p53 regulates diverse tissue-specific outcomes to endogenous DNA damage in mice.

DNA repair deficiency can lead to segmental phenotypes in humans and mice, in which certain tissues lose homeostasis while others remain seemingly unaffected. This may be due to different tissues facing varying levels of damage or having different reliance on specific DNA repair pathways. However, we find that the cellular response to DNA damage determines different tissue-specific outcomes. Here, we use a mouse model of the human XPF-ERCC1 progeroid syndrome (XFE) caused by loss of DNA repair. We find that p53, a central regulator of the cellular response to DNA damage, regulates tissue dysfunction in Ercc1-/- mice in different ways. We show that ablation of p53 rescues the loss of hematopoietic stem cells, and has no effect on kidney, germ cell or brain dysfunction, but exacerbates liver pathology and polyploidisation. Mechanistically, we find that p53 ablation led to the loss of cell-cycle regulation in the liver, with reduced p21 expression. Eventually, p16/Cdkn2a expression is induced, serving as a fail-safe brake to proliferation in the absence of the p53-p21 axis. Taken together, our data show that distinct and tissue-specific functions of p53, in response to DNA damage, play a crucial role in regulating tissue-specific phenotypes.

Autopsy of a failed trial part 2: Outcomes, challenges, and lessons learnt from the DAISIES trial.

OBJECTIVE: The relative merits of inpatient or day-treatment for adults with anorexia nervosa (AN) are unknown. The DAISIES trial aimed to establish the non-inferiority of a stepped-care day patient treatment (DPT) approach versus inpatient treatment as usual (IP-TAU) for improving body mass index (BMI) at 12 months in adults with AN. The trial was terminated due to poor recruitment. This paper presents outcomes and investigates the reasons behind the trial's failure. METHOD: Fifteen patients with AN (of 53 approached) participated and were followed-up to 6 or 12 months. Summary statistics were calculated due to low sample size, and qualitative data concerning treatment experiences were analysed using thematic analysis. RESULTS: At baseline, participants in both trial arms rated stepped-care DPT as more acceptable. At 12 months, participants' BMIs had increased in both trial arms. Qualitative analysis highlighted valued and challenging aspects of care across settings. Only 6/12 sites opened for recruitment. Among patients approached, the most common reason for declining participation was their treatment preference (n = 12/38). CONCLUSIONS: No conclusions can be drawn concerning the effectiveness of IP-TAU and stepped-care DPT, but the latter was perceived more positively. Patient-related, service-related and systemic factors (COVID-19) contributed to the trial's failure. Lessons learnt can inform future studies.

Autopsy of a failed trial part 1: A qualitative investigation of clinician's views on and experiences of the implementation of the DAISIES trial in UK-based intensive eating disorder services.

OBJECTIVE: The DAISIES trial, comparing inpatient and stepped-care day patient treatment for adults with severe anorexia nervosa was prematurely terminated in March 2022 due to poor recruitment. This qualitative study seeks to understand the difficulties faced during the trial by investigating stakeholders' views on and experiences of its implementation. METHOD: Semi-structured interview and focus group transcripts, and trial management and oversight group meeting minutes from May 2020-June 2022 were analysed using thematic analysis. Participants were 47 clinicians and co-investigators involved with the DAISIES trial. The Non-Adoption, Abandonment, Scale-up, Spread, and Sustainability (NASSS) framework was applied to the interpretive themes to classify barriers and facilitators to implementation. RESULTS: Five themes were identified: incompatible participation interests; changing standard practice; concerns around clinical management; systemic capacity and capability issues; and Covid-19 disrupting implementation. Applying the NASSS framework indicated the greatest implementation challenges to arise with the adopters (e.g. patients, clinicians), the organisational systems (e.g. service capacity), and the wider socio-political context (e.g. Covid-19 closing services). CONCLUSIONS: Our findings emphasise the top-down impact of systemic-level research implementation challenges. The impact of the Covid-19 pandemic accentuated pre-existing organisational barriers to trial implementation within intensive eating disorder services, further limiting the capacity for research.

A description of virtual skills workshops for supporters of loved ones with eating disorders: Indicators of benefit and acceptability, clinical reflections and consideration of neurodiversity.

