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Background: Despite the availability of evidence-based treatments for anorexia nervosa (AN), remission rates are moderate, and mortality is high. Olanzapine is used as adjunct therapy for AN in case of insufficient response to first-line treatments, even though the evidence is limited. Its effect on eating disorder (ED) psychopathology, its efficacy and tolerability, and its acceptability and adherence rate are unclear., Methods: We assessed the feasibility of a future definitive trial on olanzapine in young people with AN in an open-label, one-armed feasibility study that aimed to include 55 patients with AN or atypical AN aged 12-24 who gained < 2 kg within at least one month of treatment as usual (TAU) during outpatient, inpatient, or day-care treatment. Time points for assessments were at baseline, 8 weeks, 16 weeks, and 6 or 12 months. We estimated the following planning parameters: Recruitment rate (number of patients who agreed to take olanzapine/number eligible), adherence rate (number adhering to treatment/number recruited) and attrition rate (number completing study assessments/number recruited). In addition, two exploratory effect size parameters were estimated: Mean change in body mass index (BMI) and mean change in ED psychopathology., Results: Fifty-two people were pre-screened (June 2022 to May 2023; 10 study sites in England). 13 were ineligible at pre-screening . Of the 39  approached, 4 were found ineligible at screening. Of the remaining 35 eligible, 10 declined and 5 did not take part for other reasons. Thus, 20 participants were recruited and started olanzapine (recruitment rate: 20/35 = 57%). 15 out of 20 (75%) continued olanzapine for ≥ 16 weeks, and 13 participants (65%) remained in the trial until follow-up (either 6 or 12 months). Participants experienced, on average, a decrease over time in their Eating Disorder Examination Questionnaire (EDE-Q) Global scores (0.07 per week, N = 20) and an increase in BMI (0.08 kg/m 2 per week, N = 20) during treatment with olanzapine plus TAU., Conclusions: Possible reasons for the recruitment difficulties and low adherence rate include the high clinical workload of ED services during the COVID-19 pandemic and the reluctance of patients to agree to take olanzapine under the relatively restricted conditions of a clinical study., Trial Registration: International standard randomised controlled trial register number: ISRCTN80075010. Registration date: 27/04/2022., (© 2024. The Author(s).)

Background: Exploration of client identity negotiations during treatment for Anorexia Nervosa (AN) is a relatively new area of research. Research suggests that difficulties with identity negotiations may present as a barrier to treatment. This study sought to explore individuals' identity negotiations during therapy sessions using Compulsive Exercise Activity Therapy (LEAP) combined with Cognitive Behaviour Therapy for Anorexia Nervosa (CBT-AN). Analysis focused on moments in therapy where individuals' identities were dominated or defined by AN and where alternative identities could be generated., Method: 40 in-session transcripts from sessions at early, mid and end points of the CBT-AN (with LEAP) treatment were qualitatively analysed for nine of the 78 participants in the original randomised control trial. Through a constructivist framework, thematic analysis was used to identify surface and latent meanings and discursive material participants used to negotiate their identities in the context of therapy sessions., Results: Analysis of in-therapy transcripts generated two themes pertaining to identity negotiations: (1) troubled identities and (2) rebuilding identities and lives outside of AN. Early therapy sessions explored fragmented and AN dominated identities, including how AN was troubling to participants' sense of self, contributed to conflicted identities, positioned them outside of normality, and was associated with isolated and othering identities. Within therapy sessions, participants engaged in a recursive process of shifting relationships with AN and themselves and building identities and lives outside of the AN identity. This included generating hopes for recovery and the future more frequently in mid- to late- therapy sessions., Conclusion: Identity negotiations evident in the therapeutic conversations aligned with the key components of the CBT-AN intervention, including addressing (1) the characterisation of oneself as 'an anorexic' and (2) the diversification of roles and activities to broaden and enhance self-concepts. Future developments of therapeutic interventions for AN would benefit from greater consideration of ways to assist individuals to more comprehensively address problematic identities, including uncovering identities hidden by the AN identity and generating preferred identities., Trial Registration: Ethics approval was obtained at the time of the initial study and for this embedded research by the HREC at the Western Sydney University (HR777332)., (© 2024. Crown.)

