiences of expressing their views in health care were mostly positive, their views are not always taken seriously or given due weight. This research impacts child health professionals in Australia and internationally. REPORTING METHOD: The study is reported using the Standards for Reporting Qualitative Research (SRQR). PATIENT OR PUBLIC CONTRIBUTION: Members of the Youth Advisory Council of two tertiary children's hospitals were consulted and invited to become members of the research team.

Factors influencing women to accept diet and exercise messages on social media during COVID-19 lockdowns: A qualitative application of the health belief model.

This study investigates how engagement with social media leads women to adopt diet and exercise practices. We base our analysis on qualitative research, including surveys and in-depth interviews, with thirty (30) Australian women aged 18-35 years between April and August 2021. Our findings reveal how healthism discourse on social media, namely Facebook, Instagram and TikTok, underpin the adoption of diet and exercise practices by enhancing experiences of digital intimacy, repeat messages and personal testimonials from other women, and supporting new routines during COVID-19 lockdowns. This article contributes to health marketing literature by providing critical knowledge about women's experiences that prompt and shape complex ideologies of health that are often masked through diet and exercise practices on social media.

Registered nurses' attitudes towards e-learning and technology in healthcare: A cross-sectional survey.

BACKGROUND: Online learning, also known as e-learning, has increased considerably during the COVID-19 pandemic and is now an important feature of nursing education globally. An understanding of registered nurses' online self-regulated learning, attitudes to e-learning and the relationship of these to attitudes to Information and Communication Technology (ICT) in healthcare facilitates successful educational outcomes. OBJECTIVE: To explore the association between registered nurses' attitudes to e-learning and self-regulated online learning skills on their attitudes towards the use of ICT in healthcare. DESIGN: A quantitative study employing a cross-sectional survey. SETTINGS AND PARTICIPANTS: A convenience sample of registered nurses (n = 120) enrolled in a nursing degree conversion program delivered in Singapore. METHODS: Participants (n = 120) completed an online anonymous survey consisting of three validated instruments (Information Technology Attitude Scale for Health (ITASH), Attitudes towards e-learning and, Online Self-regulated Learning Questionnaire. Descriptive and inferential statistics analyses were conducted. RESULTS: Participant's levels of online self-regulated learning were positively correlated with attitudes to e-learning (r = 0.663, p < 0.001). Attitudes to e-learning (70.4, SD 11.5) were also positively predictive of ITASH (R2 = 0.306, p < 0.001), but online self-regulated learning was not contributory to the prediction of attitudes to ICT in healthcare. CONCLUSIONS: It is recommended that educators involved in online learning focus on strategies aimed at promoting positive attitudes to e-learning and ICT prior to employing those aimed at developing online self-regulation skills. Further research exploring online learning and ICT needs in the workplace are required.

DNA Repair and Therapeutic Strategies in Cancer Stem Cells.

First-line cancer treatments successfully eradicate the differentiated tumour mass but are comparatively ineffective against cancer stem cells (CSCs), a self-renewing subpopulation thought to be responsible for tumour initiation, metastasis, heterogeneity, and recurrence. CSCs are thus presented as the principal target for elimination during cancer treatment. However, CSCs are challenging to drug target because of numerous intrinsic and extrinsic mechanisms of drug resistance. One such mechanism that remains relatively understudied is the DNA damage response (DDR). CSCs are presumed to possess properties that enable enhanced DNA repair efficiency relative to their highly proliferative bulk progeny, facilitating improved repair of double-strand breaks induced by radiotherapy and most chemotherapeutics. This can occur through multiple mechanisms, including increased expression and splicing fidelity of DNA repair genes, robust activation of cell cycle checkpoints, and elevated homologous recombination-mediated DNA repair. Herein, we summarise the current knowledge concerning improved genome integrity in non-transformed stem cells and CSCs, discuss therapeutic opportunities within the DDR for re-sensitising CSCs to genotoxic stressors, and consider the challenges posed regarding unbiased identification of novel DDR-directed strategies in CSCs. A better understanding of the DDR mediating chemo/radioresistance mechanisms in CSCs could lead to novel therapeutic approaches, thereby enhancing treatment efficacy in cancer patients.

