Cardiac lipotoxicity and fibrosis underlie impaired contractility in a mouse model of metabolic dysfunction-associated steatotic liver disease.

The leading cause of death among patients with metabolic dysfunction-associated steatotic liver disease (MASLD) is cardiovascular disease. A significant percentage of MASLD patients develop heart failure driven by functional and structural alterations in the heart. Previously, we observed cardiac dysfunction in hepatocyte-specific peroxisome proliferator-activated receptor alpha knockout (Ppara HepKO), a mouse model that exhibits hepatic steatosis independent of obesity and insulin resistance. The goal of the present study was to determine mechanisms that underlie hepatic steatosis-induced cardiac dysfunction in Ppara HepKO mice. Experiments were performed in 30-week-old Ppara HepKO and littermate control mice fed regular chow. We observed decreased cardiomyocyte contractility (0.17 ± 0.02 vs. 0.24 ± 0.02 µm, p < 0.05), increased cardiac triglyceride content (0.96 ± 0.13 vs. 0.68 ± 0.06 mM, p < 0.05), collagen type 1 (4.65 ± 0.25 vs. 0.31 ± 0.01 AU, p < 0.001), and collagen type 3 deposition (1.32 ± 0.46 vs. 0.05 ± 0.03 AU, p < 0.05). These changes were associated with increased apoptosis as indicated by terminal deoxynucleotidyl transferase dUTP nick end labeling staining (30.9 ± 4.7 vs. 13.1 ± 0.8%, p < 0.006) and western blots showing increased cleaved caspase-3 (0.27 ± 0.006 vs. 0.08 ± 0.01 AU, p < 0.003) and pro-caspase-3 (5.4 ± 1.5 vs. 0.5 ± 0.3 AU, p < 0.02), B-cell lymphoma protein 2-associated X (0.68 ± 0.07 vs. 0.04 ± 0.04 AU, p < 0.001), and reduced B-cell lymphoma protein 2 (0.29 ± 0.01 vs. 1.47 ± 0.54 AU, p < 0.05). We further observed elevated circulating natriuretic peptides and exercise intolerance in Ppara HepKO mice when compared to controls. Our data demonstrated that lipotoxicity, and fibrosis underlie cardiac dysfunction in MASLD.

Effectiveness of oseltamivir in reducing COVID-19-related in-hospital deaths: A pharmacoepidemiological study.

BACKGROUND: Oseltamivir is a low-cost antiviral agent that could support or complement treatment of COVID-19. This study assessed whether oseltamivir is effective in reducing COVID-19-related mortality. METHODS: This retrospective cohort study evaluated real-world data from a nationwide database of hospitalisation due to severe acute respiratory syndrome in Brazil. Propensity score matching was used to mimic a randomised controlled trial with 'oseltamivir' and 'no antivirals at all' as the intervention and control groups, respectively. RESULTS: A total of 21 480 and 268 486 patients admitted between February 2020 and January 2023 were included in the intervention and control groups, respectively. After matching, the odds ratio (OR) for death was 0.901 (95% confidence interval [CI] 0.873-0.930). The OR (95% CI) for death in patients who were admitted to the ICU, and on non-invasive or invasive ventilation was 0.868 (0.821-0.917), 0.935 (0.893-0.980), and 0.883 (0.814-0.958), respectively. CONCLUSIONS: Overall, the use of oseltamivir was associated with an attributable risk reduction of 2.50% (95% CI 1.77-3.29). Similar results were observed in patients who were admitted to the ICU, and on non-invasive or invasive ventilation. Oseltamivir is a low-cost potential antiviral treatment for COVID-19.

Digitally augmented, parent-led CBT versus treatment as usual for child anxiety problems in child mental health services in England and Northern Ireland: a pragmatic, non-inferiority, clinical effectiveness and cost-effectiveness randomised controlled trial.