Background: Anorexia nervosa (AN) has amongst the highest mortality rates and the highest treatment costs of any psychiatric disorder. Recently, interest in non-invasive brain stimulation as a novel treatment for AN has grown. These include repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS)., Methods: This double-blind, randomised sham-controlled trial will compare the relative acceptability and efficacy of tDCS and rTMS in people with AN. 70 participants will be randomised to active or sham tDCS, or active or sham rTMS treatment (2:1:2:1 ratio) over an 8-week treatment period. Participants will receive treatment as usual across the study duration. The primary outcomes are change on the Eating Disorder Examination Questionnaire and treatment acceptability. Secondary outcomes will include change in weight, cognition, mood, interpersonal functioning, and quality of life. Following the 8-week assessment, all participants will have the option of receiving an additional 12 weeks of at-home tDCS. A follow-up assessment will be conducted at 20 weeks post treatment., Discussion: Research into non-invasive brain stimulation as treatments for AN has potential to improve clinical outcomes for patients by comparing the relative efficacy and acceptability of both treatment modalities in the inpatient and at-home setting (i.e., for at-home tDCS) results from this study will provide important information for informing future larger clinical trials of these treatments for AN., Trial Registration: ClinicalTrials.gov Identifier: NCT05788042., (© 2023. The Author(s).)

Background: Despite the availability of effective treatments for bulimia nervosa (BN), a number of barriers to accessibility exist. Examples include access to trained clinicians, the expense of treatment, geographical limitations, and personal limitations such as stigma regarding help seeking. Self-help interventions, delivered via a digital platform, have the potential to overcome treatment gaps by providing patients with standardised, evidence-based treatments that are easily accessible, cost-effective, and require minimal clinician support. Equally, it is important to examine the shortcomings of digital interventions when compared to traditional to face-to-face delivery (e.g., high dropout rates) in order to maximise the therapeutic effectiveness of online, self-help interventions., Methods: A three-arm, multisite randomised controlled trial will be conducted in Australia examining the effectiveness and cost-effectiveness of a newly developed online self-help intervention, Binge Eating eTherapy (BEeT), in a sample of patients with full or sub-threshold BN. The BEeT program consists of 10, multimedia sessions delivering the core components of cognitive behaviour therapy. Eligible participants will be randomised to one of three groups: independent completion of BEeT as a purely self-help program, completion of BEeT alongside clinician support (in the form of weekly telemedicine sessions), or waitlist control. Assessments will take place at baseline, weekly, post-intervention, and three-month follow up. The primary outcome is frequency of objective binge episodes. Secondary outcomes include frequency of other core eating disorder behavioural symptoms and beliefs, psychological distress, and quality of life. Statistical analyses will examine treatment effectiveness, feasibility, acceptability and cost effectiveness., Discussion: There is limited capacity within the mental health workforce in Australia to meet the demand of people seeking treatment for eating disorders. This imbalance has only worsened following outbreak of the COVID-19 pandemic. Further research is required into innovative digital modes of treatment delivery with the capacity to service mental health needs in an accessible and affordable manner. Self-help programs may also appeal to individuals who are more reluctant to engage in traditional face-to-face treatment formats. This study will provide rigorous evidence on how to diversify treatment options for individuals with BN, ensuring more people with the illness can access evidence-based treatment. The study has been registered with the Australia New Zealand Clinical Trials Registry (ANZCTR Registration Number: ACTRN12619000123145p). Registered 22 January 2019, https://www.australianclinicaltrials.gov.au/anzctr/trial/ACTRN12619000123145 ., Competing Interests: Competing interestsST has received honoraria from the Takeda Group of Companies for commissioned reports, preparation of educational materials and public speaking engagements. He has also received both travel and research grants. He has also chaired their Clinical advisory Group for Binge Eating Disorders. ST has also received royalties for published book and/or book chapters from Hogrefe and Huber, McGraw Hill and Taylor and Francis. He is a member of the Technical Advisory Group for Eating Disorders established by the Commonwealth Department of Health and is also a member of the National Eating Disorders Collaboration (NEDC)., (© 2021. The Author(s).)

