Pluripotent and Multipotent Stem Cells Display Distinct Hypoxic miRNA Expression Profiles

MicroRNAs are reported to have a crucial role in the regulation of self-renewal and differentiation of stem cells. Hypoxia has been identified as a key biophysical element of the stem cell culture milieu however, the link between hypoxia and miRNA expression in stem cells remains poorly understood. We therefore explored miRNA expression in hypoxic human embryonic and mesenchymal stem cells (hESCs and hMSCs). A total of 50 and 76 miRNAs were differentially regulated by hypoxia (2% O2) in hESCs and hMSCs, respectively, with a negligible overlap of only three miRNAs. We found coordinate regulation of precursor and mature miRNAs under hypoxia suggesting their regulation mainly at transcriptional level. Hypoxia response elements were located upstream of 97% of upregulated hypoxia regulated miRNAs (HRMs) suggesting hypoxia-inducible-factor (HIF) driven transcription. HIF binding to the candidate cis-elements of specific miRNAs under hypoxia was confirmed by Chromatin immunoprecipitation coupled with qPCR. Role analysis of a subset of upregulated HRMs identified linkage to reported inhibition of differentiation while a downregulated subset of HRMs had a putative role in the promotion of differentiation. MiRNA-target prediction correlation with published hypoxic hESC and hMSC gene expression profiles revealed HRM target genes enriched in the cytokine:cytokine receptor, HIF signalling and pathways in cancer. Overall, our study reveals, novel and distinct hypoxia-driven miRNA signatures in hESCs and hMSCs with the potential for application in optimised culture and differentiation models for both therapeutic application and improved understanding of stem cell biology

A renal colic fast track pathway to improve waiting times and outcomes for patients presenting to the emergency department

Introduction: Renal colic is commonly encountered in the emergency department (ED). We validated a fast track renal colic (FTRC) initiative to decrease patient waiting times and streamline patient flow. Method: The FTRC pathway was devised according to the National Institute for Health and Care Excellence clinical summary criteria for the management of patients with suspected renal colic. ED triage nurses use the pathway to identify patients with likely renal colic suitable for fast track to analgesia, investigation and management. Investigations, diagnosis and patient demographics were recorded for 1157 consecutive patients coded as renal colic at a single-center ED over 12 months. Results: Three hundred and two patients were suitable for the FTRC pathway (26.1%), while 855 were seen by the ED clinicians prior to onward referral. Also, 83.9% of patients underwent computed tomography scan. In the FTRC group, 57.3% of patients had radiologically confirmed calculi versus 53.8% in the non-FTRC group (p=0.31). Alternative diagnoses among FTRC patients (2.6%) included ovarian pathology (n=1), diverticulitis (n=2) and incidental renal cell carcinoma (n=2), while 26.1% had no identifiable pathology. No immediately life-threatening diagnoses were identified on imaging. Computed tomography scans performed in the non-FTRC group identified two ruptured abdominal aortic aneurysms and alternative diagnoses (2.57%) including ovarian pathology (n=7), cholecystitis (n=2), incidental renal cell carcinoma (n=3) and inflammatory bowel disease (n=1); 31.2% identified no pathology. Time in ED and time to radiologist-reported imaging were lower for the FTRC group versus non-FTRC group (p<0.0001). Conclusion: The FTRC pathway is a safe and efficacious method of reducing diagnostic delay and improving patient flow in the ED

Hypoxia-Modified Cancer Cell Metabolism

While oxygen is critical to the continued existence of complex organisms, extreme levels of oxygen within a system, known as hypoxia (low levels of oxygen) and hyperoxia (excessive levels of oxygen), potentially promote stress within a defined biological environment. The consequences of tissue hypoxia, a result of a defective oxygen supply, vary in response to the gravity, extent and environment of the malfunction. Persistent pathological hypoxia is incompatible with normal biological functions, and as a result, multicellular organisms have been compelled to develop both organism-wide and cellular-level hypoxia solutions. Both direct, including oxidative phosphorylation down-regulation and inhibition of fatty-acid desaturation, and indirect processes, including altered hypoxia-sensitive transcription factor expression, facilitate the metabolic modifications that occur in response to hypoxia. Due to the dysfunctional vasculature associated with large areas of some cancers, sections of these tumors continue to develop in hypoxic environments. Crucial to drug development, a robust understanding of the significance of these metabolism changes will facilitate our understanding of cancer cell survival. This review defines our current knowledge base of several of the hypoxia-instigated modifications in cancer cell metabolism and exemplifies the correlation between metabolic change and its support of the hypoxic-adapted malignancy

Perception of stability correlates with objective performance of dynamic stability for people with chronic ankle instability