Establishing a framework for listening to children in healthcare.

The principle that children and young people are capable of forming their own views, have the right to express those views, and are entitled to have those views taken seriously was introduced by the United Nations Convention on the Rights of the Child (UNCRC) in 1989. The implications for the delivery of healthcare are clear; however, children and young people continue to experience difficulty in having their views heard and taken seriously during healthcare encounters and the effectiveness of the UNCRC, in particular Article 12 appears to be limited. This article will discuss how, 30 years on, significant barriers continue to impede the full implementation of Article 12. In recognition of the limited awareness of its scope or even existence by health professionals working with children, a framework that can facilitate a better understanding of the concept of voice, and articulate healthcare organisations' full responsibilities when it comes to Article 12, is presented.

Arginine methylation and ubiquitylation crosstalk controls DNA end-resection and homologous recombination repair.

Cross-talk between distinct protein post-translational modifications is critical for an effective DNA damage response. Arginine methylation plays an important role in maintaining genome stability, but how this modification integrates with other enzymatic activities is largely unknown. Here, we identify the deubiquitylating enzyme USP11 as a previously uncharacterised PRMT1 substrate, and demonstrate that the methylation of USP11 promotes DNA end-resection and the repair of DNA double strand breaks (DSB) by homologous recombination (HR), an event that is independent from another USP11-HR activity, the deubiquitylation of PALB2. We also show that PRMT1 is a ubiquitylated protein that it is targeted for deubiquitylation by USP11, which regulates the ability of PRMT1 to bind to and methylate MRE11. Taken together, our findings reveal a specific role for USP11 during the early stages of DSB repair, which is mediated through its ability to regulate the activity of the PRMT1-MRE11 pathway.

Implementation of CRISPR/Cas9 Genome Editing to Generate Murine Lung Cancer Models That Depict the Mutational Landscape of Human Disease.

Lung cancer is the most common cancer worldwide and the leading cause of cancer-related deaths in both men and women. Despite the development of novel therapeutic interventions, the 5-year survival rate for non-small cell lung cancer (NSCLC) patients remains low, demonstrating the necessity for novel treatments. One strategy to improve translational research is the development of surrogate models reflecting somatic mutations identified in lung cancer patients as these impact treatment responses. With the advent of CRISPR-mediated genome editing, gene deletion as well as site-directed integration of point mutations enabled us to model human malignancies in more detail than ever before. Here, we report that by using CRISPR/Cas9-mediated targeting of Trp53 and KRas, we recapitulated the classic murine NSCLC model Trp53 fl/fl :lsl-KRas G12D/wt . Developing tumors were indistinguishable from Trp53 fl/fl :lsl-KRas G12D/ wt -derived tumors with regard to morphology, marker expression, and transcriptional profiles. We demonstrate the applicability of CRISPR for tumor modeling in vivo and ameliorating the need to use conventional genetically engineered mouse models. Furthermore, tumor onset was not only achieved in constitutive Cas9 expression but also in wild-type animals via infection of lung epithelial cells with two discrete AAVs encoding different parts of the CRISPR machinery. While conventional mouse models require extensive husbandry to integrate new genetic features allowing for gene targeting, basic molecular methods suffice to inflict the desired genetic alterations in vivo. Utilizing the CRISPR toolbox, in vivo cancer research and modeling is rapidly evolving and enables researchers to swiftly develop new, clinically relevant surrogate models for translational research.

Structural and biochemical evaluation of bisubstrate inhibitors of protein arginine N-methyltransferases PRMT1 and CARM1 (PRMT4).