BACKGROUND: Anxiety problems are common in children, yet few affected children access evidence-based treatment. Digitally augmented psychological therapies bring potential to increase availability of effective help for children with mental health problems. This study aimed to establish whether therapist-supported, digitally augmented, parent-led cognitive behavioural therapy (CBT) could increase the efficiency of treatment without compromising clinical effectiveness and acceptability. METHODS: We conducted a pragmatic, unblinded, two-arm, multisite, randomised controlled non-inferiority trial to evaluate the clinical effectiveness and cost-effectiveness of therapist-supported, parent-led CBT using the Online Support and Intervention (OSI) for child anxiety platform compared with treatment as usual for child (aged 5-12 years) anxiety problems in 34 Child and Adolescent Mental Health Services in England and Northern Ireland. We examined acceptability of OSI plus therapist support via qualitative interviews. Participants were randomly assigned (1:1) to OSI plus therapist support or treatment as usual, minimised by child age, gender, service type, and baseline child anxiety interference. Outcomes were assessed at week 14 and week 26 after randomisation. The primary clinical outcome was parent-reported interference caused by child anxiety at week 26 assessment, using the Child Anxiety Impact Scale-parent report (CAIS-P). The primary measure of health economic effect was quality-adjusted life-years (QALYs). Outcome analyses were conducted blind in the intention-to-treat (ITT) population with a standardised non-inferiority margin of 0·33 for clinical analyses. The trial was registered with ISRCTN, 12890382. FINDINGS: Between Dec 5, 2020, and Aug 3, 2022, 706 families (706 children and their parents or carers) were referred to the study information. 444 families were enrolled. Parents reported 255 (58%) child participants' gender to be female, 184 (41%) male, three (<1%) other, and one (<1%) preferred not to report their child's gender. 400 (90%) children were White and the mean age was 9·20 years (SD 1·79). 85% of families for whom clinicians provided information in the treatment as usual group received CBT. OSI plus therapist support was non-inferior for parent-reported anxiety interference on the CAIS-P (SMD 0·01, 95% CI -0·15 to 0·17; p<0·0001) and all secondary outcomes. The mean difference in QALYs across trial arms approximated to zero, and OSI plus therapist support was associated with lower costs than treatment as usual. OSI plus therapist support was likely to be cost effective under certain scenarios, but uncertainty was high. OSI plus therapist support acceptability was good. No serious adverse events were reported. INTERPRETATION: Digitally augmented intervention brought promising savings without compromising outcomes and as such presents a valuable tool for increasing access to psychological therapies and meeting the demand for treatment of child anxiety problems. FUNDING: Department for Health and Social Care and United Kingdom Research and Innovation Research Grant, National Institute for Health and Care (NIHR) Research Policy Research Programme, Oxford and Thames Valley NIHR Applied Research Collaboration, Oxford Health NIHR Biomedical Research Centre.

Statistical analysis plan for a cluster randomised controlled trial to compare screening, feedback and intervention for child anxiety problems to usual school practice: identifying Child Anxiety Through Schools-identification to intervention (iCATS-i2i).

BACKGROUND: The Identifying Child Anxiety Through Schools-identification to intervention (iCATS-i2i) trial is being conducted to establish whether 'screening and intervention', consisting of usual school practice plus a pathway comprising screening, feedback and a brief parent-led online intervention (OSI: Online Support and Intervention for child anxiety), bring clinical and health economic benefits compared to usual school practice and assessment only - 'usual school practice', for children aged 8-9 years in the following: (1) the 'target population', who initially screen positive for anxiety problems according to a two-item parent-report child anxiety questionnaire - iCATS-2, and (2) the 'total population', comprising all children in participating classes. This article describes the detailed statistical analysis plan for the trial. METHODS AND DESIGN: iCATS-i2i is a definitive, superiority, pragmatic, school-based cluster randomised controlled trial (with internal pilot), with two parallel groups. Schools are randomised 1:1 to receive either screening and intervention or usual school practice. This article describes the following: trial objectives and outcomes; statistical analysis principles, including detailed estimand information necessary for aligning trial objectives, conduct, analyses and interpretation when there are different analysis populations and outcome measures to be considered; and planned main analyses, sensitivity and additional analyses. TRIAL REGISTRATION: ClinicalTrials.gov ISRCTN76119074. Registered on 4 January 2022.

Loss of hepatic PPARα in mice causes hypertension and cardiovascular disease.