OBJECTIVE: Providing information and support to those supporting a loved one with an eating disorder is a key part of evidence-based service provision. We report on how we took our workshops for supporters online during the Covid-19 Pandemic when country-side physical distancing restrictions meant we were unable to work face to face. METHODS: We outline the structure of an eight-session 2-h workshop series delivered fortnightly facilitated by a multidisciplinary team of clinicians, researchers and experts by experience. We use a repeated-measures design to understand the possible benefits of the workshops on supporter skills (n = 76). RESULTS: Measured using the Caregiver Skills Scale, we observed small-sized improvements in the overall skills (D = 0.43) of n = 17 supporters who provided data at the end of the intervention. Supporters gave largely positive feedback on the virtual format. They particularly liked the opportunity to interact with other supporters. As facilitators, we overcome our initial anxiety around workshop delivery using a new platform and reflected that having more time to cover key information and for skills practice over a period of 16 weeks offered opportunities to develop and reflect on new skill together as a group. We were also able to work with larger groups of supporters, as several barriers to access were removed. CONCLUSIONS: As the workshops reached a larger number of supporters than through face to face delivery and were of benefit to those who reported on their skills, we plan to continue offering workshops to supporters online in future.

Clinicians' perspectives on supporting individuals with severe anorexia nervosa in specialist eating disorder intensive treatment settings during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has significantly affected intensive treatment settings (i.e., inpatient [IP] and day patient [DP]) in specialist eating disorder services. However, the impact on clinicians working in these services is largely unknown. We therefore explored the perspectives of those supporting individuals with severe anorexia nervosa (AN) in intensive treatment settings during the pandemic. METHODS: Between May 2020 and June 2021, we interviewed clinicians (n = 21) who delivered IP and/or DP treatment to patients with severe AN in four specialist eating disorder services in the United Kingdom. Data relating to experiences during COVID-19 were analysed using reflexive thematic analysis. RESULTS: We identified six themes: Disruptions to Routine Treatment; Introduction of Virtual Treatment; Separation from Treatment, Others and the World; Impact on Recovery; Impact on Staff; and Pressure on Referral Pathways. COVID-19 posed significant challenges to IP and DP services: forcing closures, operating with restrictions and virtual treatment, and impacting delivery of essential treatment components, referral pathways, clinician wellbeing, risk management, and patient isolation and recovery trajectories. Opportunities arose, in particular in DP services offering virtual support. CONCLUSIONS: COVID-19 challenged the continuation of multidisciplinary treatment. The findings underline the necessity for medical, psychological, practical, and nutritional support, as well as carer involvement and fostering social connections to remain at the forefront of intensive treatment for severe AN. They also emphasise the uncertainty surrounding which intensive treatment may be best suited to which patient when, particularly within the context of virtual DP support.

The COVID-19 pandemic has significantly affected eating disorder inpatient and day patient treatment. However, the impact of the pandemic on clinicians working in these settings is largely unknown. We interviewed twenty-one clinicians working in specialist inpatient and day patient eating disorder services to explore their views on supporting people with severe anorexia nervosa during the pandemic. We analysed the transcripts using thematic analysis. We identified that COVID-19 posed significant challenges for intensive treatment settings, forcing the closure or merging of eating disorder services, the delivery of treatment under restrictions, and the introduction of virtual treatment. These changes challenged the delivery of multidisciplinary treatment for people with severe anorexia nervosa and impacted referral pathways, clinicians' wellbeing, risk management, and patients' isolation and recovery trajectories. We also identified some opportunities as a result of the pandemic, in particular in day patient services offering virtual support. These opportunities included more accessible treatment for patients and their families, more individualised treatment, and the chance for treatment innovation and creativity.

Clinicians' perspectives on supporting individuals with severe anorexia nervosa in specialist eating disorder intensive treatment settings.

