Correlation of mitochondrial respiration in platelets, peripheral blood mononuclear cells and muscle fibers.

There is a growing interest for the possibility of using peripheral blood cells (including platelets) as markers for mitochondrial function in less accessible tissues. Only a few studies have examined the correlation between respiration in blood and muscle tissue, with small sample sizes and conflicting results. This study investigated the correlation of mitochondrial respiration within and across tissues. Additional analyses were performed to elucidate which blood cell type would be most useful for assessing systemic mitochondrial function. There was a significant but weak within tissue correlation between platelets and peripheral blood mononuclear cells (PBMCs). Neither PBMCs nor platelet respiration correlated significantly with muscle respiration. Muscle fibers from a group of athletes had higher mass-specific respiration, due to higher mitochondrial content than non-athlete controls, but this finding was not replicated in either of the blood cell types. In a group of patients with primary mitochondrial diseases, there were significant differences in blood cell respiration compared to healthy controls, particularly in platelets. Platelet respiration generally correlated better with the citrate synthase activity of each sample, in comparison to PBMCs. In conclusion, this study does not support the theory that blood cells can be used as accurate biomarkers to detect minor alterations in muscle respiration. However, in some instances, pronounced mitochondrial abnormalities might be reflected across tissues and detectable in blood cells, with more promising findings for platelets than PBMCs.

Neurocognitive development after pediatric brain tumor - a longitudinal, retrospective cohort study.

Survivors of Pediatric Brain Tumors (PBTs) treated with cranial radiation therapy (CRT) often experience a decline in neurocognitive test scores. Less is known about the neurocognitive development of non-irradiated survivors of PBTs. The aim of this study was to statistically model neurocognitive development after PBT in both irradiated and non-irradiated survivors and to find clinical variables associated with the rate of decline in neurocognitive scores. A total of 151 survivors were included in the study. Inclusion criteria: Diagnosis of PBT between 2001 and 2013 or earlier diagnosis of PBT and turning 18 years of age between 2006 and 2013. Exclusion criteria: Death within a year from diagnosis, neurocutaneous syndromes, severe intellectual disability. Clinical neurocognitive data were collected retrospectively from medical records. Multilevel linear modeling was used to evaluate the rate of decline in neurocognitive measures and factors associated with the same. A decline was found in most measures for both irradiated and non-irradiated survivors. Ventriculo-peritoneal (VP) shunting and treatment with whole-brain radiation therapy (WBRT) were associated with a faster decline in neurocognitive scores. Male sex and supratentorial lateral tumor were associated with lower scores. Verbal learning measures were either stable or improving. Survivors of PBTs show a pattern of decline in neurocognitive scores irrespective of treatment received, which suggests the need for routine screening for neurocognitive rehabilitation. However, survivors treated with WBRT and/or a VP shunt declined at a faster rate and appear to be at the highest risk of negative neurocognitive outcomes and to have the greatest need for neurocognitive rehabilitation.

Healthcare use in patients with cardiovascular disease and depressive symptoms - The impact of a nurse-led internet-delivered cognitive behavioural therapy program. A secondary analysis of a RCT.

Background: Depressive symptoms in patients with cardiovascular disease (CVD) can lead to increased healthcare use. In a randomized controlled trial (ClinicalTrials.gov, NCT02778074), we reported that a 9-week internet-delivered cognitive behavioural therapy (iCBT) program (n = 72) compared to an online discussion forum (ODF) (n = 72) had moderate to large effect on depression in CVD outpatients. In this secondary analysis, we aimed to describe and compare the effect of iCBT compared to ODF regarding healthcare use and to identify factors impacting healthcare use in these groups. Methods: Data on healthcare use were retrieved from care data registries in five hospitals in Southeastern Sweden. Results: The year prior to intervention, the iCBT group had a mean of 31 outpatient clinic/primary care contacts per patient compared with 21 contacts the year after. The corresponding numbers for the ODF group were 37 and 25. The decrease was 32 % in both groups and did not differ significantly (p = 0.261 and p = 0.354) between the groups. Regarding hospital admissions, the iCBT group had 0.8 admissions per patient the year before and 0.6 the year after the intervention, a decrease by 25 %, whereas the ODF group had 1.1 and 0.6 admissions respectively, a decrease by 45 %. The difference was not statistically significant (p = 0.270 and p = 0.883) between the groups. Improvement in depressive symptoms post intervention were significantly (Beta = 0.459, p = 0.047) associated with a decrease in number of outpatient contacts in the iCBT group. In the ODF group, better mental health-related quality of life post intervention was significantly (Beta = -0.429, p = 0.045) associated with a decrease in number of hospital admissions. Conclusion: Reduced depressive symptom scores following intervention were associated with lower outpatient service use, but iCBT was not superior compared to ODF. This implicates that reducing depression in CVD patients, regardless of the type of internet-delivered intervention used, is important since it may reduce healthcare use in these patients.