The leading cause of death in patients with nonalcoholic fatty liver disease (NAFLD) is cardiovascular disease (CVD). However, the mechanisms are unknown. Mice deficient in hepatocyte proliferator-activated receptor-α (PPARα) (PparaHepKO) exhibit hepatic steatosis on a regular chow diet, making them prone to manifesting NAFLD. We hypothesized that the PparaHepKO mice might be predisposed to poorer cardiovascular phenotypes due to increased liver fat content. Therefore, we used PparaHepKO and littermate control mice fed a regular chow diet to avoid complications with a high-fat diet, such as insulin resistance and increased adiposity. After 30 wk on a standard diet, male PparaHepKO mice exhibited elevated hepatic fat content compared with littermates as measured by Echo MRI (11.95 ± 1.4 vs. 3.74 ± 1.4%, P < 0.05), hepatic triglycerides (1.4 ± 0.10 vs. 0.3 ± 0.01 mM, P < 0.05), and Oil Red O staining, despite body weight, fasting blood glucose, and insulin levels being the same as controls. The PparaHepKO mice also displayed elevated mean arterial blood pressure (121 ± 4 vs. 108 ± 2 mmHg, P < 0.05), impaired diastolic function, cardiac remodeling, and enhanced vascular stiffness. To determine mechanisms controlling the increase in stiffness in the aorta, we used state-of-the-art PamGene technology to measure kinase activity in this tissue. Our data suggest that the loss of hepatic PPARα induces alterations in the aortas that reduce the kinase activity of tropomyosin receptor kinases and p70S6K kinase, which might contribute to the pathogenesis of NAFLD-induced CVD. These data indicate that hepatic PPARα protects the cardiovascular system through some as-of-yet undefined mechanism.

The potential fire risk of emollients when dried on viscose bandages.

BACKGROUND: the potential fire risk of fabrics impregnated with emollients has been described within the health service, including ignition of bandages. The role of emollients in fire fatalities have also been included in coroner reports, as accelerating fires when present. AIMS: although changes in burning behaviour is known, no standard tests have been carried out on bandages which are often used in conjunction with emollients. METHOD: using a standard vertical flammability test, the flammability of viscose bandage was compared to when impregnated with nine dried on emollients with low to high and non-paraffin content. FINDINGS: the time to ignition was significantly reduced with an emollient present and the glowing time was longer. CONCLUSIONS: the same safety advice applies to viscose bandages as other fabrics with emollients; do not expose them to naked flames or high heat sources or allow emollients to build up on bandages.

A randomised controlled trial to compare clinical and cost-effectiveness of an online parent-led treatment for child anxiety problems with usual care in the context of COVID-19 delivered in Child and Adolescent Mental Health Services in the UK (Co-CAT): a study protocol for a randomised controlled trial.

BACKGROUND: In the context of COVID-19, NHS Child and Adolescent Mental Health Services (CAMHS) and other children's mental health services have faced major challenges in providing psychological treatments that (i) work when delivered remotely and (ii) can be delivered efficiently to manage increases in referrals as social distancing measures have been relaxed. Anxiety problems are a common reason for referral to CAMHS, children with pre-existing anxiety problems are particularly vulnerable in the context of COVID-19, and there were concerns about increases in childhood anxiety as schools reopened. The proposed research will evaluate the clinical and cost-effectiveness of a brief online parent-led cognitive behavioural treatment (CBT) delivered by the OSI (Online Support and Intervention for child anxiety) platform with remote support from a CAMHS therapist compared to 'COVID-19 treatment as usual' (C-TAU) in CAMHS and other children's mental health services throughout the COVID-19 pandemic. METHODS: We will conduct a two-arm, multi-site, randomised controlled non-inferiority trial to evaluate the clinical and cost-effectiveness of OSI with therapist support compared to CAMHS and other child mental health services 'COVID-19 treatment as usual' (C-TAU) during the COVID-19 outbreak and to explore parent and therapists' experiences. DISCUSSION: If non-inferiority is shown, the research will provide (1) a solution for efficient psychological treatment for child anxiety disorders while social distancing (for the COVID-19 context and future pandemics); (2) an efficient means of treatment delivery as 'normal service' resumes to enable CAMHS to cope with the anticipated increase in referrals; and (3) a demonstration of rapid, high-quality evaluation and application of online interventions within NHS CAMHS to drive forward much-needed further digital innovation and evaluation in CAMHS settings. The primary beneficiaries will be children with anxiety disorders and their families, NHS CAMHS teams, and commissioners who will access a potentially effective, cost-effective, and efficient treatment for child anxiety problems. TRIAL REGISTRATION: ISRCTN ISRCTN12890382 . Registered prospectively on 23 October 2020.

Identifying Child Anxiety Through Schools-identification to intervention (iCATS-i2i): protocol for a cluster randomised controlled trial to compare screening, feedback and intervention for child anxiety problems to usual school practice.

