Biallelic Variants in PYROXD2 Cause a Severe Infantile Metabolic Disorder Affecting Mitochondrial Function.

Pyridine Nucleotide-Disulfide Oxidoreductase Domain 2 (PYROXD2; previously called YueF) is a mitochondrial inner membrane/matrix-residing protein and is reported to regulate mitochondrial function. The clinical importance of PYROXD2 has been unclear, and little is known of the protein's precise biological function. In the present paper, we report biallelic variants in PYROXD2 identified by genome sequencing in a patient with suspected mitochondrial disease. The child presented with acute neurological deterioration, unresponsive episodes, and extreme metabolic acidosis, and received rapid genomic testing. He died shortly after. Magnetic resonance imaging (MRI) brain imaging showed changes resembling Leigh syndrome, one of the more common childhood mitochondrial neurological diseases. Functional studies in patient fibroblasts showed a heightened sensitivity to mitochondrial metabolic stress and increased mitochondrial superoxide levels. Quantitative proteomic analysis demonstrated decreased levels of subunits of the mitochondrial respiratory chain complex I, and both the small and large subunits of the mitochondrial ribosome, suggesting a mitoribosomal defect. Our findings support the critical role of PYROXD2 in human cells, and suggest that the biallelic PYROXD2 variants are associated with mitochondrial dysfunction, and can plausibly explain the child's clinical presentation.

Views on online self-help programmes from people with eating disorders and their carers in UK.

BACKGROUND: Digitalizing the healthcare system has been declared a priority by the UK government. People with eating disorders (EDs), especially those with bulimia nervosa (BN) or binge eating disorder (BED), and ED carers may benefit from online self-help programmes, due to the shame and stigma associated with EDs and barriers in accessing treatment, skills-training or support. Qualitative studies are needed to explore stakeholders' needs, attitudes to and views about online self-help, to optimize intervention design and delivery. METHODS: Focus groups and telephone interviews were conducted with people with BN or BED, and carers of people with anorexia nervosa, between March and September 2018 in the UK. RESULTS: People with EDs and carers perceived online self-help positively in the context of barriers to seeking and accessing treatment and support, despite some seeing it as inferior to face-to-face support. Most reported little experience with online interventions. Participants thought the disadvantages of online interventions could be overcome by reminders, progress summaries, regular engagement and engaging with peers. Receiving guidance was seen as an important functionality in the intervention by people with EDs. CONCLUSIONS: People with EDs and their carers are aware of the potential benefits of online self-help despite having little experience with this form of intervention. A stepped-care approach that utilizes technology-based interventions as a first step and makes such interventions available directly to the consumer may fit the attitudes and needs of stakeholders. The study provides a foundation for future research on design and delivery of ED online self-help.

Online prevention programmes for university students: stakeholder perspectives from six European countries.

BACKGROUND: Students beginning university are at a heightened risk for developing mental health disorders. Online prevention and early intervention programmes targeting mental health have the potential to reduce this risk, however, previous research has shown uptake to be rather poor. Understanding university stakeholders' (e.g. governing level and delivery staff [DS] and students) views and attitudes towards such online prevention programmes could help with their development, implementation and dissemination within university settings. METHODS: Semi-structured interviews, focus groups and online surveys were completed with staff at a governing level, university students and DS (i.e. student health or teaching staff) from six European countries. They were asked about their experiences with, and needs and attitudes towards, online prevention programmes, as well as the factors that influence the translation of these programmes into real-world settings. Results were analyzed using thematic analysis. RESULTS: Participating stakeholders knew little about online prevention programmes for university settings; however, they viewed them as acceptable. The main themes to emerge were the basic conditions and content of the programmes, the awareness and engagement, the resources needed, the usability and the responsibility and ongoing efforts to increase reach. CONCLUSIONS: Overall, although these stakeholders had little knowledge about online prevention programmes, they were open to the idea of introducing them. They could see the potential benefits that these programmes might bring to a university setting as a whole and the individual students and staff members.

Internet-Based Interventions for Carers of Individuals With Psychiatric Disorders, Neurological Disorders, or Brain Injuries: Systematic Review.

