AAV gene therapy for Duchenne muscular dystrophy: the EMBARK phase 3 randomized trial.

Duchenne muscular dystrophy (DMD) is a rare, X-linked neuromuscular disease caused by pathogenic variants in the DMD gene that result in the absence of functional dystrophin, beginning at birth and leading to progressive impaired motor function, loss of ambulation and life-threatening cardiorespiratory complications. Delandistrogene moxeparvovec, an adeno-associated rh74-viral vector-based gene therapy, addresses absent functional dystrophin in DMD. Here the phase 3 EMBARK study aimed to assess the efficacy and safety of delandistrogene moxeparvovec in patients with DMD. Ambulatory males with DMD, ≥4 years to <8 years of age, were randomized and stratified by age group and North Star Ambulatory Assessment (NSAA) score to single-administration intravenous delandistrogene moxeparvovec (1.33 × 1014 vector genomes per kilogram; n = 63) or placebo (n = 62). At week 52, the primary endpoint, change from baseline in NSAA score, was not met (least squares mean 2.57 (delandistrogene moxeparvovec) versus 1.92 (placebo) points; between-group difference, 0.65; 95% confidence interval (CI), -0.45, 1.74; P = 0.2441). Secondary efficacy endpoints included mean micro-dystrophin expression at week 12: 34.29% (treated) versus 0.00% (placebo). Other secondary efficacy endpoints at week 52 (between-group differences (95% CI)) included: Time to Rise (-0.64 (-1.06, -0.23)), 10-meter Walk/Run (-0.42 (-0.71, -0.13)), stride velocity 95th centile (0.10 (0.00, 0.19)), 100-meter Walk/Run (-3.29 (-8.28, 1.70)), time to ascend 4 steps (-0.36 (-0.71, -0.01)), PROMIS Mobility and Upper Extremity (0.05 (-0.08, 0.19); -0.04 (-0.24, 0.17)) and number of NSAA skills gained/improved (0.19 (-0.67, 1.06)). In total, 674 adverse events were recorded with delandistrogene moxeparvovec and 514 with placebo. There were no deaths, discontinuations or clinically significant complement-mediated adverse events; 7 patients (11.1%) experienced 10 treatment-related serious adverse events. Delandistrogene moxeparvovec did not lead to a significant improvement in NSAA score at week 52. Some of the secondary endpoints numerically favored treatment, although no statistical significance can be claimed. Safety was manageable and consistent with previous delandistrogene moxeparvovec trials. ClinicalTrials.gov: NCT05096221.

A feasibility trial of olanzapine for young people with Anorexia Nervosa (OPEN): clinicians' perspectives.

BACKGROUND: The OPEN feasibility trial testing olanzapine in anorexia nervosa (AN) in young people (YP) was not successful due to poor recruitment. This study aims to understand clinicians' views and experiences of using olanzapine in AN and the challenges in implementing the trial in National Health Service (NHS) clinical settings. METHODS: We conducted qualitative interviews with eating disorders (ED) clinicians involved with the study (n = 11). Framework analysis was applied to qualitative data to identify barriers and facilitators to recruitment and study implementation. A web-based semi-structured Qualtrics survey was administered to ED clinicians (n = 24). Findings from the survey were used to corroborate and expand on the information derived from qualitative interviews. RESULTS: Qualitative analysis identified four main themes: (1) Acknowledging Service User (SU) / Family Concerns, (2) Prioritising person-centred care, (3) Limited Service Capacity and (4) Study eligibility criteria. Subthemes are outlined accordingly. Clinicians appeared confident addressing SU concerns around olanzapine in clinical discussions, but timing was critical, and olanzapine was considered one aspect of treatment that needed to align with their holistic approach. Service pressures restricted opportunities for recruitment and the ability to offer regular review. At the same time, some YP were ineligible for the trial, as they were already taking olanzapine, or needed to be prescribed it more promptly than the study procedures allowed. Survey findings underlined confidence in prescribing and informing on olanzapine, the various possible benefits of olanzapine besides weight gain, and the importance of therapeutic alliances and informed consent. Both data sets highlight the need for further evidence on long-term safety, side effects and efficacy of olanzapine use for AN. Where clinical service capacity is at a premium, research implementation is not prioritised, particularly in intensive clinical settings. CONCLUSIONS: Findings provide first-hand insight into individual and systemic challenges with research implementation in the NHS, which need to be considered when designing future clinical research studies. We emphasise a person-centred approach when discussing olanzapine to consider a holistic recovery from AN beyond weight-gain as an isolated outcome for improvement.