BACKGROUND: Systematically screening for child anxiety problems, and offering and delivering a brief, evidence-based intervention for children who are identified as likely to benefit would minimise common barriers that families experience in accessing treatment. We have developed a short parent-report child anxiety screening questionnaire, and procedures for administering screening questionnaires, sharing screening outcomes with families, and offering and delivering a brief parent-led online intervention (OSI: Online Support and Intervention for child anxiety) through schools. This trial aims to evaluate clinical and health economic outcomes for (1) children (aged 8-9) who screen positive for anxiety problems at baseline (target population) and (2) the wider population of all children in participating classes (total population) in schools randomly allocated to receive identification-to-intervention procedures and usual school practice ('screening and intervention'), compared to assessment and usual school practice only ('usual school practice').  METHODS: The trial design is a parallel-group, superiority cluster randomised controlled trial, with schools (clusters) randomised to 'screening and intervention' or 'usual school practice' arms in a 1:1 ratio stratified according to the level of deprivation within the school. We will recruit schools and participants in two phases (a pilot phase (Phase 1) and Phase 2), with progression criteria assessed prior to progressing to Phase 2. In total, the trial will recruit 80 primary/junior schools in England, and 398 children (199 per arm) who screen positive for anxiety problems at baseline (target population). In schools allocated to 'screening and intervention': (1) parents/carers will complete a brief parent-report child anxiety screening questionnaire (at baseline) and receive feedback on their child's screening outcomes (after randomisation), (2) classes will receive a lesson on managing fears and worries and staff will be provided with information about the intervention and (3) parents/carers of children who screen positive for anxiety problems (target population) will be offered OSI. OSI will also be available for any other parents/carers of children in participating classes (total population) who request it. We will collect child-, parent- and teacher-report measures for the target population and total population at baseline (before randomisation), 4 months, 12 months and 24 months post-randomisation. The primary outcome will be the proportion of children who screen positive for anxiety problems at baseline (target population) who screen negative for anxiety problems 12 months post-randomisation. DISCUSSION: This trial will establish if systematic screening for child anxiety problems, sharing screening outcomes with families and delivering a brief parent-led online intervention through schools is effective and cost-effective. TRIAL REGISTRATION: ISRCTN registry ISRCTN76119074. Prospectively registered on 4.1.2022.

Mitochondrial function and oxidative stress in white adipose tissue in a rat model of PCOS: effect of SGLT2 inhibition.

BACKGROUND: Polycystic ovary syndrome (PCOS), characterized by androgen excess and ovulatory dysfunction, is associated with a high prevalence of obesity and insulin resistance (IR) in women. We demonstrated that sodium-glucose cotransporter-2 inhibitor (SGLT2i) administration decreases fat mass without affecting IR in the PCOS model. In male models of IR, administration of SGLT2i decreases oxidative stress and improves mitochondrial function in white adipose tissue (WAT). Therefore, we hypothesized that SGLT2i reduces adiposity via improvement in mitochondrial function and oxidative stress in WAT in PCOS model. METHODS: Four-week-old female rats were treated with dihydrotestosterone for 90 days (PCOS model), and SGLT2i (empagliflozin) was co-administered during the last 3 weeks. Body composition was measured before and after SGLT2i treatment by EchoMRI. Subcutaneous (SAT) and visceral (VAT) WAT were collected for histological and molecular studies at the end of the study. RESULTS: PCOS model had an increase in food intake, body weight, body mass index, and fat mass/lean mass ratio compared to the control group. SGLT2i lowered fat mass/lean ratio in PCOS. Glucosuria was observed in both groups, but had a larger magnitude in controls. The net glucose balance was similar in both SGLT2i-treated groups. The PCOS SAT had a higher frequency of small adipocytes and a lower frequency of large adipocytes. In SAT of controls, SGLT2i increased frequencies of small and medium adipocytes while decreasing the frequency of large adipocytes, and this effect was blunted in PCOS. In VAT, PCOS had a lower frequency of small adipocytes while SGLT2i increased the frequency of small adipocytes in PCOS. PCOS model had decreased mitochondrial content in SAT and VAT without impacting oxidative stress in WAT or the circulation. SGLT2i did not modify mitochondrial function or oxidative stress in WAT in both treated groups. CONCLUSIONS: Hyperandrogenemia in PCOS causes expansion of WAT, which is associated with decreases in mitochondrial content and function in SAT and VAT. SGLT2i increases the frequency of small adipocytes in VAT only without affecting mitochondrial dysfunction, oxidative stress, or IR in the PCOS model. SGLT2i decreases adiposity independently of adipose mitochondrial and oxidative stress mechanisms in the PCOS model.