Background: Aberrant PI3K signalling is implicated in trastuzumab resistance in HER2-positive gastric cancer (GC). The role of PI3K or MEK inhibitors in sensitising HER2-positive GCs to trastuzumab or in overcoming trastuzumab resistance is unclear., Methods: Using mass spectrometry-based genotyping we analysed 105 hotspot, non-synonymous somatic mutations in PIK3CA and ERBB-family (EGFR, ERBB2, ERBB3 and ERBB4) genes in gastric tumour samples from 69 patients. A panel of gastric cell lines (N87, OE19, ESO26, SNU16, KATOIII) were profiled for anti-proliferative response to the PI3K inhibitor copanlisib and the MEK1/2 inhibitor refametinib alone and in combination with anti-HER2 therapies., Results: Patients with HER2-positive GC had significantly poorer overall survival compared to HER2-negative patients (15.9 months vs. 35.7 months). Mutations in PIK3CA were only identified in HER2-negative tumours, while ERBB-family mutations were identified in HER2-positive and HER2-negative tumours. Copanlisib had anti-proliferative effects in 4/5 cell lines, with IC50s ranging from 23.4 (N87) to 93.8 nM (SNU16). All HER2-positive cell lines except SNU16 were sensitive to lapatinib (IC50s 0.04 µM-1.5 µM). OE19 cells were resistant to trastuzumab. The combination of lapatinib and copanlisib was synergistic in ESO-26 and OE-19 cells (ED50: 0.83 ± 0.19 and 0.88 ± 0.13, respectively) and additive in NCI-N87 cells (ED50:1.01 ± 0.55). The combination of copanlisib and trastuzumab significantly improved growth inhibition compared to either therapy alone in NCI-N87, ESO26 and OE19 cells (p < 0.05)., Conclusions: PI3K or MEK inhibition alone or in combination with anti-HER2 therapy may represent an improved treatment strategy for some patients with HER2-positive GC, and warrants further investigation in a clinical trial setting.

Background: Metastatic breast cancer is a major cause of cancer-related deaths in woman. Brain metastasis is a common and devastating site of relapse for several breast cancer molecular subtypes, including oestrogen receptor-positive disease, with life expectancy of less than a year. While efforts have been devoted to developing therapeutics for extra-cranial metastasis, drug penetration of blood-brain barrier (BBB) remains a major clinical challenge. Defining molecular alterations in breast cancer brain metastasis enables the identification of novel actionable targets., Methods: Global transcriptomic analysis of matched primary and metastatic patient tumours (n = 35 patients, 70 tumour samples) identified a putative new actionable target for advanced breast cancer which was further validated in vivo and in breast cancer patient tumour tissue (n = 843 patients). A peptide mimetic of the target's natural ligand was designed in silico and its efficacy assessed in in vitro, ex vivo and in vivo models of breast cancer metastasis., Results: Bioinformatic analysis of over-represented pathways in metastatic breast cancer identified ADAM22 as a top ranked member of the ECM-related druggable genome specific to brain metastases. ADAM22 was validated as an actionable target in in vitro, ex vivo and in patient tumour tissue (n = 843 patients). A peptide mimetic of the ADAM22 ligand LGI1, LGI1MIM, was designed in silico. The efficacy of LGI1MIM and its ability to penetrate the BBB were assessed in vitro, ex vivo and in brain metastasis BBB 3D biometric biohybrid models, respectively. Treatment with LGI1MIM in vivo inhibited disease progression, in particular the development of brain metastasis., Conclusion: ADAM22 expression in advanced breast cancer supports development of breast cancer brain metastasis. Targeting ADAM22 with a peptide mimetic LGI1MIM represents a new therapeutic option to treat metastatic brain disease.