Developing and designing an internet-based support and education program for patients awaiting kidney transplantation with deceased donors through: a Delphi study.

AIMS: The aim of this study was to develop and refine the content and design of an internet-based support and education program for patients awaiting kidney transplantation from deceased donors. DESIGN: A Delphi process was used. METHODS: A prototype internet-based intervention was drafted, based on previous research. The intervention included educational and psychological support to manage the uncertain waiting time and specific education enabling preparation for transplantation and adjustment to life after transplantation. In a two-round Delphi process, patients who had received a kidney transplant from a deceased donor within the last 2 years (n = 27), significant others (n = 6), health-care personnel with renal (n = 20) or transplant (n = 14) expertise, rated importance of content and design aspects of the prototype intervention on a 5-point scale using web questionnaires. A median of ≥ 3 was considered as consensus. Quantitative data was analyzed using descriptive statistics. Free text answers were encouraged and analyzed using deductive content analysis. The STROBE-checklist was used. RESULTS: Consensus was reached for all suggested content and design items in round 1, with median ratings of 4 or 5. Qualitative analysis from round 1 suggested four new content and design items which were rated in round 2, on all which consensus was reached; information about life with young children as relatives, expansion of kidney transplantation specific information, program extension by one week and individualization by making information available based on individual needs. CONCLUSION: There was consensus among heterogenous experts regarding suggested educational and psychological support content and design aspects, and additional content and design aspects were identified for an internet-based support and education program for patients awaiting kidney transplantation from deceased donors.

The effects of internet-based cognitive behavior therapy for depression in cardiovascular disease on symptoms of anxiety: A secondary analysis of a randomized trial.

AIMS: The aims of this study were to evaluate: (I) the short- and long-term effects of the internet-based cognitive behavior (iCBT) program on symptoms of distress and fear disorder in CVD patients, and (II) the association between changes in depression and changes in symptoms of distress and fear disorder from baseline to 12-months follow-up. METHODS AND RESULTS: Secondary analysis of data collected in a randomized controlled study evaluating the effects on depression of an iCBT program compared to an online discussion forum (ODF) in CVD patients (n = 144). Data were collected at baseline, at post-intervention (nine weeks), and at 6- and 12-month follow-up.The results showed that symptoms of distress disorder were statistically significantly more reduced in the iCBT group than the ODF group. For symptoms of fear disorder, no differences were found except for avoidance, which showed a statistically significant reduction in the iCBT group. The long-term analysis in the iCBT group showed that CAQ total score and fear decreased from baseline to 6- and 12-months follow-up respectively. Avoidance and attention both decreased statistically significantly from baseline to post-intervention, but not between post-intervention and 12-months follow-up. CONCLUSION: The results suggest that the iCBT program targeted depression in CVD patients successfully reduced symptoms of distress disorder, and to a lesser extent symptoms of fear disorder. Change in depression was more strongly associated with change in distress than change in fear disorder. REGISTRATION: clinicaltrials.gov NCT02778074.

Childhood tuberous sclerosis complex in southern Sweden: a paradigm shift in diagnosis and treatment.

AIM: To investigate the complete clinical spectrum of individuals with paediatric tuberous sclerosis complex in southern Sweden and explore changes over time. METHODS: In this retrospective observational study, 52 individuals aged up to 18 years at the study start were followed-up at regional hospitals and centres for habilitation from 2000 to 2020. RESULTS: Cardiac rhabdomyoma was detected prenatally/neonatally in 69.2% of the subjects born during the latest ten years of the study period. Epilepsy was diagnosed in 82.7% of subjects, and 10 (19%) were treated with everolimus, mainly (80%) for a neurological indication. Renal cysts were detected in 53%, angiomyolipomas in 47%, astrocytic hamartomas in 28% of the individuals. There was a paucity of standardized follow-up of cardiac, renal, and ophthalmological manifestations and no structured transition to adult care. CONCLUSION: Our in-depth analysis shows a clear shift towards an earlier diagnosis of tuberous sclerosis complex in the latter part of the study period, where more than 60% of cases showed evidence of this condition already in utero due to the presence of a cardiac rhabdomyoma. This allows for preventive treatment of epilepsy with vigabatrin and early intervention with everolimus for potential mitigation of other symptoms of tuberous sclerosis complex.

Experience of internet-delivered cognitive behavioural therapy among patients with non-cardiac chest pain.

