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To assess the relationship of E2 gene disruption with viral gene expression and clinical outcome in human papillomavirus (HPV) positive head and neck squamous cell carcinoma, we evaluated 31 oropharyngeal and 17 non-oropharyngeal HPV16 positive carcinomas using two PCR-based methods to test for disruption of E2, followed by Sanger sequencing. Expression of HPV16 E6, E7 and E2 transcripts, along with cellular ARF and INK4A, were also assessed by RT-qPCR. Associations between E2 disruption, E2/E6/E7 expression, and clinical outcome were evaluated by Kaplan-Meier analysis for loco-regional recurrence and disease-specific survival. The majority (n = 21, 68%) of HPV16 positive oropharyngeal carcinomas had an intact E2 gene, whereas the majority of HPV16 positive non-oropharyngeal carcinomas (n = 10, 59%) had a disrupted E2 gene. Three of the oropharyngeal tumors and two of the non-oropharyngeal tumors had deletions within E2. Detection of an intact E2 gene was associated with a higher DNA viral load and increased E2/E6/E7, ARF and INK4A expression in oropharyngeal tumors. Oropharyngeal carcinomas with an intact E2 had a lower risk of loco-regional recurrence (log-rank p = 0.04) and improved disease-specific survival (p = 0.03) compared to tumors with disrupted E2. In addition, high E7 expression was associated with lower risk of loco-regional recurrence (p = 0.004) as was high E6 expression (p = 0.006). In summary, an intact E2 gene is more common in HPV16 positive oropharyngeal than non-oropharyngeal carcinomas; the presence of an intact E2 gene is associated with higher HPV viral load, higher viral oncogene expression, and improved clinical outcome compared to patients with a disrupted E2 gene in oropharyngeal cancer.

\"What would finance look like without Wall Street? Or the workplace with responsibility shared by the entire workforce? From a campaign to limit work hours, to a program for full employment, to proposals for a new feminism, [the young authors of collective manifesto have] the courage to think of alternatives that are both utopian and possible\"--Amazon.com.

The current interest in epigenetic priming is underpinned by the belief that remodelling of the epigenetic landscape will sensitise tumours to subsequent therapy. In this pre-clinical study, paediatric AML cells expanded in culture and primary AML xenografts were treated with decitabine, a DNA demethylating agent, and cytarabine, a frontline cytotoxic agent used in the treatment of AML, either alone or in combination. Sequential treatment with decitabine and cytarabine was found to be more effective in reducing tumour burden than treatment with cytarabine alone suggesting that the sequential delivery of these agents may a have real clinical advantage in the treatment of paediatric AML. However we found no evidence to suggest that this outcome was dependent on priming with a hypomethylating agent, as the benefits observed were independent of the order in which these drugs were administered.

Children in custodial settings are a vulnerable group. Prior to the COVID-19 pandemic there were concerns about the safety of children in these settings. COVID-19 has had an impact on everyone but given the vulnerability of children in custody, there were concerns about the impact of COVID-19 restrictions. All custody settings for children are independently inspected and this research aimed to analyse data from inspection reports. Twenty-six inspection reports undertaken between March 2020 and October 2021 were analysed to understand the impact of COVID-19 on delivery of usual care/regime. Data showed that across all site's children spent considerable amounts of time isolated and in some cases, this was deemed to amount to solitary confinement. There was evidence of some positive experiences, in the smaller sites, around COVID-19 slowing the pace of life allowing staff and children could foster relationships. However, in the larger sites, isolation was extreme and COVID-19 policies such as 'bubbles' appear to have created unintended consequences as sites have moved into recovery, leading to increased violence and stress. COVID-19 directly impacted staffing levels. This and the COVID-19 policies to reduce mixing also had an impact on how children's behaviour, welfare and safeguarding was managed. In some larger sites, being COVID-19 secure was prioritised over the needs of the children. This research highlights the importance of multi-site longitudinal research to understand how children, staff and institution's function. The experiences of children in custody during COVID-19 differed by site type. The research suggests that the larger sites are struggling to keep children safe and there should be a shift towards smaller, more therapeutic environments. More research is needed to understand the longer-term unintended consequences of COVID-19 policy in custody, for these vulnerable children.