Online Support and Intervention for Child Anxiety (OSI): Development and Usability Testing.

BACKGROUND: Internet-based treatments for child anxiety may help to increase access to evidence-based therapies; however, user engagement, uptake, and adherence within routine clinical practice remain as challenges. Involving the intended end users in the development process through user-centered design and usability testing is crucial for maximizing user engagement and adoption of internet-based treatments, but so far this has been lacking for internet-based treatments for child anxiety. OBJECTIVE: The aim of this study is to develop an internet-based treatment for child anxiety through a process of user-centered design (phase 1) and usability testing (phase 2), based on an existing evidence-based, face-to-face, therapist-supported, parent-led cognitive behavioral therapy intervention. It is intended that the internet-based version of this treatment would consist of a parent website, case management system for clinicians, and mobile game app for children. METHODS: Parents, children, and clinicians who were familiar with the face-to-face version of the treatment were recruited from 2 National Health Service clinics. In phase 1, participants participated in 3 workshops to gain feedback on the overall concept, explore their wants and needs for the websites and game, generate ideas on how the treatment may look, and gain feedback on initial mock-ups of the websites and game. In phase 2, participants attended 3 individual usability testing sessions where they were presented with working prototypes of the website or game and asked to perform a series of tasks on the website (parents and clinicians) or play the game (children). The frequency and details on usability errors were recorded. Participants were asked for their feedback on the website and game using a standardized usability questionnaire and semistructured interviews. The websites and game were iterated after each round of usability testing in response to this feedback. RESULTS: In phase 1, participants approved the general concept and rated the initial mock-ups of the website and game positively. In phase 2, working prototypes were rated positively and usability errors declined across the iterations and were mainly cosmetic or minor issues relating to esthetic preference, with few issues regarding ability to navigate the website or technical issues affecting functionality. Feedback from the semistructured interviews further supported the positive response of participants to the website and game, and helped identify areas for improvement during the iteration process. The final iteration of the website and game are presented. CONCLUSIONS: Taking an iterative approach to development through user-centered design and usability testing has resulted in an internet-based treatment for child anxiety (Online Support and Intervention for child anxiety) that appears to meet the needs and expectations of the intended users (parents, children, and clinicians) and is easy and enjoyable to use.

Development of a professional competency framework for Australian sonographers-perspectives for developing competencies using a Delphi methodology.

BACKGROUND: Professional competencies are important for enhancing alignment between the needs of education, industry and health consumers, whilst describing public expectations around health professionals. The development of competency standards for the sonography profession defines the behaviours, skills and knowledge sonographers should demonstrate for each learning and experience level. OBJECTIVE: The objective of this project was to develop a set of professional competency standards for the sonography profession which described in depth the behaviours, skills and knowledge sonographers should demonstrate across multiple learning and experience levels. METHODS: Representatives of three Australian ultrasound professional associations and seven tertiary institutions involved in entry-level sonographer education in Australia formed a research team (RT). The RT recruited an expert panel that responded to six survey rounds. Using a Delphi methodology, the results and free-text comments from each previous round were fed back to participants in the subsequent survey rounds to achieve a consensus. RESULTS: The project developed a professional competency framework for sonographers, which included four major domains: detailed competency standards, sonographer knowledge, sonographer attitudes and a holistic competency matrix [https://doi.org/10.6084/m9.figshare.17148035.v2.]. CONCLUSION: The Delphi methodology is an effective way to develop professional competency standards. This paper describes the methods and challenges in developing such standards for sonographers which could be translated to other health professionals.

Extended reality anatomy undergraduate teaching: A literature review on an alternative method of learning.

