Long-term safety and efficacy of Oleogel-S10 (birch triterpenes) in epidermolysis bullosa wounds: 24-month open-label data from the EASE study

Objectives: The 90-day double-blind phase (DBP) of the Phase 3 EASE study demonstrated accelerated wound healing for Oleogel-S10 (birch triterpenes) versus control gel in epidermolysis bullosa (EB). Here, we report safety and total wound burden results from the 24-month open-label phase (OLP) in which all patients received treatment with Oleogel-S10. Method(s): Total wound burden was assessed using EB Disease Activity and Scarring Index (EBDASI) and Body Surface Area Percentage (BSAP). Data are reported without visit windows to reflect a realworld situation more accurately, particularly considering the COVID- 19 pandemic. Result(s): The patient population was made up of dystrophic EB (n = 178, 86.8%) and junctional EB (n = 25, 12.2%);71.7% (n = 147) of patients were aged <18 years. 141 patients (68.8%) completed the OLP. The mean (SD) treatment duration for all patients was 584.7 (246.1) days. Adverse events were reported in 77.1% of all patients in the OLP versus 81.7% of those receiving Oleogel-S10 in the DBP. Mean BSAP for patients treated with Oleogel-S10 in the DBP reduced from 12.1% at study entry to 6.1% with 27 months of treatment. Similarly, the mean EBDASI skin activity score in the Oleogel-S10 group improved from 19.6 to 15.1 after 27 months. In addition, reductions in both BSAP and EBDASI from OLP baseline were observed in patients who transitioned from control gel to Oleogel-S10 in the OLP. Discussion(s): These data support a reassuring long-term safety profile of Oleogel-S10. Furthermore, the reduction in wound burden previously reported with 15 months of Oleogel-S10 treatment is maintained to the end of OLP. This is encouraging given the nature of this chronic genetic disorder in which there is regular cycling of patients' fragile wounds.

A Comprehensive Model to Support a Resilient Workforce

Historically, low resiliency has been an issue for nursing when considering work and societal-related stressors. COVID-19 has exacerbated the need for supporting policies, structural change, and resilient practices across health care. A new model was developed that guides leaders in considering structural changes to support a more resilient workforce. This model features 5 tiers—transformational leadership;policy change and physical space adaptation;compensation and time;representation;and individual and team self-care practices. This model is adaptable to the cultural needs of a hospital or health system, while also offering a structure for evaluation of resiliency interventions. © 2023 Elsevier Inc.

'It's not a big deal': customer misbehaviour and social washing in hospitality

Purpose This study aims to examine customer misbehaviour in the hospitality sector during the COVID-19 pandemic. Design/methodology/approach The study draws on a cross-sectional survey of employees in the Scottish hospitality sector highlighting customer misbehaviour as a key concern during the pandemic. Prevalent types of abuse and harassment experienced are outlined along with employee and management responses to incidents of misbehaviour. Findings Verbal abuse and sexual harassment from customers are the most prevalent types of misbehaviour either experienced or witnessed by respondents. Customer misbehaviour is commonly thought of as "part of the job" and therefore "not a big deal". Managers, largely, expect workers to tolerate abusive behaviours from customers and do not take reports of incidents seriously. Practical implications Transformational managers need to foster workplace well-being with a focus on physical and psychological safety. Recognition of the issue and greater support for victims are furthermore required at an industry level and on the policy front. Social implications The research points to an uncomfortable reality in the service economy that needs to be confronted by society. It has, therefore, important implications for key stakeholders in ensuring fair, dignified and safe hospitality workplaces. Originality/value Customer misbehaviour is reportedly worsening in times of COVID-19 as demonstrated by this study. Despite rhetoric that abuse and harassment are not tolerated, dismissive attitudes from managers - who expect workers to tolerate abusive behaviour - and employee silence about incidents lead the authors to argue that the failure to acknowledge and address this issue constitutes a form of "social washing" in hospitality.

Proteomic approaches define rocaglates as translation remodelers with multiple protein targets

Intro: Deregulated protein synthesis is a common trait across solid and hematologic malignancies and an attractive target for cancer therapy. Rocaglates compounds that inhibit eukaryotic initiation factor 4A1 (eIF4A1), the essential DEAD-box RNA helicase that resolves mRNA 5'UTR secondary structures during cap-dependent translation initiation. Rocaglates' unique mechanism of action causes sequence-selective mRNA binding by eIF4A1, clamping the inactive helicase onto the transcript. This suppresses translation globally and affects many oncogenic and pro-survival transcripts in particular. Zotatifin, the first-in class synthetic rocaglate, is currently in Phase I clinical trials for the treatment of solid tumors and as an antiviral against SARS-CoV2. Currently, eIF4A1 and DDX3 are the only reported targets of rocaglate-mediated RNA clamping. Employing unbiased proteomic approaches, we have discovered that rocaglates, thought to act as pure eIF4A/translation inhibitors, extensively remodel the translation machinery and translatome. Additionally, mass-spec interrogation for proteins interacting with specific RNA sequences reveals novel targets of rocaglate-mediated, sequence-specific RNA clamping. Methods: We conducted original mass-spectrometry analyses of translational reprogramming by rocaglates. TMT-pSILAC assessed acute changes in protein production, while MATRIX, which captures high-resolution profiles of the translation machinery, revealed translation factors that drive reprogramming in response to rocaglate exposure. We validated results biochemically, in cellulo, and in vivo using patient-derived xenograft (PDX) mouse models. To probe existing and novel rocaglate RNA-clamping targets, we developed unbiased “clampome” assays - in cellulo protein-RNA-pull downs followed by mass-spec analysis of proteins with increased binding to RNA in the presence of rocaglates. Results: We find rocaglates, including zotatifin, have effects far more complex than simple “translational inhibition” as currently defined. Indeed, translatome analysis by TMT-pSILAC revealed myriad up-regulated proteins that drive hitherto unrecognized cytotoxic mechanisms. The GEF-H1 guanine exchange factor, for example, drives anti-survival RHOA/JNK activation, suggesting novel candidate biomarkers of rocaglate clinical outcomes. Translation-machinery analysis by MATRIX identifed rocaglate-induced dependence on specific translation factors including eEF1ϵ1 that drive remodeling. Novel rocaglate RNA-binding targets revealed by clampome studies remain under detailed evaluation as mediators of drug activities. Discussion: Our original proteome-level interrogation revealed that the complete cellular response to these historical “translation inhibitors” is mediated by comprehensive translational landscape remodeling. Effects on a broader suite of RNA binding proteins than eIF4A1 alone we suggest mediate the potent antitumor activities of these unique compounds, elucidation of which permits development of novel precision approaches to targeted translational deregulation in cancer.