Background: An increasing number of anti-cancer therapeutic agents target specific mutant proteins that are expressed by many different tumor types. Successful use of these therapies is dependent on the presence or absence of somatic mutations within the patient's tumor that can confer clinical efficacy or drug resistance., Methods: The aim of our study was to determine the type, frequency, overlap and functional proteomic effects of potentially targetable recurrent somatic hotspot mutations in 47 cancer-related genes in multiple disease sites that could be potential therapeutic targets using currently available agents or agents in clinical development., Results: Using MassArray technology, of the 1300 patient tumors analysed 571 (43.9%) had at least one somatic mutation. Mutations were identified in 30 different genes. KRAS (16.5%), PIK3CA (13.6%) and BRAF (3.8%) were the most frequently mutated genes. Prostate (10.8%) had the lowest number of somatic mutations identified, while no mutations were identified in sarcoma. Ocular melanoma (90.6%), endometrial (72.4%) and colorectal (66.4%) tumors had the highest number of mutations. We noted high concordance between mutations in different parts of the tumor (94%) and matched primary and metastatic samples (90%). KRAS and BRAF mutations were mutually exclusive. Mutation co-occurrence involved mainly PIK3CA and PTPN11, and PTPN11 and APC. Reverse Phase Protein Array (RPPA) analysis demonstrated that PI3K and MAPK signalling pathways were more altered in tumors with mutations compared to wild type tumors., Conclusions: Hotspot mutational profiling is a sensitive, high-throughput approach for identifying mutations of clinical relevance to molecular based therapeutics for treatment of cancer, and could potentially be of use in identifying novel opportunities for genotype-driven clinical trials.

Background: High levels of physical activity (PA) have long been described in patients with Anorexia Nervosa (AN). Despite the importance of measuring PA in this population, there are two important factors that remain unknown. First, it is not clear how accurate self-report measures of PA are among patients. Second, little is known about how clinical characteristics are associated with the accuracy of self-reported PA. Therefore, this study aimed to examine the accuracy of self-reported PA compared to an objective measure of PA in patients with AN. It also investigated whether levels of accuracy/inaccuracy were associated with compulsive exercise, motivation to change, and psychological distress., Method: Data were analysed from 34 adult outpatients with AN. Patients wore an accelerometer device (ActiGraph) for 4 days and completed a retrospective self-report measure of exercise (Exercise Participation Screening Questionnaire). They also completed measures of compulsive exercise (Compulsive Exercise Test), motivation to change (The Anorexia Nervosa Stages of Change Questionnaire), and psychological distress (Kessler-10)., Results: On the self-report measure, patients accurately reported their time spent in moderate and vigorous intensity PA, however, they significantly under-reported their light physical activity (compared to the accelerometer data). Accurate reporting of total PA was positively associated with higher levels of compulsive exercise. There was evidence to suggest that clinical features, such as motivation to change and psychological distress, may be associated with inaccurate reporting at some levels of PA intensity and not others., Conclusions: Results indicate that patients with AN are likely to under-report their light intensity PA. We also found preliminary evidence for how compulsive exercise, motivation to change, and distress are associated with self-reported PA accuracy. Clinical implications and directions for future research are considered., Trial Registration: ACTRN12610000585022. Taking a LEAP forward in the treatment of anorexia nervosa: a randomized controlled trial. NHMRC grant: 634922., Competing Interests: Competing interestsST and PH receive royalties from Routledge, Hogrefe, and Huber and McGraw-Hill publishers for printed contributions on eating disorders. SM received, and PH and ST receive honoraria from Shire Pharmaceuticals. PH received royalties from Oxford University Press and receives sessional fees and lecture fees from the Australian Medical Council, Therapeutic Guidelines publication, and New South Wales Institute of Psychiatry. PH and ST are Editors-in-Chief of this journal, and CM, JA, SM, KP, and SY are on the editorial board. All authors have other published papers cited in this manuscript.