Abstract Context Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by endocrine and neuropsychiatric problems including hyperphagia, anxiousness, and distress. Intranasal carbetocin, an oxytocin analog, was investigated as a selective oxytocin replacement therapy. Objective To evaluate safety and efficacy of intranasal carbetocin in PWS. Design Randomized, double-blind, placebo-controlled phase 3 trial with long-term follow-up. Setting Twenty-four ambulatory clinics at academic medical centers. Participants A total of 130 participants with PWS aged 7 to 18 years. Interventions Participants were randomized to 9.6 mg/dose carbetocin, 3.2 mg/dose carbetocin, or placebo 3 times daily during an 8-week placebo-controlled period (PCP). During a subsequent 56-week long-term follow-up period, placebo participants were randomly assigned to 9.6 mg or 3.2 mg carbetocin, with carbetocin participants continuing at their previous dose. Main outcome measures Primary endpoints assessed change in hyperphagia (Hyperphagia Questionnaire for Clinical Trials [HQ-CT]) and obsessive-compulsive symptoms (Children's Yale-Brown Obsessive-Compulsive Scale [CY-BOCS]) during the PCP for 9.6 mg vs placebo, and the first secondary endpoints assessed these same outcomes for 3.2 mg vs placebo. Additional secondary endpoints included assessments of anxiousness and distress behaviors (PWS Anxiousness and Distress Behaviors Questionnaire [PADQ]) and clinical global impression of change (CGI-C). Results Because of onset of the COVID-19 pandemic, enrollment was stopped prematurely. The primary endpoints showed numeric improvements in both HQ-CT and CY-BOCS which were not statistically significant; however, the 3.2-mg arm showed nominally significant improvements in HQ-CT, PADQ, and CGI-C scores vs placebo. Improvements were sustained in the long-term follow-up period. The most common adverse event during the PCP was mild to moderate flushing. Conclusions Carbetocin was well tolerated, and the 3.2-mg dose was associated with clinically meaningful improvements in hyperphagia and anxiousness and distress behaviors in participants with PWS. Clinical Trials Registration Number NCT03649477

'Engager' is an innovative 'through-the-gate' complex care intervention for male prison-leavers with common mental health problems. In parallel to the randomised-controlled trial of Engager (Trial registration number: ISRCTN11707331), a set of process evaluation analyses were undertaken. This paper reports on the depth multiple case study analysis part of the process evaluation, exploring how a sub-sample of prison-leavers engaged and responded to the intervention offer of one-to-one support during their re-integration into the community. To understand intervention delivery and what response it elicited in individuals, we used a realist-informed qualitative multiple 'case' studies approach. We scrutinised how intervention component delivery lead to outcomes by examining underlying causal pathways or 'mechanisms' that promoted or hindered progress towards personal outcomes. 'Cases' (n = 24) were prison-leavers from the intervention arm of the trial. We collected practitioner activity logs and conducted semi-structured interviews with prison-leavers and Engager/other service practitioners. We mapped data for each case against the intervention logic model and then used Bhaskar's (2016) 'DREIC' analytic process to categorise cases according to extent of intervention delivery, outcomes evidenced, and contributing factors behind engagement or disengagement and progress achieved. There were variations in the dose and session focus of the intervention delivery, and how different participants responded. Participants sustaining long-term engagement and sustained change reached a state of 'crises but coping'. We found evidence that several components of the intervention were key to achieving this: trusting relationships, therapeutic work delivered well and over time; and an in-depth shared understanding of needs, concerns, and goals between the practitioner and participants. Those who disengaged were in one of the following states: 'Crises and chaos', 'Resigned acceptance', 'Honeymoon' or 'Wilful withdrawal'. We demonstrate that the 'implementability' of an intervention can be explained by examining the delivery of core intervention components in relation to the responses elicited in the participants. Core delivery mechanisms often had to be 'triggered' numerous times to produce sustained change. The improvements achieved, sustained, and valued by participants were not always reflected in the quantitative measures recorded in the RCT. The compatibility between the practitioner, participant and setting were continually at risk of being undermined by implementation failure as well as changing external circumstances and participants' own weaknesses. ISRCTN11707331, Wales Research Ethics Committee, Registered 02-04-2016-Retrospectively registered https://doi.org/10.1186/ISRCTN11707331.