Age and chronotype associated with sleep timing changes during COVID-19-related lockdowns in the US

Introduction: Global lockdowns implemented to reduce spread of the Coronavirus Disease 2019 (COVID-19) have offered unique insight into how sleep patterns change when typical social obligations are significantly reduced. Here, we aimed to replicate findings of sleep timing delays and reduced social jetlag during lockdown using a large, regionally-diverse sample of participants from the United States (US). Further, we conducted exploratory analyses to determine if observed sleep changes were associated with age and self-reported chronotype. Methods: A sample of 691 US adults (age 18-89) completed the Ultrashort Munich Chronotype Questionnaire twice during the same assessment: once querying retrospective memory for sleep patterns in the 6-weeks prior to February 1, 2020 (Pre-Lockdown) and a second time for sleep patterns in the 6-weeks prior to ∼May 20th (Peak-Lockdown in the US). Participants also completed the abbreviated Morningness- Eveningness Questionnaire to assess chronotype. We compared sleep duration (SDur), sleep onset time (SO), sleep end time (SEnd), social jetlag (SJL;difference between work-day and free-day sleep midpoint) and social sleep restriction (SSR;difference between work-day and freeday sleep duration) Pre- to Peak-Lockdown. We conducted exploratory analyses to determine whether Pre- to Peak-Lockdown changes in these sleep metrics were associated with age or chronotype. Main analyses were preregistered with Open Science Framework (https://osf.io/4a3fx). Results: During the Peak-Lockdown period, participants, on average, reported significantly later SO and SEnd times and significantly reduced SJL and SSR compared with the Pre-Lockdown period. Change in SJL and SSR Pre- to Peak-Lockdown was significantly positively associated with age and chronotype such that SJL and SSR decreased more during lockdown in younger participants and those with an evening chronotype. Conclusion: Our results support lockdown-associated sleep timing delays and reduced SJL and SSR. Younger age and evening chronotype were associated with greater reductions in SJL and SSR during lockdown. These findings suggest that individuals, particularly young individuals and those with an evening chronotype, experience greatest desynchrony between intrinsic and social sleep timing when conforming to typical pre-pandemic social schedules.

A survey of ethical views and experiences during a pandemic: A critical care perspective

INTRODUCTION: As the COVID19 pandemic persists across the globe, health care professionals and institutions continue to face ethical challenges and often are uncertain about their responses to those challenges. While some of these ethical issues have been experienced before, e.g., ventilator allocation during H1N1, refusing CPR during Ebola outbreak, similar and other unique ethical issues have developed during the COVID19 pandemic. To better understand individual and institutional perspectives, we designed and distributed a survey to capture those working health care and others perceive issues surrounding institutional responses to COVID-19. Given the nature of COVID-19, and our interim analysis, it is likely that many of these issues will arise in the critical care setting. METHODS: We sent a survey out weekly to two large bioethics listservs starting in April 2020. Members of the listserv were asked to complete the survey each week and to forward the survey to interdisciplinary colleagues who may not be members of these listservs. At this point in our analysis we have completed basic descriptive statistics, including X-tabs and Fischer's exact test. RESULTS: Using only 6 months of data for participants who complete the survey for the first time, we received 446 respondents since April 2020. The average age of participants was 47.6 and over 71% of participants identified as female. 95% of the respondents work primarily in the US with 62% working in critical care setting at least part-time. Overall, when asked about the extent to which it is ethically reasonable to limit CPR (during crisis standards of care) for patients with COVID-19, for the sake of conserving scarce resource, nearly 50% of respondents choose the response, ?Can be reasonable, but generally one should not limit CPR.? Relatedly, 64% of respondents believed it was always reasonable to require providers to don all PPE before initiating CPR on a patient with COVID. This is especially relevant in light of the finding that over 78% of participants replied that their institution does not or that they were unsure whether or not their institution has a policy that limits CPR for COVID19 patients when there is insufficient PPE. CONCLUSIONS: The survey identified the need for broadly collaborative efforts to resolve ethical issues during COVID-19.