BACKGROUND: Nonprofessional carers who provide support to an individual with a psychiatric or neurological disorder will often themselves experience symptoms of stress, anxiety, or low mood, and they perceive that they receive little support. Internet-based interventions have previously been found to be effective in the prevention and treatment of a range of mental health difficulties in carers. OBJECTIVE: This review seeks to establish the status of internet-based interventions for informal (nonprofessional) carers of people with psychiatric or neurological disorders by investigating (1) the number and quality of studies evaluating the efficacy or effectiveness of internet-based carer interventions and (2) the impact that such interventions have on carer mental health, as well as (3) how internet-based interventions compare with other intervention types (eg, face-to-face treatment). METHODS: A systematic literature search was conducted in January 2019 using the EMBASE (1974-present), Ovid MEDLINE (1946-present), PsychARTICLES, PsychINFO (1806-present), and Global Health (1973-present) databases, via the Ovid Technologies database. Search terms included carer, caregiver, online, technology, internet-based, internet, interactive, intervention, and evaluation. Studies selected for inclusion in this review met the following predetermined criteria: (1) delivering an intervention aimed primarily at informal carers, (2) carers supporting individuals with psychiatric disorders, stroke, dementia, or brain injury, (3) the intervention delivered to the carers was primarily internet based, (4) the study reported a pre- and postquantitative measure of carer depression, anxiety, stress, burden, or quality of life, (5) appeared in a peer-reviewed journal, and (6) was accessible in English. RESULTS: A total of 46 studies were identified for inclusion through the detailed search strategy. The search was conducted, and data were extracted independently by 2 researchers. The majority of studies reported that 1 or more measures relating to carer mental health improved following receipt of a relevant intervention, with interventions for carers of people with traumatic brain injury showing a consistent link with improved outcomes. CONCLUSIONS: Studies investigating internet-based interventions for carers of individuals with diverse psychiatric or neurological difficulties show some evidence in support of the effectiveness of these interventions. In addition, such interventions are acceptable to carers. Available evidence is of varying quality, and more high-quality trials are needed. Further research should also establish how specific intervention components, such as structure or interactivity, contribute to their overall efficacy with regard to carer mental health.

An Interview Study of Patient and Caregiver Perspectives on Advance Care Planning in ESRD.

BACKGROUND: Advance care planning (ACP) empowers patients to consider and communicate their current and future treatment goals. However, it can be an emotionally charged process for patients with kidney disease and their caregivers. This study aimed to describe the perspectives and attitudes of patients with end-stage renal disease (ESRD) and their caregivers toward ACP. STUDY DESIGN: Qualitative study. SETTING & PARTICIPANTS: Patients with ESRD (n=24) and their caregivers (n=15) aged 36 to 91 years at various stages of ACP ("not commenced," "in progress," or "completed") from 3 renal services. METHODOLOGY: Semistructured interviews. ANALYTICAL APPROACH: Transcripts were analyzed using thematic analysis. RESULTS: 5 major themes were identified: articulating core values (avoiding futile and undignified treatment, reevaluating terms of dialysis, framing a life worth living, and refusing to be a burden), confronting conversations (signifying death and defeat, accepting inevitable death, and alleviating existential tension), negotiating mutual understanding (broaching taboos and assisting conflicted caregivers), challenging patient autonomy (family pressures to continue dialysis, grief diminishing caregivers' capacity, and leveraging support), and decisional disempowerment (lacking medical transparency and disappointment with clinical disinterest). LIMITATIONS: Only English-speaking patients/caregivers participated in the interview. CONCLUSIONS: ACP provides patients with ESRD and their caregivers a conduit for accepting and planning for impending death and to express treatment preferences based on self-dignity and value of living. However, ACP can be considered taboo, may require caregivers to overcome personal and decisional conflict, and may be complex if patients and caregivers are unable to accept the reality of the patient's illness. We suggest that ACP facilitators and clinicians make ACP more acceptable and less confrontational to patients and caregivers and that strategies be put in place to support caregivers who may be experiencing overwhelming grief or who have conflicting goals, particularly when they are called on to make end-of-life decisions.

Clinicians' Perspectives on Advance Care Planning for Patients With CKD in Australia: An Interview Study.