Attenuating the function of protein arginine methyltransferases (PRMTs) is an objective for the investigation and treatment of several diseases including cardiovascular disease and cancer. Bisubstrate inhibitors that simultaneously target binding sites for arginine substrate and the cofactor (S-adenosylmethionine (SAM)) have potential utility, but structural information on their binding is required for their development. Evaluation of bisubstrate inhibitors featuring an isosteric guanidine replacement with two prominent enzymes PRMT1 and CARM1 (PRMT4) by isothermal titration calorimetry (ITC), activity assays and crystallography are reported. Key findings are that 2-aminopyridine is a viable replacement for guanidine, providing an inhibitor that binds more strongly to CARM1 than PRMT1. Moreover, a residue around the active site that differs between CARM1 (Asn-265) and PRMT1 (Tyr-160) is identified that affects the side chain conformation of the catalytically important neighbouring glutamate in the crystal structures. Mutagenesis data supports its contribution to the difference in binding observed for this inhibitor. Structures of CARM1 in complex with a range of seven inhibitors reveal the binding modes and show that inhibitors with an amino acid terminus adopt a single conformation whereas the electron density for equivalent amine-bearing inhibitors is consistent with preferential binding in two conformations. These findings inform the molecular basis of CARM1 ligand binding and identify differences between CARM1 and PRMT1 that can inform drug discovery efforts.

Places as fuzzy locational categories.

This paper offers a new way of considering places as special types of categories, in human cognition of larger-scale environments. This may provide an explanatory cognitive model for a range of known phenomena from environmental psychology and human geography - notably places' semantic salience and vague, unstable boundaries. Using such a model to apply suitable classification approaches may enhance geographic information (GI) for key public-facing users, such as emergency services and planners. Two empirical studies confirmed that a spatially extended place (e.g., suburban locality or neighborhood) may be stored as a category whose exemplars are memorable individual locations or scenes. Using a questionnaire-based method to partly replicate key findings from the semantic memory literature (Barsalou, 1985; Lynch et al., 2000), the studies tested the relevance to such places of known semantic memory phenomena including graded membership, typicality versus ideals, expertise and context effects. The discussion considers the link between semantic and spatial vagueness of places.

PRMTs and Arginine Methylation: Cancer's Best-Kept Secret?

Post-translational modification (PTM) of proteins is vital for increasing proteome diversity and maintaining cellular homeostasis. If the writing, reading, and removal of modifications are not controlled, cancer can develop. Arginine methylation is an understudied modification that is increasingly associated with cancer progression. Consequently protein arginine methyltransferases (PRMTs), the writers of arginine methylation, have rapidly gained interest as novel drug targets. However, for clinical success a deep mechanistic understanding of the biology of PRMTs is required. In this review we focus on advances made regarding the role of PRMTs in stem cell biology, epigenetics, splicing, immune surveillance and the DNA damage response, and highlight the rapid rise of specific inhibitors that are now in clinical trials for cancer therapy.

Linking PRMT5 to breast cancer stem cells: New therapeutic opportunities?

The arginine methyltransferase PRMT5 has been increasingly associated with cancer development. Here we describe our recent findings that PRMT5 is a critical regulator of breast cancer stem cell survival via the epigenetic regulation of FOXP1. Consequently, PRMT5 inhibitors could potentially eradicate cancer stem cells thereby preventing tumour relapse.

PRMT5 Is a Critical Regulator of Breast Cancer Stem Cell Function via Histone Methylation and FOXP1 Expression.

Breast cancer progression, treatment resistance, and relapse are thought to originate from a small population of tumor cells, breast cancer stem cells (BCSCs). Identification of factors critical for BCSC function is therefore vital for the development of therapies. Here, we identify the arginine methyltransferase PRMT5 as a key in vitro and in vivo regulator of BCSC proliferation and self-renewal and establish FOXP1, a winged helix/forkhead transcription factor, as a critical effector of PRMT5-induced BCSC function. Mechanistically, PRMT5 recruitment to the FOXP1 promoter facilitates H3R2me2s, SET1 recruitment, H3K4me3, and gene expression. Our findings are clinically significant, as PRMT5 depletion within established tumor xenografts or treatment of patient-derived BCSCs with a pre-clinical PRMT5 inhibitor substantially reduces BCSC numbers. Together, our findings highlight the importance of PRMT5 in BCSC maintenance and suggest that small-molecule inhibitors of PRMT5 or downstream targets could be an effective strategy eliminating this cancer-causing population.

The nursing assessment of infants with bronchiolitis.