Background: For people with anorexia nervosa (AN), compulsive exercise is characterized by extreme concerns about the perceived negative consequences of stopping/reducing exercise, dysregulation of affect, and inflexible exercise routines. It is associated with increased eating disorder psychopathology and poor clinical outcome. However, its relationships with two important clinical issues, quality of life (QoL) and motivation to change, are currently unknown. This study aimed to assess the cross-sectional relationships between compulsive exercise, QoL, psychological distress (anxiety and depressive symptoms, and obsessive-compulsive traits) and motivation to change in patients with AN., Method: A total of 78 adults with AN participated in this study, which was nested within a randomized controlled trial of psychological treatments for AN. At baseline (pre-treatment), participants completed questionnaires assessing compulsive exercise, eating disorder (ED) psychopathology, QoL, psychological distress and motivation to change., Results: Baseline correlational analyses demonstrated a moderate positive relationship between compulsive exercise and ED psychopathology, and a weak positive relationship between compulsive exercise and psychological distress. There was a moderate negative relationship between compulsive exercise and eating disorder QoL., Conclusions: These results indicate compulsive exercise is moderately associated with poorer QoL and weakly associated with higher distress. Targeting compulsive exercise in the treatment of anorexia nervosa may help reduce the burden of illness and improve patients' engagement in treatment., Trial Registration: ACTRN12610000585022. Taking a LEAP forward in the treatment of anorexia nervosa: a randomized controlled trial. NHMRC grant: 634922., Competing Interests: Ethics approval was granted by the Western Sydney University Human Research Ethics Committee; the National Health Service Research Ethics Committee in the UK, as part of the Health Research Authority; and the Institutional Review Board at Columbia University in New York, USA.Not applicable as the project did not report individual data.ST and PH receive royalties from Routledge, Hogrefe, and Huber and McGraw-Hill publishers for printed contributions on eating disorders. SM and ST receive honoraria from Shire Pharmaceuticals. PH received royalties from Oxford University Press and receives sessional fees and lecture fees from the Australian Medical Council, Therapeutic Guidelines publication, and New South Wales Institute of Psychiatry. RDC is a statistical consultant to Health Outcome Solutions, in Winter Park, Florida. PH and ST are Editors-in-Chief of this journal, and CM, JA, SM, KP, JA, RDC and SY are on the editorial board. All authors have other published papers cited in this manuscript. SY submitted an alternate version of this manuscript as a part of her PhD thesis.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: The aim of this research was to investigate the relationship between family functioning, adolescent-parent attachment and remission, as well as changes in these variables over time for adolescents with severe anorexia nervosa treated with family based treatment (FBT). Understanding how families respond to treatment is important because the family will be the ongoing context for psychosocial development in the longer term. The relationship between family functioning and outcome is also an important variable because it is potentially modifiable during treatment and this may improve outcome., Methods: Fifty-seven female adolescents treated with FBT in a randomised controlled trial were assessed at baseline, FBT session 20 and 12-months post FBT session 20. Data on family functioning and adolescent-parent attachment was collected from patients and their parents at each time point. A series of regression analyses were used to determine the relationship between family functioning and comorbidity at baseline, and the relationship with remission status over time. Repeat measure mixed-effects models were used to assess changes in family functioning and attachment quality over time., Results: Greater adolescent perceived family functioning impairment was positively related to psychiatric comorbidity at the start of treatment. Conversely, better family functioning predicted higher self-esteem and stronger attachment quality. Adolescent's reporting better general family functioning, communication and problem solving were more likely to be remitted at session 20, but not at 12-month follow-up. There was no overall improvement in family functioning for any respondent either during treatment or at follow-up, and no significant relationship between change and remission at either session 20 or follow-up., Conclusions: The adolescent's perspective on family functioning at the start of treatment impacts on a positive outcome. Addressing family issues earlier in FBT may be important for some patients. Further research is needed in this area to determine how these findings could be integrated into the current FBT model., Trial Registration: Australian Clinical Trials Register number: ACTRN012607000009415 (www.anzctr.org.au)., Competing Interests: Not applicable.This study was approved by the Human Research Ethics Committee of Sydney Children’s Hospital Network, Westmead Campus (2006/114). Participants gave informed written consent.Not applicable.Andrew Wallis is a faculty members of the Training Institute for Child and Adolescent Eating Disorders. Paul Rhodes and Andrew Wallis receive royalties from IP Communications. Stephen Touyz has received fees for serving as consultant to Shire Pharmaceuticals advisory board and receives royalties from Hogrefe Publications, McGraw Hill Pubs and honoraria from Biomed Central.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: This study investigated patient experience in a Family Admissions Program (FAP) - a pilot treatment program for adolescents with Anorexia Nervosa at the Children's Hospital, Westmead. Based on Maudsley Family Based Treatment (FBT), the FAP involves an adolescent and his/her family undergoing a two-week family-based hospital admission at the outset of treatment. The program aims to increase intensity and support to a level needed by some families struggling to engage with or access FBT., Method: Narrative Inquiry and Interpretative Phenomenological Analysis were used as a dual methodological approach to explore the prospective expectations and retrospective experiences of participants partaking in the program., Results: Results indicated that in cases where the family unit has been particularly fractured as a result of the eating disorder, the FAP offers an opportunity for relational strengthening and reunification. Combined with the program's intensive support and proximity to hospital services, this serves to provide struggling families with enhanced skills and a stronger foundation for outpatient FBT., Conclusions: For families deemed at risk of unsuccessful outcomes with FBT, the FAP can be considered as an appropriate treatment adjunct to place alongside or before the commencement of FBT.