BACKGROUND: Admissions to intensive treatment (i.e., inpatient [IP] and/or day patient [DP]) for individuals with severe anorexia nervosa (AN) are common. Growing literature indicates potential risks and benefits of each intensive treatment approach; however, existing research has focused on patient and carer perspectives of these treatments. Also, there is scant empirical evidence available for guiding the parameters of intensive treatments for AN. We therefore explored clinicians' perspectives and experience of supporting adults with severe AN in intensive settings. METHODS: We conducted twenty one semi-structured interviews with clinicians who deliver intensive treatments (i.e., IP and/or DP) for individuals with severe AN across four specialist Eating Disorder Services in the United Kingdom between May 2020 and June 2021. We asked clinicians about their views and experiences of supporting individuals with severe AN in intensive treatment settings and the challenges and opportunities associated with IP and DP treatment. Data were analysed using reflexive thematic analysis supported by NVivo software. RESULTS: Five broad and interrelated themes were identified: (1) Intensive Support; (2) The Severity of Patients' Illnesses; (3) Hope and Recovery; (4) Which Treatment When; (5) Limited Resources; and (6) Carer Burden. We identified various similarities between the two intensive treatment approaches, including the value of intensive and multidisciplinary support and carer involvement, and the challenge of managing complex and unique needs in resource-limited intensive settings. We also found differences in the relationship of treatment to patients' home environments, the necessity of patient motivation, and the management of risk. CONCLUSIONS: Both intensive treatment settings are valued by clinicians; however, there are unique challenges and opportunities for supporting individuals with severe AN within each. Our findings suggest DP treatment may be used as an alternative to IP treatment for individuals with severe AN. However, clear questions remain over which intensive treatment setting is best suited to which patient when and should be the focus of future research.

Some people with anorexia nervosa will need intensive treatment (e.g., inpatient and day patient treatment) during the course of their illness. We interviewed twenty-one clinicians working in Specialist Eating Disorder Services to explore their views on supporting people with severe anorexia nervosa in inpatient and day patient services and about the perceived advantages and disadvantages of these. We analysed the transcripts of these interviews using thematic analysis. We identified similarities between the two intensive treatment approaches. These included the value of intensive and multidisciplinary support, the importance of carer involvement, and the challenge of managing patient's complex and unique needs in services with limited resources. We also found differences between inpatient and day patient treatment. These included how treatment relates to patients' home environments, the importance of patient motivation, and managing risk. Day patient treatment may be an alternative to inpatient treatment for people with severe anorexia nervosa. Future research should investigate which intensive treatment setting is best suited to which patient and when.

Identity Development and Social-Emotional Disorders During Adolescence and Emerging Adulthood: A Systematic Review and Meta-Analysis.

Depression, anxiety and eating disorders ("social-emotional disorders") are common during adolescence/emerging adulthood, periods of intense identity development. Despite this, there are few reviews of existing research on the relationship between symptoms of these disorders and ongoing identity development. This study systematically reviewed, narratively synthesized and meta-analyzed longitudinal investigations of the relationship between identity synthesis/confusion and depression, anxiety and eating disorders symptoms during adolescence/emerging adulthood. Three databases (PsycInfo, Medline, Embase) were searched. Study quality was systematically appraised, findings were qualitatively synthesized and (where possible) meta-analyzed. 20 studies (55% "fair" quality, 45% "poor" quality) were identified, including 13,787 participants (54.2% female, mean age = 14.48 years, range 10-29 years). The narrative synthesis found evidence of bidirectional relationships between identity synthesis/confusion and depression, anxiety and eating disorder symptoms. Meta-analyses and meta-regressions of a sub-sample of studies (N = 9) indicated no significant associations between identity synthesis or confusion and anxiety or depression symptoms. More high-quality research is needed before firm conclusions can be drawn.

Environmentally sustainable emergency medicine.

Emergency clinicians worldwide are demonstrating increasing concern about the effect of climate change on the health of the populations they serve. The movement for sustainable healthcare is being driven by the need to address the climate emergency. Globally, healthcare contributes significantly to carbon emissions, and the healthcare sector has an important role to play in contributing to decarbonisation of the global economy. In this article, we consider the implications for emergency medicine of climate change, and suggest ways to improve environmental sustainability within emergency departments. We identify examples of sustainable clinical practice, as well as outlining research proposals to address the knowledge gap that currently exists in the area of provision of environmentally sustainable emergency care.