BACKGROUND: Advance care planning (ACP) empowers patients to consider and communicate their current and future treatment goals. However, ACP is not widely implemented in chronic kidney disease (CKD) care settings. This study aims to describe clinicians' beliefs, challenges, and perspectives of ACP in patients with CKD. STUDY DESIGN: Qualitative study. SETTING & PARTICIPANTS: Nephrologists (n=20), nurses (n=7), and social workers (n=4) with a range of experience in facilitating ACP for patients with CKD across Australia. METHODOLOGY: Semistructured interviews were digitally recorded and transcribed verbatim. ANALYTICAL APPROACH: Transcripts were analyzed using thematic analysis. RESULTS: 5 major themes were identified: facilitating informed decision making (avoiding preconceptions, conveying complete truths, focusing on supportive care, and synchronizing with evolving priorities), negotiating moral boundaries (contending with medical futility and respecting patient vs family autonomy), navigating vulnerable conversations (jeopardizing the therapeutic relationship, compromising professional confidence, emotionally invested, and enriching experiences), professional disempowerment (unsupportive culture, doubting logistical feasibility, and making uncertain judgments), and clarifying responsibilities (governing facilitation, managing tensions, and transforming multidisciplinary relationships). LIMITATIONS: Some findings may be specific to the Australian context. CONCLUSIONS: The tensions among themes reflect that ACP is paradoxically rewarding for clinicians because ACP empowers patients yet can expose personal and professional vulnerabilities. Clinicians believe that a more collaborative approach is needed, with increased efforts to identify the evolving and individualized needs and goals of patients with CKD. Models of ACP that address clinicians' personal and professional vulnerabilities when initiating ACP may foster greater confidence and cultural acceptance of ACP in the CKD setting.

Advance care planning in chronic kidney disease: A survey of current practice in Australia.

AIM: Advance care planning (ACP) in nephrology is widely advocated but not always implemented. The aims of this study were to describe current ACP practice and identify barriers/facilitators and perceived need for health professional education and chronic kidney disease (CKD)-specific approaches. METHODS: An anonymous cross-sectional survey was administered online. Nephrology health professionals in Australia and New Zealand were recruited via professional societies, email lists and nephrology conferences. Multiple regression explored the influence of respondents' attributes on extent of involvement in ACP and willingness to engage in future. RESULTS: A total of 375 respondents included nephrologists (23%), nurses (65%), social workers (4%) and others (8%) with 54% indicated that ACP at their workplace was performed ad hoc and 61% poorly. Perceived barriers included patient/family discomfort (84%), difficulty engaging families (83%), lack of clinician expertise (83%) and time (82%), health professional discomfort (72%), cultural/language barriers (65%), lack of private space (61%) and lack of formal policy/procedures (60%). Respondents overwhelmingly endorsed the need for more dialysis-specific ACP programs (96%) and education (95%). Whilst 85% thought ACP would be optimally performed by specially trained staff, comments emphasized that all clinicians should have a working proficiency. Respondents who were more willing to engage in future ACP tended to be non-physicians (odds ratio (OR) 4.96, 95% confidence intervals (CI) 1.74-14.07) and reported a greater need for CKD-specific ACP materials (OR 10.88, 95% CI 2.38-49.79). CONCLUSION: Advance care planning in nephrology needs support through education and CKD-specific resources. Endorsement by nephrologists is important. A multidisciplinary approach with a gradient of ACP expertise is also recommended.

Diagnosis and stabilisation of familial chylomicronemia syndrome in two infants presenting with hypertriglyceridemia-induced acute pancreatitis.