BACKGROUND: The majority of undergraduate anatomy learning has shifted online, or to a mixture of virtual and face-to-face teaching, due to the COVID-19 pandemic. Cadaveric shortages have also influenced the need for alternative methods of anatomical education. This study examines the current literature on the use of extended reality technologies (XR) such as Virtual reality (VR), Augmented reality (AR), and Mixed reality (MR) for anatomy teaching and explores its potential for implementation in medical education. METHODS: A literature review was performed of PubMed, ProQuest, Science Direct, and Springer databases. Included studies were assessed for user satisfaction, perceived effectiveness, cost, acceptability and side effects. RESULTS: The database search identified 1687 papers, of which 45 papers were included in this review. Both AR and VR had high rates of satisfaction and acceptability as a supplementary teaching aid amongst undergraduate participants. AR was found to have higher effectiveness than VR. VR is more expensive than AR. Results and comparisons were limited due to short length of study. CONCLUSIONS: VR is a popular choice with undergraduates as an aid to supplement teaching, in spite of the associated cost and side effects such as nausea. AR has shown the most potential for independent study. Larger and long-term studies are required to determine true effectiveness, and consideration of the clinical relevance of these technologies.

Thinking ahead in advanced illness: Exploring clinicians' perspectives on discussing resuscitation with patients and families from ethnic minority communities.

BACKGROUND: Evidence suggests that discussing resuscitation with patients and relatives from ethnic minority groups is problematic for healthcare professionals (HCPs), but there is limited evidence exploring these issues or offering guidance for HCPs in navigating these challenging discussions. This study explores the barriers and enablers to HCPs discussing deterioration and resuscitation decisions with patients and families from ethnic minority groups. RESULTS: Personal, cultural, religious/spiritual and health beliefs, emotions, and communication quality and skills were discussed. Participants described that the interaction between these factors as complex, impacting the way some patients and families responded to do not attempt cardiopulmonary resuscitation (DNACPR) orders and the particular challenges these pose. CONCLUSION: Key barriers and enablers for healthcare professionals discussing resuscitation with patients and families from Black, Asian and minority ethnic communities were identified. The findings highlight areas of improvement for training, both relating to DNACPR discussions and 'cultural competence'.

Delivering cognitive therapy for adolescent social anxiety disorder in NHS CAMHS: a qualitative analysis of the experiences of young people, their parents and clinicians-in-training.

BACKGROUND: Social anxiety disorder (SAD) is common. It usually starts in adolescence, and without treatment can disrupt key developmental milestones. Existing generic treatments are less effective for young people with SAD than with other anxiety disorders, but an adaptation of an effective adult therapy (CT-SAD-A) has shown promising results for adolescents. AIMS: The aim of this study was to conduct a qualitative exploration to contribute towards the evaluation of CT-SAD-A for adoption into Child and Adolescent Mental Health Services (CAMHS). METHOD: We used interpretative phenomenological analysis (IPA) to analyse the transcripts of interviews with a sample of six young people, six parents and seven clinicians who were learning the treatment. RESULTS: Three cross-cutting themes were identified: (i) endorsing the treatment; (ii) finding therapy to be collaborative and active; challenging but helpful; and (iii) navigating change in a complex setting. Young people and parents found the treatment to be useful and acceptable, although simultaneously challenging. This was echoed by the clinicians, with particular reference to integrating CT-SAD-A within community CAMHS settings. CONCLUSIONS: The acceptability of the treatment with young people, their parents and clinicians suggests further work is warranted in order to support its development and implementation within CAMHS settings.

Delivering cognitive therapy for adolescent social anxiety disorder in NHS CAMHS: a clinical and cost analysis.

BACKGROUND: Cognitive therapy, based on the Clark and Wells (1995) model, is a first-line treatment for adults with social anxiety disorder (SAD), and findings from research settings suggest it has promise for use with adolescents (Cognitive Therapy for Social Anxiety Disorder in Adolescents; CT-SAD-A). However, for the treatment to be suitable for delivery in routine clinical care, two questions need to be addressed. AIMS: Can therapists be trained to achieve good outcomes in routine Child and Adolescent Mental Health Services (CAMHS), and what are the costs associated with training and treatment? METHOD: CAMHS therapists working in two NHS trusts received training in CT-SAD-A. They delivered the treatment to adolescents with SAD during a period of supervised practice. We examined the clinical outcomes for the 12 patients treated during this period, and estimated costs associated with treatment and training. RESULTS: Treatment produced significant improvements in social anxiety symptoms, general anxiety and depression symptoms, and reductions in putative process measures. Seventy-five per cent (9 out of 12) patients showed a reliable and clinically significant improvement in social anxiety symptoms, and 64% (7/11) lost their primary diagnosis of SAD. The total cost to the NHS of the CT-SAD-A treatment was £4047 (SD = £1003) per adolescent treated, of which £1861 (SD = £358) referred to the specific estimated cost of face-to-face delivery; the remaining cost was for training and supervising therapists who were not previously familiar with the treatment. CONCLUSIONS: This study provides preliminary evidence that clinicians can deliver good patient outcomes for adolescents with SAD in routine CAMHS during a period of supervised practice after receiving a 2-day training workshop. Furthermore, the cost of delivering CT-SAD-A with adolescents appeared to be no more than the cost of delivering CT-SAD with adults.