Although olanzapine, an atypical antipsychotic medication, is commonly used in eating disorder services across the world, it is not currently recommended by clinical guidelines in the United Kingdom. We interviewed clinicians working in eating disorder services that took part in a research study looking at olanzapine for young people with anorexia nervosa (AN), and published a survey asking clinicians about their experiences with and views on using olanzapine for AN. The lack of official long-term evidence concerned both clinicians and services users (SU)s. Many clinicians suggested that people with AN might be fearful of weight-gain as a side effect from olanzapine and therefore declined to take part in the study. Having a good relationship built on trust and consistency was deemed very important by clinicians to talk about medication and to provide good health care that focuses on the needs of SUs. Clinicians explained that it was a challenge to introduce the study to SUs in their day-to-day work, as mental health services are increasingly overburdened. Clinicians were also clear that SUs should only be prescribed olanzapine within the study if it was at the right time for them and fitted their treatment pathway.

Thrombospondin-4 as potential cerebrospinal fluid biomarker for therapy response in pediatric spinal muscular atrophy.

BACKGROUND AND PURPOSE: Spinal muscular atrophy (SMA) as the second most common neurodegenerative disorder in childhood is characterized by the deficiency of survival of motor neuron (SMN) protein leading predominantly to degeneration of alpha motor neurons and consequently to progressive muscle weakness and atrophy. Besides some biomarkers like SMN2 copy number therapeutic biomarkers for SMA with known relevance for neuromuscular transmission are lacking. Here, we examined the potential of Thrombospondin-4 (TSP4) to serve as a cerebrospinal fluid (CSF) biomarker, which may also indicate treatment response. METHODS: We used untargeted proteomic analyses to determine biomarkers in CSF samples derived from pediatric pre-symptomatic (n = 6) and symptomatic (n = 4) SMA patients. The identified biomarker TSP4 was then validated in additional 68 CSF samples (9 adult and 24 pediatric SMA patients, 5 adult and 13 pediatric non-disease controls in addition to 17 pediatric disease controls) by enzyme-linked immunosorbent assay (ELISA) as an additional analytical approach. RESULTS: Untargeted proteomic analyses of CSF identified a dysregulation of TSP4 and revealed a difference between pre-symptomatic SMA patients and patients identified after the onset of first symptoms. Subsequent ELISA-analyses showed that TSP4 is decreased in pediatric but not adult SMA patients. CSF of pediatric patients with other neurological disorders demonstrated no alteration of TSP4 levels. Furthermore, CSF TSP4 levels of pediatric SMA patients increased after first dose of Nusinersen. CONCLUSIONS: We found that TSP4 levels are exclusively reduced in CSF of pediatric SMA patients and increase after treatment, leading us to the hypothesis that TSP4 could serve as a CSF biomarker with the potential to monitor treatment response in pediatric SMA patients. Moreover, TSP4 enable to distinguish pre-symptomatic and symptomatic patients suggesting a potential to serve as a stratification marker.

Early intervention for eating disorders.