AIMS AND OBJECTIVE: To explore the experiences of patients with non-cardiac chest pain and cardiac anxiety regarding participation in an internet-delivered cognitive behavioural therapy program. BACKGROUND: Non-cardiac chest pain is common and leads to cardiac anxiety. Internet-delivered cognitive behavioural therapy may be a possible option to decrease cardiac anxiety in these patients. We have recently evaluated the effect of an internet-delivered cognitive behavioural therapy program on cardiac anxiety. DESIGN: An inductive qualitative study using content analysis and the COREQ checklist. METHODS: Semi-structured interviews with 16 Swedish patients, who had participated in the internet-delivered cognitive behavioural therapy program. RESULTS: Three categories were found. The first, 'Driving factors for participation in the internet-delivered cognitive behavioural therapy program' described the impact of pain on their lives and struggle that led them to participating in the program. The second, 'The program as a catalyst' described that the program was helpful, trustworthy and useful and the last category, 'Learning to live with chest pain' described the program as a tool for gaining the strength and skills to live a normal life despite chest pain. CONCLUSIONS: The program was experienced as an opportunity to return to a normal life. The program was perceived as helpful, trustworthy and useful, which helped the participants challenge their fear of chest pain and death, and gain strength and new insights into their ability to live a normal life. RELEVANCE TO CLINICAL PRACTICE: A tailored internet-delivered cognitive behavioural therapy program delivered by a nurse therapist with clinical experience of the patient group is important to improve cardiac anxiety. PATIENT OR PUBLIC CONTRIBUTION: Patients or the general public were not involved in the design, analysis or interpretation of the data of this study, but two patients with experience of non-cardiac chest pain were involved in the development of the pilot study. TRIAL REGISTRATION: ClinicalTrials.gov NCT03336112; https://www. CLINICALTRIALS: gov/ct2/show/NCT03336112.

Concerns experienced by parents of children treated for cancer: A qualitative study to inform adaptations to an internet-administered, low-intensity cognitive behavioral therapy intervention.

OBJECTIVE: Childhood cancer treatment completion is associated with mental health difficulties and negative socioeconomic consequences for parents. However, psychological support needs are often unmet. We developed an internet-administered, guided, low-intensity cognitive behavioral therapy-based self-help intervention (EJDeR) and examined feasibility and acceptability with a single-arm feasibility trial (ENGAGE). Results suggest EJDeR is acceptable, however, adherence, especially for fathers, could be improved. Following the Medical Research Council complex interventions framework, this study explores concerns experienced by parents actively seeking support related to their child's cancer who were recruited into ENGAGE to inform further adaptation of EJDeR. METHOD: Seventy-three semi-structured interviews (26 fathers, 47 mothers) were conducted, with data analyzed using manifest content analysis. RESULTS: Analysis resulted in seven categories: (1) Feeling lost and lonely in life; (2) Low mood; (3) Parenting difficulties; (4) Productivity difficulties; (5) Relationship challenges; (6) Stress reactions; and (7) Worry. With the exception of subcategories Afraid of not being a good parent, Cancer recurrence, and Child's development and future a somewhat higher percentage of mothers than fathers mentioned all identified concerns. CONCLUSION: Parents described experiencing a range of concerns after their child had completed cancer treatment. EJDeR will be adapted to address these concerns and include indirect intervention modules targeting concerns such as stress. Information to support parenting, relationships, finance, and employment difficulties, alongside signposting to inform help-seeking, will be included. Findings also suggest a need to improve the gender-sensitivity of EJDeR.

Internet-administered, low-intensity cognitive behavioral therapy for parents of children treated for cancer: A feasibility trial (ENGAGE).

BACKGROUND: Parents of children treated for cancer may experience mental health difficulties, such as depression and anxiety. There is a lack of evidence-based psychological interventions for parents, with psychological support needs unmet. An internet-administered, guided, low-intensity cognitive behavioral therapy-based (LICBT) self-help intervention may provide a solution. METHODS: The feasibility and acceptability of such an intervention was examined using a single-arm feasibility trial (ENGAGE). Primary objectives examined: (1) estimates of recruitment and retention rates; (2) feasibility and acceptability of data collection instruments and procedures; and (3) intervention feasibility and acceptability. Clinical outcomes were collected at baseline, post-treatment (12 weeks), and follow-up (6 months). RESULTS: The following progression criteria were met: sample size was exceeded within 5 months, with 11.0% enrolled of total population invited, study dropout rate was 24.0%, intervention dropout was 23.6%, missing data remained at ≤10% per measure, and no substantial negative consequences related to participation were reported. Intervention adherence was slightly lower than progression criteria (47.9%). CONCLUSION: Findings suggest an internet-administered, guided, LICBT self-help intervention may represent a feasible and acceptable solution for parents of children treated for cancer. With minor study protocol and intervention modifications, progression to a pilot randomized controlled trial (RCT) and subsequent superiority RCT is warranted.