Cognitive therapy compared with CBT for social anxiety disorder in adolescents: a feasibility study.

BACKGROUND: Social anxiety disorder (SAD) is common, typically starts in adolescence and has a low natural recovery rate. Existing psychological treatments for adolescent SAD are only moderately effective. It is possible that recovery rates for adolescents could be substantially improved by adapting a psychological therapy that is highly effective among adults with SAD. OBJECTIVES: To train child and adolescent mental health services (CAMHS) therapists to deliver cognitive therapy for SAD in adolescents (CT-SAD-A) and assess therapist competence. To estimate the costs to the NHS of training therapists to deliver CT-SAD-A and the mean cost per adolescent treated. To examine the feasibility of a randomised controlled trial (RCT) to compare CT-SAD-A with the general form of cognitive-behavioural therapy that is more commonly used. DESIGN: During the training phase of the study, it became clear that the RCT would not be feasible because of high staff turnover and unfilled posts within CAMHS and changes in the nature of referrals, which meant that few young people with primary SAD were accessing some of the participating services. The study design was altered to comprise the following: a training case series of CT-SAD-A delivered in routine CAMHS, an estimate of the cost to the NHS of training therapists to deliver CT-SAD-A and of the mean cost per adolescent treated, and qualitative interviews with participating young people, parents, therapists and service managers/leads. SETTING: Five CAMHS teams within Berkshire Healthcare and Oxford Health NHS Foundation Trusts. PARTICIPANTS: Eight therapists received training in CT-SAD-A. Twelve young people received CT-SAD-A, delivered by six therapists. Six young people, six parents, seven therapists and three managers participated in qualitative interviews. INTERVENTIONS: Cognitive therapy for social anxiety disorder in adolescents (CT-SAD-A). MAIN OUTCOME MEASURES: Measured outcomes included social anxiety symptoms and diagnostic status, comorbid symptoms of anxiety and depression, social and general functioning, concentration in class and treatment acceptability. Patient level utilisation of the intervention was collected using clinicians' logs. RESULTS: Nine out of 12 participants achieved good outcomes across measures (r ≥ 0.60 across social anxiety measures). The estimated cost of delivering CT-SAD-A was £1861 (standard deviation £358) per person. Qualitative interviews indicated that the treatment was acceptable to young people, parents and therapists, but therapists and managers experienced challenges when implementing the training and treatment within the current CAMHS context. LIMITATIONS: Findings were based on a small, homogeneous sample and there was no comparison arm. CONCLUSIONS: CT-SAD-A is a promising treatment for young people with SAD, but the current CAMHS context presents challenges for its implementation. FUTURE WORK: Further work is needed to ensure that CAMHS can incorporate and test CT-SAD-A. Alternatively, CT-SAD-A should be delivered and tested in other settings that are better configured to treat young people whose lives are held back by SAD. The new schools Mental Health Support Teams envisaged in the 2017 Children's Mental Health Green Paper may provide such an opportunity. FUNDING: The National Institute for Health Research (NIHR) Health Technology Assessment programme. Individual funding was also provided for Cathy Creswell, David M Clark and Eleanor Leigh as follows: NIHR Research Professorship (Cathy Creswell); Wellcome Senior Investigator Award (Anke Ehlers and David M Clark); and the Wellcome Clinical Research Training Fellowship (Eleanor Leigh).