PURPOSE OF REVIEW: Research on early intervention for eating disorders has started to gain traction and examples of this in practice are increasing. This review summarizes findings over the past 3 years, focusing on the clinical effectiveness of early intervention in practice and the barriers and facilitators to its implementation. RECENT FINDINGS: Recent developments in early intervention for eating disorders can be divided into three broad themes: research that has examined the efficacy of early intervention pathways in practice, research that has informed understanding of the target patient groups of early intervention (via clinical staging models, e.g.), and research that has suggested new ways to progress early intervention, towards becoming a standard part of best practice care. SUMMARY: Early intervention pathways have shown promising clinical outcomes and are viewed positively by patients, clinicians and other stakeholders. However, more robust trials of their efficacy, effectiveness and cost-effectiveness are needed. Additionally, barriers to early intervention have been identified (e.g. delayed help-seeking); research must now develop and evaluate strategies to address these. Finally, the early intervention models in practice are underpinned partly by clinical staging models for eating disorders, which require further development, especially for eating disorders other than anorexia nervosa.

Experiences of intensive treatment for people with eating disorders: a systematic review and thematic synthesis.

BACKGROUND: Eating disorders are complex difficulties that impact the individual, their supporters and society. Increasing numbers are being admitted to intensive treatment settings (e.g., for inpatient treatment, day-patient treatment or acute medical treatment). The lived experience perspectives of what helps and hinders eating disorder recovery during intensive treatment is an emerging area of interest. This review aims to explore patients' perspectives of what helps and hinders recovery in these contexts. METHODS: A systematic review was conducted to identify studies using qualitative methods to explore patients' experiences of intensive treatment for an eating disorder. Article quality was assessed using the Critical Appraisal Skill Programme (CASP) checklist and thematic synthesis was used to analyse the primary research and develop overarching analytical themes. RESULTS: Thirty articles met inclusion criteria and were included in this review. The methodological quality was mostly good. Thematic synthesis generated six main themes; collaborative care supports recovery; a safe and terrifying environment; negotiating identity; supporting mind and body; the need for specialist support; and the value of close others. The included articles focused predominantly on specialist inpatient care and were from eight different countries. One clear limitation was that ethnicity data were not reported in 22 out of the 30 studies. When ethnicity data were reported, participants predominantly identified as white. CONCLUSIONS: This review identifies that a person-centred, biopsychosocial approach is necessary throughout all stages of eating disorder treatment, with support from a sufficiently resourced and adequately trained multidisciplinary team. Improving physical health remains fundamental to eating disorder recovery, though psychological support is also essential to understand what causes and maintains the eating disorder and to facilitate a shift away from an eating disorder dominated identity. Carers and peers who instil hope and offer empathy and validation are valuable additional sources of support. Future research should explore what works best for whom and why, evaluating patient and carer focused psychological interventions and dietetic support during intensive treatment. Future research should also explore the long-term effects of, at times, coercive and distressing treatment practices and determine how to mitigate against potential iatrogenic harm.

Some people with eating disorders will need intensive treatment (e.g., inpatient treatment, day-patient treatment or acute medical treatment) during the course of their illness. Understanding what helps and hinders eating disorder recovery during intensive treatment is an important part of developing effective interventions. This review summarises research exploring people with eating disorders' perspectives of intensive treatment, with the aim of identifying what helps and hinders eating disorder recovery. We searched in scientific databases for all published qualitative studies that explored people with eating disorders' perspectives of intensive treatment. Thirty studies meet the inclusion criteria of this literature review. The results sections of these studies were analysed by extracting relevant findings relating to eating disorder recovery. We found that a person-centred, holistic approach is necessary throughout all stages of eating disorder treatment, with support from healthcare professionals and carers with specialist knowledge of how to support people with eating disorders. Improving physical health is fundamental to eating disorder recovery. However, psychological support is also essential to help people with eating disorders to understand what causes and maintains the eating disorder and support them to move away from an eating disorder dominated identity. Areas for future research are outlined.

Views and experiences of eating disorders treatments in East Asia: a meta-synthesis.