Facilitators and barriers to supporting young people with eating disorders during their transition to, and time at, university: An exploration of clinicians' perspectives.

BACKGROUND: Eating disorders (EDs) are common in student populations and present formidable challenges as to how best to treat and support these young people, especially at points of transition. Yet research exploring these challenges is lacking, particularly from the perspective of those providing treatment and support. METHODS: A qualitative design was used to explore clinicians' perspectives of supporting students with EDs. Twelve clinicians from a large ED service in the United Kingdom participated in one-to-one semi-structured interviews. Data were analysed using thematic analysis. RESULTS: Facilitators and barriers to supporting students with EDs fell into four overarching themes: Health System, University, Patient and Carer Factors. Reported facilitators were; ED service awareness, flexibility and resources, university as a motivator, and carer support. Reported barriers were; poor links and communication between institutions, the primary care system, poor university provision for and awareness of EDs, young people's denial and ambivalence, inconsistent implementation of guidelines, and carer anxiety. CONCLUSIONS: The findings revealed challenges unique to the university transition, including the need for more collaborative working between healthcare and education institutions, improved training of non-specialised ED professionals, and the benefits of a flexible, adapted ED treatment approach specifically tailored to the unique needs of students with EDs.

Salmonella enterica colonization and fitness in pre-harvest cantaloupe production.

Cantaloupes have emerged as significant vehicles of widespread foodborne illness outbreaks caused by bacterial pathogens, including Salmonella. The purpose of this study was to investigate the efficiency of Salmonella colonization and internalization in cantaloupes by relevant routes of contamination. Cantaloupe plants (Cucumis melo 'reticulatus') from two cultivars 'Athena' (Eastern) and 'Primo' (Western) were grown from commercial seed. Plants were maintained in the NCSU BSL-3P phytotron greenhouse. Salmonella enterica (a cocktail of cantaloupe-associated outbreak serovars Javiana, Newport, Panama, Poona and Typhimurium) contamination was introduced via blossoms or soil at ca. 4.4 log10 CFU/blossom or 8.4 log10 CFU/root zone, respectively. Cantaloupes were analyzed for Salmonella by enrichment in accordance with modified FDA-BAM methods. Five randomly chosen colonies from each Salmonella-positive sample were typed using the Agilent 2100 bioanalyzer following multiplex PCR. Data were analyzed for prevalence of contamination and serovar predominance in fruit, stems and soil. Of the total cantaloupe fruit harvested from Salmonella-inoculated blossoms (n = 63), 89% (56/63) were externally contaminated and 73% (46/63) had Salmonella internalized into the fruit. Serovar Panama was the most commonly isolated from the surface of fruit while S. Panama and S. Poona were the most prevalent inside the fruit. When soil was inoculated with Salmonella at one day post-transplant, 13% (8/60) of the plants were shown to translocate the organism to the lower stem (ca. 4 cm) by 7 days post-inoculation (dpi). We observed Salmonella persistence in the soil up to 60 dpi with S. Newport being the predominant serovar at 10 and 20 dpi. These data demonstrate that contaminated soil and blossoms can lead to Salmonella internalization into the plant or fruit at a relatively high frequency.

Virtual visiting and other technological adaptations for critical care.

Social distancing measures introduced in response to the COVID-19 pandemic resulted in an almost complete cessation of family bedside interaction, with negative effects on patients, families and staff. Here we report on measures introduced in response to this situation at the critical care unit in one hospital involving the use of videoconferencing technology. The solutions used also had the potential to be extended to clinical use, for example when seeking advice for colleagues, and to the provision of training.

Colonization and Internalization of Salmonella enterica and Its Prevalence in Cucumber Plants.