WHY DID WE DO THIS STUDY?: People with social anxiety disorder (SAD) are scared of social situations because they fear embarrassment or humiliation. SAD usually starts at around 13 years of age, typically does not go away without treatment, and leads to personal and social difficulties. Clark and Wells' cognitive therapy for SAD in adults (CT-SAD) is a talking therapy that produces excellent outcomes. CT-SAD has not previously been adapted for or tested with adolescents. WHAT DID WE DO?: We adapted CT-SAD so that it was suitable for adolescents (CT-SAD-A). We intended to compare this with current practice in child and adolescent mental health services (CAMHS). However, we were not able to complete the trial owing to a high staff turnover and a lack of young people with SAD coming into CAMHS. Instead, we examined outcomes for young people who received CT-SAD-A during the therapist training phase and explored the views of young people, their parents, the therapists and CAMHS managers about CT-SAD-A and the study. WHAT DID WE FIND?: Young people's outcomes were very promising; for example, 10 out of 12 participants reported a reliable improvement in social anxiety. The young people and their parents were generally positive about the treatment. Therapists were also positive about the treatment, but they and their managers found it difficult to implement the treatment within their CAMHS teams. The cost to the NHS to treat young people with SAD within this study compared favourably with the cost of treating adults. WHAT DOES THIS MEAN?: We need to be careful about drawing conclusions from a small sample size, but we suggest that further work is needed to ensure that CT-SAD-A can be delivered and tested in CAMHS. Alternatively, CT-SAD-A should be delivered and tested in community or school settings that can treat young people whose lives are held back by SAD.

The common diabetes drug metformin can diminish the action of citral against Rhabdomyosarcoma cells in vitro.

Rhabdomyosarcoma (RMS) is a rare type of soft tissue sarcoma most commonly found in pediatric patients. Despite progress, new and improved drug regimens are needed to increase survival rates. Citral, a natural product plant oil can induce cell death in cancer cells. Another compound, metformin, isolated originally from French lilac and used by diabetics, has been shown to reduce the incidence of cancer in these patients. Application of citral to RMS cells showed increase in cell death, and RD and RH30 cells showed half maximal inhibitory concentration (IC50 ) values as low as 36.28 µM and 62.37 µM, respectively. It was also shown that the citral initiated cell apoptosis through an increase in reactive oxygen species (ROS) and free calcium. In comparison, metformin only showed moderate cell death in RMS cell lines at a very high concentration (1,000 µM). Combinatorial experiments, however, indicated that citral and metformin worked antagonistically when used together. In particular, the ability of metformin to quench the ROS induced by citral could lead to the suppression of activity. These results clearly indicate that while clinical use of citral is a promising anti-tumor therapy, caution should be exercised in patients using metformin for diabetes.

Clinical syndromes and treatment location predict utility of carbapenem sparing therapies in ceftriaxone-non-susceptible Escherichia coli bloodstream infection.

BACKGROUND: Cefiderocol, ceftazidime-avibactam, ceftolozane-tazobactam, intravenous fosfomycin and plazomicin represent potential carbapenem sparing agents for extended-spectrum-beta-lactamase or AmpC beta-lactamase producing Escherichia coli infection. However, available data is limited in predicting the volume of carbapenem therapy which could be substituted and real-world contraindications. METHODS: We determined the number of carbapenem days of therapy (DOT) which could be substituted and frequent contraindications accounting for antimicrobial susceptibility and site of infection in an unselected cohort with ceftriaxone-non-susceptible E. coli bacteremia at a single health network from 2015 to 2016. Individual patient data was used to calculate DOT and substitution for each agent. RESULTS: There were 108 episodes of E. coli bacteremia resulting in 67.2 carbapenem DOT/100 patient-days of antimicrobial therapy administered. Ceftazidime-avibactam could be used to substitute 36.2 DOT/100 patient-days (54%) for inpatient definitive therapy, ceftolozane-tazobactam for 34.7 DOT/100 patient-days (52%), cefiderocol for 27.1 DOT/100 patient-days (40%), fosfomycin for 23.3 DOT /100 patient-days (35%) and plazomicin for 27.1 DOT/100 patient-days (40%). Non-urinary tract source of infection was the most frequent contraindication to fosfomycin (25), plazomicin (26) and cefiderocol (26). Use in outpatient parenteral antimicrobial therapy (OPAT) programs accounted for 40% of DOT, all of which could be substituted if stability data allowed for ceftazidime-avibactam and ceftolozane-tazobactam. CONCLUSIONS: All tested agents could be used to replace a significant volume of carbapenem therapy. Establishing stability of these agents for use in OPAT is required for maximizing their use as carbapenem sparing agents while randomized clinical data is awaited for some of these agents in resistant E. coli bacteremia.