INTRODUCTION: Although there have been qualitative meta-syntheses on experiences of eating disorders treatments, there is a paucity of syntheses specifically examining the perspectives and experiences of eating disorders treatments (ED) in East Asia (EA). Such synthesis could facilitate a better understanding of culture-specific perspectives and experiences. This review complements a quantitative scoping review published on ED treatments in EA (Yim & Schmidt, 2023), where most interventions reviewed focused on cognitive behavioural therapy (CBT) and internet interventions. The present meta-synthesis summarises stakeholders' views on treatments and to synthesise clinical and research recommendations. METHOD: A systematic search of five databases and a citation search were conducted to identify relevant studies and data were analysed using thematic synthesis. Out of the 301 studies found, a total of 12 papers were included in the analysis. RESULTS: A diverse range of treatments, such as family therapy, paediatric/psychiatric inpatient care, CBT, and counselling, were discussed. Three overarching themes were identified: Delineating Physical and Psychological Recovery; 'I am not alone in this battle'; and Barriers to Change. The themes further delve into the various obstacles to recovery, including financial concerns and limited access to professionals and services. Culture-specific factors include family obligations and promoting family harmony. Balancing interdependence and independence from one's family, as well as understanding family body ideals versus broader societal body ideals, are important considerations in ED interventions. DISCUSSION: Some themes paralleled other qualitative syntheses, highlighting improved family relationships, perceived authoritarianism in treatments, and financial barriers. The review extends beyond the previous findings, revealing nuanced factors like family roles, cultural values, and norms. Clinical recommendations include incorporating family context in treatment and considering cultural influences on body image ideals. Capacity building through telemedicine and increased training is essential for advancing ED treatment in East Asia. Continued research is needed to better understand and treat people affected by ED in EA.

Skeletal muscle vulnerability in a child with Pitt-Hopkins syndrome.

BACKGROUND: TCF4 acts as a transcription factor that binds to the immunoglobulin enhancer Mu-E5/KE5 motif. Dominant variants in TCF4 are associated with the manifestation of Pitt-Hopkins syndrome, a rare disease characterized by severe mental retardation, certain features of facial dysmorphism and, in many cases, with abnormalities in respiratory rhythm (episodes of paroxysmal tachypnea and hyperventilation, followed by apnea and cyanosis). Frequently, patients also develop epilepsy, microcephaly, and postnatal short stature. Although TCF4 is expressed in skeletal muscle and TCF4 seems to play a role in myogenesis as demonstrated in mice, potential myopathological findings taking place upon the presence of dominant TCF4 variants are thus far not described in human skeletal muscle. METHOD: To address the pathological effect of a novel deletion affecting exons 15 and 16 of TCF4 on skeletal muscle, histological and immunofluorescence studies were carried out on a quadriceps biopsy in addition to targeted transcript studies and global proteomic profiling. RESULTS: We report on muscle biopsy findings from a Pitt-Hopkins patient with a novel heterozygous deletion spanning exon 15 and 16 presenting with neuromuscular symptoms. Microscopic characterization of the muscle biopsy revealed moderate fiber type I predominance, imbalance in the proportion of fibroblasts co-expressing Vimentin and CD90, and indicate activation of the complement cascade in TCF4-mutant muscle. Protein dysregulations were unraveled by proteomic profiling. Transcript studies confirmed a mitochondrial vulnerability in muscle and confirmed reduced TCF4 expression. CONCLUSION: Our combined findings, for the first time, unveil myopathological changes as phenotypical association of Pitt-Hopkins syndrome and thus expand the current clinical knowledge of the disease as well as support data obtained on skeletal muscle of a mouse model.

Exploring neurocognitive features in adolescents and young adults with anorexia nervosa: Evidence from a longitudinal study.