Bronchiolitis is the leading cause of morbidity and hospitalization in infants under the age of one year. Supportive treatments and regular assessment remain the mainstay of care for infants admitted to hospital. Nurses play an important role in the assessment of infants with bronchiolitis; however, this is not well described in the literature and consequently little is known about what strategies nurses employ in assessing infants with bronchiolitis. The aim of this study was to explore bronchiolitis assessment in the context of nursing practice. A naturalistic inquiry study was undertaken using think aloud and retrospective probing data collection methods. The results revealed that the information gathered by nurses in their assessment of infants with bronchiolitis was varied and the process of acquiring and evaluating this information was multifaceted and holistic in nature. A close partnership between the nurse and mother was identified, and the mother's expert knowledge and ability to identify subtle changes in the infant's clinical condition over time was essential to the assessment process. The assessment partnership with families provides nurses with the most comprehensive and holistic view of the infant's clinical condition and vital assessment information could be lost if this partnership does not occur.

PRMT5-Dependent Methylation of the TIP60 Coactivator RUVBL1 Is a Key Regulator of Homologous Recombination.

Protein post-translation modification plays an important role in regulating DNA repair; however, the role of arginine methylation in this process is poorly understood. Here we identify the arginine methyltransferase PRMT5 as a key regulator of homologous recombination (HR)-mediated double-strand break (DSB) repair, which is mediated through its ability to methylate RUVBL1, a cofactor of the TIP60 complex. We show that PRMT5 targets RUVBL1 for methylation at position R205, which facilitates TIP60-dependent mobilization of 53BP1 from DNA breaks, promoting HR. Mechanistically, we demonstrate that PRMT5-directed methylation of RUVBL1 is critically required for the acetyltransferase activity of TIP60, promoting histone H4K16 acetylation, which facilities 53BP1 displacement from DSBs. Interestingly, RUVBL1 methylation did not affect the ability of TIP60 to facilitate ATM activation. Taken together, our findings reveal the importance of PRMT5-mediated arginine methylation during DSB repair pathway choice through its ability to regulate acetylation-dependent control of 53BP1 localization.

A systematic review of the psychometric properties of bronchiolitis assessment tools.

AIM: The aim of this study was to assess the psychometric properties of tools developed for the purpose of assessing infants with bronchiolitis. BACKGROUND: Bronchiolitis is the leading cause of hospitalization in infants under the age of 1 year. Several bronchiolitis assessment tools have been developed primarily for use in randomized control trials of medical treatments for infants with bronchiolitis, however, the reliability and validity of many of these tools is not well reported. DESIGN: Systematic review. DATA SOURCES: CINAHL, MEDLINE, EMBASE and PubMed electronic databases were searched between January 1960-December 2015 using the key words 'bronchiolitis' and 'assessment' or 'screen' or 'tool' or 'scale' or 'score'. REVIEW METHODS: A systematic review of the psychometric properties of bronchiolitis assessment tools was undertaken using the COSMIN checklist. RESULTS: Fourteen studies meeting the inclusion criteria were reviewed and the methodological quality of the studies and reported psychometric properties of 11 instruments were assessed. Overall, the reliability and validity of bronchiolitis assessment tools was poorly established. Although several studies reported that their tools had good inter-rater reliability, the methodological quality of these studies was generally poor. Only one study underwent psychometric testing that was assessed as being of excellent quality. The Respiratory Distress Assessment Index was deemed to have undergone the most rigorous psychometric testing but had poor to moderate construct validity and considerable test-retest error. CONCLUSION: Current bronchiolitis assessment tools lack clearly established reliability and validity and may not be sensitive to clinically meaningful outcomes for patients.

Identifying novel protein interactions: Proteomic methods, optimisation approaches and data analysis pipelines.

The technological revolution in high-throughput nucleic acid and protein analysis in the last 15 years has launched the field of 'omics' and led to great advances in our understanding of cell biology. Consequently the study of the cellular proteome and protein dynamics, in particular interactomics, has been a matter of intense investigation, specifically the determination and description of complex protein interaction networks in the cell, not only with other proteins but also with RNA and DNA. The analysis of these interactions, beginning with their identification and ultimately resulting in structural level examination, is one of the cornerstones of modern biological science underpinning basic research and impacting on applied biology, biomedicine and drug discovery. In this review we summarise a selection of emerging and established techniques currently being applied in this field with a particular focus on affinity-based purification systems and their optimisation, including tandem affinity purification (TAP) tagging, isolation of proteins on nascent DNA (IPOND) and RNA-protein immunoprecipitation in tandem (RIPiT). The recent application of quantitative proteomics to improve stringency and specificity is also discussed, including the use of metabolic labelling by stable isotope labelling by amino acids in cell culture (SILAC), localization of organelle proteins by isotope tagging (LOPIT) and proximity-dependent biotin identification (BioID). Finally, we describe a range of software resources that can be applied to interactomics, both to handle raw data and also to scrutinise its broader biological context. In this section we focus especially on open-access online interactomic databases such as Reactome and IntAct.