Purpose: Lateral ankle sprains are one of the most prevalent musculoskeletal injuries, with one of the highest recurrence rates. One in five people develops chronic ankle instability (CAI) after a lateral ankle sprain. CAI is mainly described as a subjective phenomenon, but is associated with recurrent symptoms, reduced dynamic stability, and reduced physical activity and quality of life. Understanding the relationship between perception of stability and effect on performance for people with CAI could inform rehabilitative strategies in clinical practice. This study aimed to investigate the relationship between the perception of stability and objective performance of dynamic stability this population. Methods: This study is a sub-analysis of data from four separate studies in Australia and the United Kingdom. Participants were screened and categorised as a CAI, coper, or healthy participant. Each participant completed the Star Excursion Balance Test (SEBT) and Cumberland ankle instability tool (CAIT). Distances reached in the anterior, posterior-medial, and posterior-lateral directions, and average, of the SEBT were analysed. Results: Data from 95 participants with CAI, 45 copers, and 101 healthy participants was analysed. There was a significant moderate correlation between CAIT score and SEBT reach distance in all directions for the CAI group (p < 0.001). For copers, there was small significant correlation in the posterior-lateral direction (p < 0.05). Conclusion: This study highlights the discrepancies between the perception of stability and objective dynamic stability, and reinforces the importance of using both types of measures for continual assessment in practice to optimise selecting rehabilitative strategies

Systematic review of studies of mental health nurses' experience of anger and of its relationships with their attitudes and practice

IntroductionEmotional regulation is important in mental health nursing practice but individual emotions may require different regulation strategies. There is ample evidence that nurses experience anger specifically during their work, for example when experiencing patient aggression. It is, therefore, important to consolidate what is known about how anger manifests in mental health nursing practice.AimWe aimed to systematically identify, evaluate, and synthesise results from studies about mental health nurses and anger, where anger was measured objectively.MethodsSystematic literature review based on PRISMA guidelines.Results.We identified 12 studies. A range of validated and non-validated instruments were used. Mental health nurses may have lower levels of anger than normative samples but anger is commonly reported as an issue for them. Anger was studied in relation to its links with i) clinical management of patients, notably violence containment; and ii) employment issues more generally, notably job motivation. Anger is related to nurses’ attitudes about the acceptability of coercion but there is no evidence that it results in more coercion.Implications for practiceNurses should be aware of the potential influence of anger on their practice. Anger, specifically, should be considered when supporting mental health nurses, for example in clinical supervision. Emotional regulation training should target anger

Addressing barriers and identifying facilitators to support informed consent and recruitment in the Cavernous malformations A Randomised Effectiveness (CARE) pilot phase trial:insights from the integrated QuinteT recruitment intervention (QRI)

BackgroundIt was anticipated that recruitment to the Cavernous malformations: A Randomised Effectiveness (CARE) pilot randomised trial would be challenging. The trial compared medical management and surgery (neurosurgical resection or stereotactic radiosurgery) with medical management alone, for people with symptomatic cerebral cavernous malformation (ISRCTN41647111). Previous trials comparing surgical and medical management for intracranial vascular malformations failed to recruit to target. A QuinteT Recruitment Intervention was integrated during trial accrual, September 2021–April 2023 inclusive, to improve informed consent and recruitment.MethodsThe QuinteT Recruitment Intervention combined iterative collection and analysis of quantitative data (28 trial site screening logs recording numbers/proportions screened, eligible, approached and randomised) and qualitative data (79 audio-recorded recruitment discussions, 19 interviews with healthcare professionals, 11 interviews with patients, 2 investigator workshops, and observations of study meetings, all subject to thematic, content or conversation analysis). We triangulated quantitative and qualitative data to identify barriers and facilitators to recruitment and how and why these arose. Working with the chief investigators and trial management group, we addressed barriers and facilitators with corresponding actions to improve informed consent and recruitment.FindingsBarriers identified included how usual care practices made equipoise challenging, multi-disciplinary teams sometimes overrode recruiter equipoise and logistical issues rendered symptomatic cavernoma diagnosis and assessment for stereotactic radiosurgery challenging. Facilitators identified included the preparedness of some neurosurgeons’ to offer surgery to people otherwise offered medical management alone, multi-disciplinary team equipoise, and effective information provision presenting participation as a solution to equipoise regarding management. Actions, before and during recruitment, to improve inclusivity of site screening, approach and effectiveness of information provision resulted in 72 participants recruited following a 5-month extension, exceeding the target of 60 participants.InterpretationQuinteT Recruitment Intervention insights revealed barriers and facilitators, enabling identification of remedial actions. Recruitment to a definitive trial would benefit from further training/support to encourage clinicians to be comfortable approaching patients to whom medical management is usually offered, and broadening the pool of neurosurgeons and multi-disciplinary team members prepared to offer surgery, particularly stereotactic radiosurgery