OBJECTIVE: We aimed to evaluate longitudinal changes in set-shifting and central coherence in a predominantly adolescent cohort with anorexia nervosa (AN) and to explore whether these factors predict long-term eating disorder outcomes. METHOD: Ninety-two female patients with AN (mean age: 16.2, range: 13-21 years) completed neurocognitive tests (Rey Complex Figure Test, Adapted Version of the Wisconsin Card Sorting Test) before and after 12 months of psychotherapeutic treatment (n = 45 Maudsley AN Treatment, MANTRa; n = 47 standard psychotherapy; groups not randomised). Eating disorder severity was assessed at baseline, after 6, 12 and 18 months. RESULTS: Central coherence (indicated by an increase in the Rey Figure Style Index) and set-shifting (indicated by a reduction in the percentage of perseverative errors) significantly improved over the course of treatment, with similar outcomes across groups. Lower central coherence was associated with higher eating disorder severity. Individuals with lower baseline set-shifting ability tended to have worse eating disorder outcomes in the long-term. However, this trend did not reach statistical significance in a multilevel linear mixed model. CONCLUSIONS: Neurocognitive difficulties in adolescents and young adults with AN can improve after treatment. Interventions specifically addressing flexibility in thinking and behaviour may contribute to treatment success.

Clinician perspectives on how change occurs in multi-family therapy for adolescent anorexia nervosa: a qualitative study.

BACKGROUND: Multi-family Therapy (MFT) is being increasingly used in specialist eating disorder services internationally. Despite evidence of its efficacy, little is understood about the treatment mechanisms and what specifically promotes change. This study aimed to understand clinician perspectives on how change occurs during MFT. METHODS: Clinicians with (a) 5 or more years' experience facilitating MFT and (b) who had facilitated a minimum of two MFT groups were eligible for this study. Two individual interviews and four semi-structured focus groups were conducted online. Recordings were transcribed verbatim and analysed using reflexive thematic analysis. RESULTS: Twelve clinicians (five systemic/family psychotherapists, five clinical psychologists, and two consultant child and adolescent psychiatrists) from six different specialist services in the UK participated. Four main inter-connected themes describing how change is perceived to occur were generated; (1) Intensity and immediacy, (2) Flexibility, (3) New ideas and channels of learning and (4) Containment. CONCLUSIONS: Current data matches closely with young person and parent experiences of MFT and intensive day treatment and how they perceive change to occur. Quantitative data are now needed to evaluate the impact of these factors on outcome. Plain English Summary Multi-family Therapy (MFT) is being increasingly used in specialist eating disorder services internationally. While there is evidence that it is helpful, little is understood about how the treatment works and what specifically promotes change. This study aimed to understand how clinician believe change to occur during MFT for young people and their family members. Clinicians with (a) five or more years' experience facilitating MFT and (b) who had facilitated a minimum of two MFT groups were eligible for this study. Two individual interviews and four semi-structured focus groups were conducted online. Recordings were written out word-for-word and analysed using reflexive thematic analysis, a commonly used method for analysing this type of data. Twelve clinicians (five systemic/family psychotherapists, five clinical psychologists, and two consultant child and adolescent psychiatrists) from six different specialist services in the UK participated. Four related themes describing how change is perceived to occur were generated; (1) Intensity and immediacy, (2) Flexibility, (3) New ideas and channels of learning and (4) Containment. Current data matches closely with young person and parent experiences of MFT and intensive day treatment and how they perceive change to occur. These factors now need to be tested in future research.

Concurrent self-administered transcranial direct current stimulation and attention bias modification training in binge eating disorder: feasibility randomised sham-controlled trial.