Familial chylomicronemia syndrome (FCS) is a rare disorder of triglyceride (TG) metabolism caused by loss of function variants in one of five known canonical genes involved in chylomicron lipolysis and clearance-LPL, APOC2, APOA5, LMF1, and GPIHBP1. Pathogenic variants in LPL, which encodes the hydrolytic enzyme lipoprotein lipase, account for over 80%-90% of cases. FCS may present in infancy with hypertriglyceridemia-induced acute pancreatitis and is challenging to manage both acutely and in the long-term. Here, we report our experience managing two unrelated infants consecutively diagnosed with hypertriglyceridemia-induced acute pancreatitis caused by LPL deficiency. Both had elevated TGs at presentation (205 and 30 mmol/L, respectively) and molecular genetic testing confirmed each infant carried a different homozygous pathogenic variant in the LPL gene, specifically, c.987C>A (p.Tyr329Ter) and c.632C>A (p.Thr211Lys). The more severely affected infant had cutaneous xanthomata, lipemia retinalis and lipemic plasma at presentation, and required management in an intensive care setting. Acute stabilisation was achieved using insulin and heparin infusions together with the iterative implementation of a fat-restricted diet, low in long chain triglycerides (LCT) and supplemented with medium chain triglycerides (MCT). In both cases, provision of adequate caloric intake (~110-120 kcal/kg/day) was also found to be important for a sustained TG reduction during the acute phase of management. In summary, a high index of suspicion is required to diagnose FCS in infants with hypertriglyceridemia-induced acute pancreatitis, management of which can be challenging, highlighting the need for more evidence-based recommendations.

Using internet-based self-help to bridge waiting time for face-to-face outpatient treatment for Bulimia Nervosa, Binge Eating Disorder and related disorders: Study protocol of a randomized controlled trial.

BACKGROUND: Eating disorders are serious conditions associated with an impaired health-related quality of life and increased healthcare utilization and costs. Despite the existence of evidence-based treatments, access to treatment is often delayed due to insufficient health care resources. Internet-based self-help interventions may have the potential to successfully bridge waiting time for face-to-face outpatient treatment and, thus, contribute to overcoming treatment gaps. However, little is known about the feasibility of implementing such interventions into routine healthcare. The aim of this study is to analyze the effects and feasibility of an Internet-based self-help intervention (everyBody Plus) specifically designed for patients with Bulimia Nervosa, Binge Eating Disorder and other specified feeding and eating disorders (OSFED) on a waiting list for outpatient face-to-face treatment. The aim of this paper is to describe the study protocol. METHODS: A multi-country randomized controlled trial will be conducted in Germany and the UK. N = 275 female patients awaiting outpatient treatment will be randomly allocated either to the guided online self-help intervention "everyBody Plus" or a waitlist control group condition without access to the intervention. everyBody Plus comprises eight weekly sessions that cover topics related to eating and exercise patterns, coping with negative emotions and stress as well as improving body image. Participants will receive weekly individualized feedback based on their self-monitoring and journal entries. Assessments will take place at baseline, post-intervention as well as at 6- and 12-months follow up. In addition, all participants will be asked to monitor core eating disorder symptoms weekly to provide data on the primary outcome. The primary outcome will be number of weeks after randomization until a patient achieves a clinically relevant improvement in core symptoms (BMI, binge eating, compensatory behaviors) for the first time. Secondary outcomes include frequency of core symptoms and eating disorder related attitudes and behaviors, as well as associated psychopathology. Additional secondary outcomes will be the participating therapists' confidence in treating eating disorders as well as perceived benefits of everyBody Plus for patients. DISCUSSION: To the best of our knowledge, this is the first randomized controlled trial examining the effects of Internet-based self-help for outpatients with eating disorders awaiting face-to-face outpatient treatment. If proven to be effective and successfully implemented, Internet-based self-help programs might be used as a first step of treatment within a stepped-care approach, thus reducing burden and cost for both patients and health care providers.

A web-based intervention for carers of individuals with anorexia nervosa (We Can): Trial protocol of a randomised controlled trial investigating the effectiveness of different levels of support.