In this article, we analyze the emergence of a global security norm of the COVID-19 epidemic as a threat to international security. This crisis is one of the gravest crises that humanity has experienced since the end of World War II in terms of the number of people infected and died, but also in terms of the economic consequences. Here, we provide a framework for understanding the securitization of the COVID-19 epidemic as an international norm defined and promoted by the World Health Organization as a norm entrepreneur, and cascaded down to the level of member states. We identify the actors who developed the main strategic prescriptions of the security norm and the international mechanisms that promoted the cascading of its contents throughout the international system. We further develop the notion of primary and secondary norms, which explain the striking differences amongst industrialized states with regard to the contents, scope, and implementation timeline of the various measures aiming to curb the spread of the virus.

Vertebral hemangiomas are typically asymptomatic; however, they can also be a source of severe axial back pain. In this report, the authors describe the case of an unusually large sacral hemangioma that was effectively treated with staged cement augmentation. A 57-year-old man presented with chronic mid-sacral pain that was episodically severe. Magnetic resonance imaging revealed a massive lytic defect involving a majority of the body of S1 with features consistent with a hemangioma. It was theorized that the patient's pain could be attributed to the compromised structural integrity of the proximal sacrum with associated microfractures. Extensive conservative treatment failed to ameliorate the pain. A cement augmentation procedure was therefore recommended to stabilize the proximal sacrum. Due to concern about the potential for cement embolic complications, a staged bilateral approach was chosen. In the first procedure, 12 mL of bone cement was injected into the right proximal sacrum. The pain was partially improved by this injection. A 2-month interval was observed before the second cement injection in order to give time for pulmonary recovery from any potential microscopic emboli. In the second stage, 8 mL of bone cement was injected into the left proximal sacrum with excellent pain relief. There were no complications from either injection. At the 5-year follow-up, the patient reported no recurrence of mid-sacral pain. To the authors' knowledge, this is the first case reporting the effective treatment of a sacral hemangioma with staged cement injections. [Orthopedics. 20XX;XX(X):xx–xx.]

Little is known about factors that influence discharge decision-making for people admitted to medium-secure services from prison, particularly for those who are returned to prison following treatment. To explore the organisational influences on care pathways through medium-secure services for those admitted from prison. We recruited 24 clinicians via purposive and snowball sampling; 13 shared their experiences via a focus group, and 11 shared their experiences via individual semi-structured interviews. A thematic analysis was conducted, producing three overarching themes: maintenance of throughput and service provision, class of two systems, and desirable and undesirable patients. Data indicated external factors that direct and, at times, limit clinicians' pathway decisions, including commissioning criteria and legal status under the Mental Health Act 1983 and within the criminal courts system (i.e. whether on remand or sentenced). These factors also influence how clinicians view the role and function of medium-secure services within the wider forensic mental health system, and therefore the types of patients that are deemed 'appropriate' for continued treatment when making discretionary pathway decisions. There remains a deficit in adequate resources to meet the mental health needs of prisoners who are admitted to medium-secure services. To meet the clinical need of all admissions, criteria for prolonged treatment in medium-secure services needs to be reconsidered, and it is likely that provision for the medium-secure hospital estate will need to increase substantially if effective rehabilitation of those who transfer from prison is to take place.