BACKGROUND: Binge eating disorder (BED) is a common and disabling condition, typically presenting with multiple psychiatric and obesity-related comorbidities. Evidence-based treatments are either resource-intensive (psychotherapies) or have side-effects (medications): these achieve remission in around 50% of cases. Novel treatments are needed. AIMS: This randomised sham-controlled trial aimed to assess feasibility, acceptability and preliminary efficacy of at-home, self-administered transcranial direct current stimulation (tDCS) and attention bias modification training (ABMT) in adults with binge eating disorder. METHOD: Eighty-two participants with binge eating disorder were randomly allocated to real tDCS with ABMT, sham tDCS with ABMT, ABMT only or waitlist control. Intervention groups received ten sessions of their allocated treatment over 2-3 weeks. tDCS (2 mA, 20 min) was self-administered using a bilateral (anode right/cathode left) montage targeting the dorsolateral prefrontal cortex. Outcomes were assessed at baseline, post-treatment and 6-week follow-up. RESULTS: Prespecified feasibility criteria (recruitment ≥80 participants and retention rate ≥75%) were exceeded, and treatment completion rates were high (98.7%). All interventions reduced binge eating episodes, eating disorder symptoms and related psychopathology between baseline and follow-up, relative to waitlist control (medium-to-large between-group effect sizes for change scores). Small-to-medium effect sizes for change scores favoured real tDCS with ABMT versus comparators, suggesting the verum intervention produces superior outcomes. CONCLUSIONS: At-home, self-administered tDCS with ABMT is feasible and acceptable, and preliminary data on efficacy are promising. This approach could be a useful and scalable alternative or adjunct to established treatments for binge eating disorder. Confirmatory trials can, and should, be pursued.

[Pharmacological treatment of posttraumatic stress disorder]. / Pharmakologische Behandlung der Posttraumatischen Belastungsstörung.

In addition to trauma-focussed psychotherapy, pharmacological treatment is often unavoidable, especially in patients with severe posttraumatic stress disorder (PTSD). As long as comorbid disorders do not dictate the pharmacotherapy approach, sertraline and paroxetine, along with other off-label prescribable substances approved in Germany, can be used for the treatment of PTSD. Venlafaxine, in particular, has shown good effectiveness in studies, whereas risperidone has shown lower effectiveness in augmentation. Overall, only a small to medium effect size is to be expected for all substances. Psychopharmacotherapy plays an important role in addressing sleep disorders, which are highly prevalent in PTSD. Treatment of trauma-related nightmares can be attempted with doxazosin or clonidine. In contrast, there are limited empirical data available for sleep disorders associated with PTSD, but the pharmacological treatment of insomnia can provide some guidance.

Efficacy and cost-effectiveness of a digital guided self-management intervention to support transition from intensive care to community care in anorexia nervosa (TRIANGLE): pragmatic multicentre randomised controlled trial and economic evaluation.

Background: There is uncertainty regarding how best to support patients with anorexia nervosa following inpatient or day care treatment. This study evaluated the impact of augmenting intensive treatment with a digital, guided, self-management intervention (ECHOMANTRA) for patients with anorexia nervosa and their carers. Methods: In this pragmatic multicentre randomised controlled trial and economic evaluation, patients with a diagnosis of anorexia nervosa or atypical anorexia nervosa, aged 16+ and attending one of the 31 inpatient or day-patient services in the UK were randomised with one of their carers to receive ECHOMANTRA plus treatment as usual (TAU), or TAU alone. ECHOMANTRA was hosted on a digital platform and included a workbook, recovery-oriented video-clips and online facilitated groups (patients only, carers only, joint patient-carer). Participants were randomised on a 1:1 ratio using a minimisation algorithm to stratify by site (N = 31) and severity (defined by BMI <15 and ≥ 15 kg/m2 at baseline). The primary outcome was patient depression, anxiety, and stress at 12 months. Primary and secondary outcomes were compared between trial arms on an intention-to-treat basis (ITT). This trial is registered with the ISRSTN registry, ISRCTN14644379. Findings: Between July 01, 2017 and July 20, 2020, 371 patient-carer dyads were enrolled and randomly assigned to ECHOMANTRA + TAU (N = 185) or TAU alone (N = 186). There were no significant differences between trial arms with regards to the primary outcome (completed by N = 143 patients in the TAU group, Mean = 61.7, SD = 29.4 and N = 109 patients in the ECHOMANTRA + TAU group, Mean = 58.3, SD = 26.9; estimated mean difference 0.48 points; 95% CI -5.36 to 6.33; p = 0.87). Differences on secondary outcomes were small and non-significant (standardised effect size estimates ≤0.25). Five patients died (2 from suicide and 3 from physical complications) over the course of the trial, and this was unrelated to their participation in the study. Interpretation: ECHOMANTRA added to TAU was not superior to TAU alone in reducing patient depression, anxiety, and stress symptoms. This may be explained by limited engagement with the intervention materials and changes in usual care practices since the beginning of the trial. Funding: National Institute for Health Research (NIHR), under its Health Technology Assessment Programme (HTA) Programme (Grant Reference Number 14/68/09). NIHR Maudsley Biomedical Research Centre (BRC), South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, Psychology and Neuroscience, and King's College London. NIHR Applied Research Collaboration South London (NIHR ARC South London) at King's College Hospital NHS Foundation Trust.

