Perioperative nursing: maintaining momentum and staying safe.

Perioperative practice underpins one of the key activities of many healthcare services but the work of perioperative nurses is little known. A better understanding of their work is important to enable articulation of their contribution to clinical practice. This study observed the practice of perioperative nurses and explored how they described their role. Using ethnographic observation and interview, eighty-five hours observation of eleven nurses were undertaken and eight nurses were interviewed. Thematic analysis was undertaken enabling themes to emerge with two being identified. The first, 'maintaining momentum', described the need to keep people and equipment moving. The second, ‘accounting for safety’, referred to the need to keep the patient safe during this dangerous period. Tension between these two phenomena was apparent. Perioperative nurses describe one of their key roles as maintaining the momentum of the patient’s journey through the operating theatre but having to balance this with the need to ensure the patient’s safety. A core component of the perioperative nurse’s work is thus management of the tension between these. This study illuminated how these nurses understand their practice

A 'synthetic-sickness' screen for senescence re-engagement targets in mutant cancer backgrounds.

Senescence is a universal barrier to immortalisation and tumorigenesis. As such, interest in the use of senescence-induction in a therapeutic context has been gaining momentum in the past few years; however, senescence and immortalisation remain underserved areas for drug discovery owing to a lack of robust senescence inducing agents and an incomplete understanding of the signalling events underlying this complex process. In order to address this issue we undertook a large-scale morphological siRNA screen for inducers of senescence phenotypes in the human melanoma cell line A375P. Following rescreen and validation in a second cancer cell line, HCT116 colorectal carcinoma, a panel of 16 of the most robust hits were selected for further validation based on significance and the potential to be targeted by drug-like molecules. Using secondary assays for detection of senescence biomarkers p21, 53BP1 and senescence associated beta-galactosidase (SAβGal) in a panel of HCT116 cell lines carrying cancer-relevant mutations, we show that partial senescence phenotypes can be induced to varying degrees in a context dependent manner, even in the absence of p21 or p53 expression. However, proliferation arrest varied among genetic backgrounds with predominantly toxic effects in p21 null cells, while cells lacking PI3K mutation failed to arrest. Furthermore, we show that the oncogene ECT2 induces partial senescence phenotypes in all mutant backgrounds tested, demonstrating a dependence on activating KRASG13D for growth suppression and a complete senescence response. These results suggest a potential mechanism to target mutant KRAS signalling through ECT2 in cancers that are reliant on activating KRAS mutations and remain refractory to current treatments

Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington\u27s Disease Patients-A Randomized Phase 2 Clinical Trial.

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington\u27s disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington\u27s Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

New Order: Political Change and the Protestant Orange Tradition in Northern Ireland

The 1998 Good Friday Agreement (GFA) led to a major realignment in unionist politics in Northern Ireland. The Ulster Unionist party (UUP), hitherto the dominant force within the Protestant British tradition, was usurped in electoral popularity by the Democratic Unionist party (DUP). In its post-GFA rise, the DUP garnered majority support from members of the Orange Order, the largest organisation in Protestant civil society. Drawing upon a recent membership survey of the Orange Order conducted by the authors, this article examines the demographic and attitudinal bases of support for unionist political parties among its members, and tests whether the locus of support for the DUP is evenly distributed, or instead biased towards particular age groups, social classes or Protestant denominations within the Order, as well as assessing whether attitudinal variations may be influential in determining party loyalties

Conflict resolution in asymmetric and symmetric situations: Northern Ireland as a case study

Conflicts between or within states can be characterized as symmetric or asymmetric by a number of objective criteria. Subjectively, however, there is often room for considerable ambiguity about the relative power of belligerents, with different perceptions associated with different political dynamics and outcomes. Here we suggest that creative use of this ambiguity can support a consensus that acknowledges that the belligerents have symmetric interests in the peace process, the peace settlement, and the rewards of peace. In the case of Northern Ireland, although the conflict there could be depicted as asymmetric, the peace process that led to the Belfast (Good Friday) Agreement only gained momentum when it began to draw on perceptions of symmetry between the factions. Crucial in this momentum towards settlement were the changing perceptions of those involved, particularly former combatants and their political representatives. Increased perceptions of symmetry allowed successive British and Irish governments to gain authority as legitimate mediators and guarantors. In turn, both republican and loyalist paramilitary organizations were able to promote the merits of a 'political' solution to their supporters. Finally, the development of a working political coalition among political representatives marked the transformation from asymmetric conflict to symmetric peac