Background: The aim of this research was to investigate the process of familial relationship change for adolescents with anorexia nervosa and their parents, who participated in Family-Based Treatment (FBT)., Method: A Constructionist grounded theory design was employed with purposive sampling. Sixteen young people between 12 and 18 years with a good outcome in FBT and twenty-eight of their parents participated. Young people and their parents took part in separate interviews at the end of treatment. Each interview was transcribed and analysed to identify a unifying phenomenon across the data to elicit a theory that explained the data and then integrated into existing theory., Results: Prior to treatment families' experienced significant conflict, disconnection and isolation. The FBT structure, therapist direction, and the specialist medical setting created a process of relational containment. This enabled parents to trust the process of FBT and develop confidence in their executive role in the family. In turn this allowed the adolescent with anorexia nervosa to trust their parents, feel more secure and gradually engage in the treatment process themselves. Improvements in closeness, communication and adolescent sense of self were reported after FBT., Conclusions: These findings illuminate a possible mechanism of change in FBT. It underscores the importance of parental management of eating disorder symptoms at the commencement of treatment to enable increased parental confidence. Meaningful changes occurred for the adolescents' that aided normal developmental and relational processes, an important aspect of recovery., Trial Registration: Australian Clinical Trials Register number: ACTRN012607000009415.

Background: The aim of the current study was to contribute to the development of a clinical profile of compulsive exercise in adolescents with Anorexia Nervosa (AN), by examining associations between compulsive exercise and eating and general psychopathology., Method: A sample of 60 female adolescent inpatients with AN completed a self-report measure of compulsive exercise and a series of standardized self-report questionnaires assessing eating and general psychopathology., Results: Higher levels of compulsive exercise were associated with increased levels of eating disorder psychopathology and anxiety. Specifically, the avoidance aspect (negatively reinforced) of compulsive exercise was associated with elevated scores on measures of eating disorder, anxiety, depression, and obsessive compulsiveness psychopathology, as well as lower self-esteem scores. The mood improvement value (positively reinforced) of compulsive exercise, however, did not reflect such trends., Conclusions: Compulsive exercise driven by avoidance of negative affect is associated with more severe psychological features in adolescent inpatients with AN. The current findings emphasize the need for research and clinical efforts in the development of treatments addressing avoidance of negative affect and compulsive exercise in adolescents with AN.