Increased Diagnostic Yield by Reanalysis of Whole Exome Sequencing Data in Mitochondrial Disease.

Background: The genetic diagnosis of mitochondrial disorders is complicated by its genetic and phenotypic complexity. Next generation sequencing techniques have much improved the diagnostic yield for these conditions. A cohort of individuals with multiple respiratory chain deficiencies, reported in the literature 10 years ago, had a diagnostic rate of 60% by whole exome sequencing (WES) but 40% remained undiagnosed. Objective: We aimed to identify a genetic diagnosis by reanalysis of the WES data for the undiagnosed arm of this 10-year-old cohort of patients with suspected mitochondrial disorders. Methods: The WES data was transferred and processed by the RD-Connect Genome-Phenome Analysis Platform (GPAP) using their standardized pipeline. Variant prioritisation was carried out on the RD-Connect GPAP. Results: Singleton WES data from 14 individuals was reanalysed. We identified a possible or likely genetic diagnosis in 8 patients (8/14, 57%). The variants identified were in a combination of mitochondrial DNA (n = 1, MT-TN), nuclear encoded mitochondrial genes (n = 2, PDHA1, and SUCLA2) and nuclear genes associated with nonmitochondrial disorders (n = 5, PNPLA2, CDC40, NBAS and SLC7A7). Variants in both the NBAS and CDC40 genes were established as disease causing after the original cohort was published. We increased the diagnostic yield for the original cohort by 15% without generating any further genomic data. Conclusions: In the era of multiomics we highlight that reanalysis of existing WES data is a valid tool for generating additional diagnosis in patients with suspected mitochondrial disease, particularly when more time has passed to allow for new bioinformatic pipelines to emerge, for the development of new tools in variant interpretation aiding in reclassification of variants and the expansion of scientific knowledge on additional genes.

Distinct personality profiles associated with disease risk and diagnostic status in eating disorders.