BACKGROUND: Anorexia nervosa (AN) is a life-threatening mental disorder that is associated with substantial caregiver burden. Carers of individuals with AN report high levels of distress and self-blame, and insufficient knowledge to help their loved ones. However, carers can have a very important role to play in aiding recovery from AN, and are often highly motivated to assist in the treatment process. This manuscript presents the protocol for a randomised controlled trial (RCT) of We Can, a web-based intervention for carers for people with AN. The study aims to investigate the effectiveness of We Can delivered with different intensities of support. METHODS: The study takes the form of a multi-site, two-country, three group RCT, comparing We Can (a) with clinician messaging support (We Can-Ind), (b) with moderated carer chatroom support (We Can-Chat) and (c) with online forum only (We Can-Forum). Participants will be 303 carers of individuals with AN as well as, where possible, the individuals with AN themselves. Recruitment will be via specialist eating disorder services and carer support services in the UK and Germany. Randomisation of carers to one of the three intervention conditions in a 1:1:1 ratio will be stratified by whether or not the individual with AN has (a) agreed to participate in the study and (b) is a current inpatient. The We Can intervention will be provided to carers online over a period of 12 weeks. Participants will complete self-report questionnaires at pre-intervention (T1), mid-intervention (mediators only; 4-weeks post-randomisation), post-intervention (T2; 3-months post randomisation), and 6 months (T3) and 12 months (T4) after randomisation. The primary outcome variables are carer symptoms of depression and anxiety. Secondary outcome variables will be measured in both carers and individuals with AN. Secondary carer outcome variables will include alcohol and drug use and quality of life, caregiving behaviour, and the acceptability and use of We Can and associated supports. Secondary outcomes measured in individuals with AN will include eating disorder symptoms, and symptoms of depression and anxiety. The study will also evaluate the cost-effectiveness of the three We Can conditions, and test for mediators and moderators of the effects of We Can. The trial is registered at the International Standard Randomisation Controlled Trial Number (ISRCTN) database, registration number: ISRCTN11399850. DISCUSSION: The study will provide insight into the effectiveness of We Can and its optimal method/s of delivery.

Web-based indicated prevention of common mental disorders in university students in four European countries - Study protocol for a randomised controlled trial.

BACKGROUND: Mental disorders and their symptoms are highly prevalent in the university student population, and the transition from secondary to tertiary education is associated with a rise in mental health problems. Existing web-based interventions for the prevention of common mental disorders in student populations often focus on just one disorder and have not been designed specifically for students. There is thus a need for transdiagnostic, student-specific preventative interventions that can be widely disseminated. This two-arm, parallel group randomised controlled trial aims to evaluate the effectiveness and cost-effectiveness of a web-based transdiagnostic mental health problem prevention programme (PLUS) across several universities in four countries. METHOD: Students (N = 5550) will be recruited through a variety of channels and asked to complete a personality assessment to determine whether they are at high risk for developing common mental disorders. Students at high risk will be randomly allocated to either PLUS or a control intervention, which provides practical support around issues commonly experienced at university. Students at low risk will be allocated to the control intervention. Both intervention groups will be assessed at baseline, 4 weeks, 3 months, 6 months and 12 months after randomisation. Depression and generalised anxiety, assessed using the Patient Health Questionnaire and the Generalised Anxiety Disorder scales, will form the primary outcomes in this study. Secondary outcome measures include alcohol and drug use, eating behaviour, self-esteem, and quality of life. The cost-effectiveness of the intervention will also be evaluated. CONCLUSIONS: This study will contribute to understanding the role of transdiagnostic indicated web-based interventions for the prevention of common mental disorders in university students. It will also be one of the first studies to investigate the cost-effectiveness of such interventions. TRIAL REGISTRATION: This trial was registered in the ISRCTN register (ISRCTN15570935) on 12th February 2016.

Identification of FBXL4 as a Metastasis Associated Gene in Prostate Cancer.

Prostate cancer is the most common cancer among western men, with a significant mortality and morbidity reported for advanced metastatic disease. Current understanding of metastatic disease is limited due to difficulty of sampling as prostate cancer mainly metastasizes to bone. By analysing prostate cancer bone metastases using high density microarrays, we found a common genomic copy number loss at 6q16.1-16.2, containing the FBXL4 gene, which was confirmed in larger series of bone metastases by fluorescence in situ hybridisation (FISH). Loss of FBXL4 was also detected in primary tumours and it was highly associated with prognostic factors including high Gleason score, clinical stage, prostate-specific antigen (PSA) and extent of disease, as well as poor patient survival, suggesting that FBXL4 loss contributes to prostate cancer progression. We also demonstrated that FBXL4 deletion is detectable in circulating tumour cells (CTCs), making it a potential prognostic biomarker by 'liquid biopsy'. In vitro analysis showed that FBXL4 plays a role in regulating the migration and invasion of prostate cancer cells. FBXL4 potentially controls cancer metastasis through regulation of ERLEC1 levels. Therefore, FBXL4 could be a potential novel prostate cancer suppressor gene, which may prevent cancer progression and metastasis through controlling cell invasion.