Consumption of cucumbers (Cucumis sativus var. sativus) has been linked to several foodborne outbreaks involving Salmonella enterica. The purpose of this work was to investigate the efficiency of colonization and internalization of S. enterica into cucumber plants by various routes of contamination. Produce-associated outbreak strains of Salmonella (a cocktail of serovars Javiana, Montevideo, Newport, Poona, and Typhimurium) were introduced to three cultivars of cucumber plants (two slicing cultivars and one pickling) via blossoms (ca. 6.4 log10 CFU/blossom, 4.5 log10 CFU/blossom, or 2.5 log10 CFU/blossom) or soil (ca. 8.3 log10 CFU/root zone) and were analyzed for prevalence of Salmonella contamination (internal and external) and serovar predominance in fruit and stems. Of the total slicing fruit harvested from Salmonella-inoculated blossoms (ca. 6.4, 4.5, or 2.5 log10 CFU/blossom), 83.9% (47/56), 81.4% (48/59) or 71.2% (84/118) were found colonized and 67.9% (38/56), 35.6% (21/59) or 22.0% (26/118) had Salmonella internalized into the fruit, respectively. S. Poona was the most prevalent serovar isolated on or in cucumber fruits at all inoculation levels. When soil was inoculated at 1 day post-transplant (dpt), 8% (10/120) of the plants were shown to translocate Salmonella to the lower stem 7 days post-inoculation (dpi). Results identified blossoms as an important route by which Salmonella internalized at a high percentage into cucumbers, and S. Poona, the same strain isolated from the 2015 outbreak of cucumbers imported from Mexico, was shown to be well-adapted to the blossom niche.

Raising the issue of DNAR orders in vascular surgery patients.

The Tracey Report has recently raised the status of Do Not Attempt Cardio Pulmonary Resuscitation (DNACPR) orders in the hospital setting.[1] Guidelines are in place both nationally and locally to provide advice to clinicians on when to discuss DNACPR, and the approach to be taken. There was concern that on a busy regional vascular surgery unit, discussion of resuscitation status was not regular practice. Consequently, some patients were at risk of being inappropriately resuscitated, particularly out of hours. The North Bristol Somerset and Gloucester DNAR decision tree[2] was the tool used to decide whether a patient should have a documented discussion and/or a DNACPR form completed. We correlated the outcome of the decision tree with the presence of a DNACPR form or documented resuscitation discussion. Baseline measurements from all vascular inpatients on the vascular surgery unit demonstrated that only 27% had a DNACPR form or documented discussion in concordance with the DNACPR Decision Tree outcome. The aim of this project was to increase the proportion of patients with concordance of the DNACPR decision tree outcome with documented discussion or DNACPR form. The following three simple interventions raised concordance from 27% to 64% of patients on the vascular surgery unit. 1. Including resuscitation status of each patient as a column in the doctors daily handover. 2. Posters in staff only areas to highlight the meaning of DNACPR and raise awareness of the DNACPR decision tree. 3. Educational meeting surrounding DNACPR with the vascular surgery consultants, led by a care of the elderly consultant . This project has highlighted how raising awareness around DNACPR increases discussion amongst the clinical team surrounding resuscitation status of a patient. Consequently, this enables discussion to be had with patient and their family.

Biocatalytic amide condensation and gelation controlled by light.

We report on a supramolecular self-assembly system that displays coupled light switching, biocatalytic condensation/hydrolysis and gelation. The equilibrium state of this system can be regulated by light, favouring in situ formation, by protease catalysed peptide synthesis, of self-assembling trans- in ambient light; however, irradiation with UV light gives rise to the cis-isomer, which readily hydrolyzes to its amino acid derivatives (cis- + ) with consequent gel dissolution.

Isolation of microplastics in biota-rich seawater samples and marine organisms.

Microplastic litter is a pervasive pollutant present in aquatic systems across the globe. A range of marine organisms have the capacity to ingest microplastics, resulting in adverse health effects. Developing methods to accurately quantify microplastics in productive marine waters, and those internalized by marine organisms, is of growing importance. Here we investigate the efficacy of using acid, alkaline and enzymatic digestion techniques in mineralizing biological material from marine surface trawls to reveal any microplastics present. Our optimized enzymatic protocol can digest >97% (by weight) of the material present in plankton-rich seawater samples without destroying any microplastic debris present. In applying the method to replicate marine samples from the western English Channel, we identified 0.27 microplastics m(-3). The protocol was further used to extract microplastics ingested by marine zooplankton under laboratory conditions. Our findings illustrate that enzymatic digestion can aid the detection of microplastic debris within seawater samples and marine biota.