BACKGROUND: Personality traits have been associated with eating disorders (EDs) and comorbidities. However, it is unclear which personality profiles are premorbid risk rather than diagnostic markers. METHODS: We explored associations between personality and ED-related mental health symptoms using canonical correlation analyses. We investigated personality risk profiles in a longitudinal sample, associating personality at age 14 with onset of mental health symptoms at ages 16 or 19. Diagnostic markers were identified in a sample of young adults with anorexia nervosa (AN, n = 58) or bulimia nervosa (BN, n = 63) and healthy controls (n = 47). RESULTS: Two significant premorbid risk profiles were identified, successively explaining 7.93 % and 5.60 % of shared variance (Rc2). The first combined neuroticism (canonical loading, rs = 0.68), openness (rs = 0.32), impulsivity (rs = 0.29), and conscientiousness (rs = 0.27), with future onset of anxiety symptoms (rs = 0.87) and dieting (rs = 0.58). The other, combined lower agreeableness (rs = -0.60) and lower anxiety sensitivity (rs = -0.47), with future deliberate self-harm (rs = 0.76) and purging (rs = 0.55). Personality profiles associated with "core psychopathology" in both AN (Rc2 = 80.56 %) and BN diagnoses (Rc2 = 64.38 %) comprised hopelessness (rs = 0.95, 0.87) and neuroticism (rs = 0.93, 0.94). For BN, this profile also included impulsivity (rs = 0.60). Additionally, extraversion (rs = 0.41) was associated with lower depressive risk in BN. LIMITATIONS: The samples were not ethnically diverse. The clinical cohort included only females. There was non-random attrition in the longitudinal sample. CONCLUSIONS: The results suggest neuroticism and impulsivity as risk and diagnostic markers for EDs, with neuroticism and hopelessness as shared diagnostic markers. They may inform the design of more personalised prevention and intervention strategies.

A framework for a brain-derived nosology of psychiatric disorders.

Current psychiatric diagnoses are not defined by neurobiological measures which hinders the development of therapies targeting mechanisms underlying mental illness 1,2 . Research confined to diagnostic boundaries yields heterogeneous biological results, whereas transdiagnostic studies often investigate individual symptoms in isolation. There is currently no paradigm available to comprehensively investigate the relationship between different clinical symptoms, individual disorders, and the underlying neurobiological mechanisms. Here, we propose a framework that groups clinical symptoms derived from ICD-10/DSM-V according to shared brain mechanisms defined by brain structure, function, and connectivity. The reassembly of existing ICD-10/DSM-5 symptoms reveal six cross-diagnostic psychopathology scores related to mania symptoms, depressive symptoms, anxiety symptoms, stress symptoms, eating pathology, and fear symptoms. They were consistently associated with multimodal neuroimaging components in the training sample of young adults aged 23, the independent test sample aged 23, participants aged 14 and 19 years, and in psychiatric patients. The identification of symptom groups of mental illness robustly defined by precisely characterized brain mechanisms enables the development of a psychiatric nosology based upon quantifiable neurobiological measures. As the identified symptom groups align well with existing diagnostic categories, our framework is directly applicable to clinical research and patient care.

Effects of repetitive transcranial magnetic stimulation in children and young people with psychiatric disorders: a systematic review.

Repetitive transcranial magnetic stimulation (rTMS) has demonstrated benefits in adults with psychiatric disorders, but its clinical utility in children and young people (CYP) is unclear. This PRISMA systematic review used published and ongoing studies to examine the effects of rTMS on disorder-specific symptoms, mood and neurocognition in CYP with psychiatric disorders. We searched Medline via PubMed, Embase, PsychINFO via OVID, and Clinicaltrials.gov up to July 2023. Eligible studies involved multiple-session (i.e., treatment) rTMS in CYP (≤ 25 years-old) with psychiatric disorders. Two independent raters assessed the eligibility of studies and extracted data using a custom-built form. Out of 78 eligible studies (participant N = 1389), the majority (k = 54; 69%) reported an improvement in at least one outcome measure of disorder-specific core symptoms. Some studies (k = 21) examined rTMS effects on mood or neurocognition,: findings were largely positive. Overall, rTMS was well-tolerated with minimal side-effects. Of 17 ongoing or recently completed studies, many are sham-controlled RCTs with better blinding techniques and a larger estimated participant enrolment. Findings provide encouraging evidence for rTMS-related improvements in disorder-specific symptoms in CYP with different psychiatric disorders. However, in terms of both mood (for conditions other than depression) and neurocognitive outcomes, evidence is limited. Importantly, rTMS is well-tolerated and safe. Ongoing studies appear to be of improved methodological quality; however, future studies should broaden outcome measures to more comprehensively assess the effects of rTMS and develop guidance on dosage (i.e., treatment regimens).