Background: The impact of severe malnutrition and medical instability in adolescent Anorexia Nervosa (AN) on immediate health and long-term development underscores the need for safe and efficient methods of refeeding. Current refeeding guidelines in AN advocate low initial caloric intake with slow increases in energy intake to avoid refeeding syndrome. This study demonstrates the potential for more rapid refeeding to promote initial weight recovery and correct medical instability in adolescent AN., Methods: Seventy-eight adolescents with AN (12-18 years), hospitalised in two specialist paediatric eating disorder units, for medical instability (bradycardia, hypotension, hypothermia, orthostatic instability and/or cardiac arrhythmia) were followed during a 2.5 week admission. Patients were refed using a standardised protocol commencing with 24-72 hours of continuous nasogastric feeds (ceased with daytime medical stability) and routine oral phosphate supplementation, followed by nocturnal feeds and a meal plan of 1200-2400 kcal/day aiming for a total caloric intake of 2400-3000 kcal/day. Along with indicators of medical stability, weight, phosphate and glucose levels were recorded., Results: All patients gained weight in week one (M = 2.79 kg, SD = 1.27 kg) and at subsequent measurement points with an average gain of 5.12 kg (SD = 2.96) at 2.5 weeks. No patient developed hypophosphatemia, hypoglycaemia, or stigmata of the refeeding syndrome., Conclusions: The refeeding protocol resulted in immediate weight gain and was well tolerated with no indicators of refeeding syndrome. There were no significant differences in outcomes between the treatment sites, suggesting the protocol is replicable., Trial Registration: Australian Clinical Trials Register number: ACTRN012607000009415.

Background: Sleep is an essential component of good physical and mental health. Previous studies have reported that poor quality sleep is associated with an increased risk of hypertension and cardiovascular disease. Hypertension is the most common and important risk factor for cardiovascular disease, and even modest reductions in blood pressure can result in significant reductions in the risk of stroke and myocardial infarction. In this trial, we will determine the efficacy of an online sleep intervention in improving blood pressure, in participants with hypertension and poor sleep quality., Trial Design: Randomized-controlled, two-group, parallel, blinded, single-center, Phase II trial of 134 participants. Population and recruitment: Primary prevention population of participants with hypertension (systolic blood pressure, 130 to 160 mm Hg; diastolic blood pressure, <110 mm Hg) and poor sleep quality in a community setting., Intervention: Multicomponent online sleep intervention consisting of sleep information, sleep hygiene education, and cognitive behavioral therapy. Comparator: Standardized cardiovascular risk factor and lifestyle-education session (usual care)., Primary Outcome: Change in mean 24-hour ambulatory systolic blood pressure between baseline and 8-week follow-up. Hypertension has been selected as the primary outcome measure because of its robust association with both poor sleep quality and cardiovascular disease., Statistical Analyses: Intention-to-treat analysis by using a linear mixed model., Trial Registration: ClinicalTrials.gov: NCT01809821, registered March 8, 2013.

Background: CCN2/CTGF is an established effector of TGFβ driven responses in diabetic nephropathy. We have identified an interaction between CCN2 and TGFβ leading to altered phenotypic differentiation and inhibited cellular migration. Here we determine the gene expression profile associated with this phenotype and define a transcriptional basis for differential actin related gene expression and cytoskeletal function., Results: From a panel of genes regulated by TGFβ and CCN2, we used co-inertia analysis to identify and then experimentally verify a subset of transcription factors, E2F1 and CREB, that regulate an expression fingerprint implicated in altered actin dynamics and cell hypertrophy. Importantly, actin related genes containing E2F1 and CREB binding sites, stratified by expression profile within the dataset. Further analysis of actin and cytoskeletal related genes from patients with diabetic nephropathy suggests recapitulation of this programme during the development of renal disease. The Rho family member Cdc42 was also found uniquely to be activated in cells treated with TGFβ and CCN2; Cdc42 interacting genes were differentially regulated in diabetic nephropathy., Conclusions: TGFβ and CCN2 attenuate CREB and augment E2F1 transcriptional activation with the likely effect of altering actin cytoskeletal and cell growth/hypertrophic gene activity with implications for cell dysfunction in diabetic kidney disease. The cytoskeletal regulator Cdc42 may play a role in this signalling response.