ERK5 is a critical mediator of inflammation-driven cancer.

Chronic inflammation is a hallmark of many cancers, yet the pathogenic mechanisms that distinguish cancer-associated inflammation from benign persistent inflammation are still mainly unclear. Here, we report that the protein kinase ERK5 controls the expression of a specific subset of inflammatory mediators in the mouse epidermis, which triggers the recruitment of inflammatory cells needed to support skin carcinogenesis. Accordingly, inactivation of ERK5 in keratinocytes prevents inflammation-driven tumorigenesis in this model. In addition, we found that anti-ERK5 therapy cooperates synergistically with existing antimitotic regimens, enabling efficacy of subtherapeutic doses. Collectively, our findings identified ERK5 as a mediator of cancer-associated inflammation in the setting of epidermal carcinogenesis. Considering that ERK5 is expressed in almost all tumor types, our findings suggest that targeting tumor-associated inflammation via anti-ERK5 therapy may have broad implications for the treatment of human tumors.

Effect of fixation method on postoperative complication rates after surgical stabilization of lateral humeral condylar fractures in dogs.

OBJECTIVES: To assess the impact of stabilization method on the complication rate after lateral humeral condylar fracture (LHCF) repair. STUDY DESIGN: Retrospective multicenter clinical cohort study. ANIMALS: Dogs (n = 151) with LHCF. METHODS: Medical records (2004-2012) were reviewed for dogs that had surgical repair of LHCF. Data retrieved included signalment, cause of fracture, evidence of incomplete ossification of the humeral condyle, occurrence of postoperative complications, presence of supracondylar comminution preoperatively, and persistence of an intracondylar fissure postoperatively. Outcome was assessed based on the most recent data available and graded as excellent, good, fair, or poor. RESULTS: LHCF (n = 135) were evaluated in 132 dogs; 61 fractures were stabilized using a transcondylar screw and supracondylar K-wire, 13 using a transcondylar screw and supracondylar screw, and 61 using a transcondylar screw and lateral epicondylar plate. Major complications were significantly (P = .01) more common after stabilization using a transcondylar screw and supracondylar K-wire (28%) than in dogs where a supracondylar screw or lateral epicondylar plate were used (11%). Cases that had postoperative complications were significantly (P = .02) more likely to have a poor outcome. CONCLUSIONS: LHCF stabilized using a transcondylar screw and supracondylar K-wire are more likely to have major complications resulting in a poorer outcome than cases stabilized using a supracondylar screw or lateral epicondylar plate.

Impaired JNK signaling cooperates with KrasG12D expression to accelerate pancreatic ductal adenocarcinoma.

The c-Jun N-terminal protein kinase (JNK) and its two direct activators, namely the mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) and MKK7, constitute a signaling node frequently mutated in human pancreatic ductal adenocarcinoma (PDAC). Here we demonstrate the cooperative interaction of endogenous expression of Kras(G12D) with loss-of-function mutations in mkk4 or both, mkk4 and mkk7 genes in the pancreas. More specifically, impaired JNK signaling in a subpopulation of Pdx1-expressing cells dramatically accelerated the appearance of Kras(G12D)-induced acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasias, which rapidly progressed to invasive PDAC within 10 weeks of age. Furthermore, inactivation of mkk4/mkk7 compromised acinar regeneration following acute inflammatory stress by locking damaged exocrine cells in a permanently de-differentiated state. Therefore, we propose that JNK signaling exerts its tumor suppressive function in the pancreas by antagonizing the metaplastic conversion of acinar cells toward a ductal fate capable of responding to oncogenic stimulation.