Internet-Based Cognitive Behavioral Therapy and its Association With Self-efficacy, Depressive Symptoms, and Physical Activity: Secondary Analysis of a Randomized Controlled Trial in Patients With Cardiovascular Disease.

BACKGROUND: In patients with cardiovascular disease (CVD), knowledge about the associations among changes in depressive symptoms, self-efficacy, and self-care activities has been requested. This is because such knowledge can be helpful in the design of behavioral interventions aimed to improve self-efficacy, reduce depressive symptoms, and improve performance of self-care activities in CVD patients. OBJECTIVE: We aim to evaluate if internet-based cognitive behavioral therapy (iCBT) improves self-efficacy and explore the relationships among changes in depressive symptoms, self-efficacy, and physical activity, as well as the influence of iCBT on these relationships. METHODS: This study received funding in January 2015. Participant recruitment took place between January 2017 and February 2018, and the main findings were published in 2019. This study is a secondary analysis of data collected in a randomized controlled study evaluating the effects of a 9-week iCBT program compared to an online discussion forum (ODF) on depressive symptoms in patients with CVD (N=144). Data were collected at baseline and at the 9-week follow-up. Analysis of covariance was used to evaluate the differences in self-efficacy between the iCBT and ODF groups. Structural equation modeling explored the relationships among changes in depressive symptoms, self-efficacy, and physical activity, as well as the influence of iCBT on these relationships. RESULTS: At follow-up, a significant difference in the increase in self-efficacy favoring iCBT was found (P=.04, Cohen d=0.27). We found an indirect association between changes in depressive symptoms and physical activity (ß=-.24, P<.01), with the change in self-efficacy acting as a mediator. iCBT had a direct effect on the changes in depressive symptoms, which in turn influenced the changes in self-efficacy (ß=.23, P<.001) and physical activity (ß=.12, P<.001). CONCLUSIONS: Self-efficacy was improved by iCBT. However, the influence of iCBT on self-efficacy and physical activity was mostly mediated by improvements in depressive symptoms. TRIAL REGISTRATION: ClinicalTrials.gov NCT02778074; https://clinicaltrials.gov/ct2/show/NCT02778074.

The experience of participating in an internet-based cognitive behavioral therapy program among patients with cardiovascular disease and depression: a qualitative interview study.

BACKGROUND: Depression in conjunction with cardiovascular disease (CVD) is associated with worsening in CVD, higher mortality, and poorer quality of life. Despite the poor outcomes there is a treatment gap of depression in CVD patients. Recently we found that an Internet-based cognitive behavioral therapy (iCBT) tailored for CVD patients led to reduced symptoms of depression. However, we still have little knowledge about CVD patients' experiences of working with iCBT. The aim of this study was therefore to explore CVD patients' experiences of engaging in a tailored iCBT program. METHODS: A qualitative interview study using inductive thematic analysis. Data was obtained from 20 patients with CVD and depressive symptoms who had participated in a randomized controlled trial (RCT) evaluating the impact of a nine-week iCBT program on depression. RESULTS: Three main themes emerged: (1) Taking control of the disease, (2) Not just a walk in the park, and (3) Feeling a personal engagement with the iCBT program. The first theme included comments that the tailored program gave the patients a feeling of being active in the treatment process and helped them achieve changes in thoughts and behaviors necessary to take control of their CVD. The second theme showed that patients also experienced the program as demanding and emotionally challenging. However, it was viewed as helpful to challenge negative thinking about living with CVD and to change depressive thoughts. In the third theme patients reported that the structure inherent in the program, in the form of organizing their own health and the scheduled feedback from the therapist created a feeling of being seen as an individual. The feeling of being acknowledged as a person also made it easier to continuously work with the changes necessary to improve their health. CONCLUSIONS: Engaging in an iCBT program tailored for patients with CVD and depression was by the patients perceived as helpful in the treatment of depression. They experienced positive changes in emotions, thoughts, and behaviors which a result of learning to take control of their CVD, being confirmed and getting support. The patients considered working with the iCBT program as demanding and emotionally challenging, but necessary to achieve changes in emotions, thoughts, and behaviors.

Cost-effectiveness of internet-delivered cognitive behavioural therapy in patients with cardiovascular disease and depressive symptoms: secondary analysis of an RCT.

INTRODUCTION: Cost-effectiveness evaluations of psychological interventions, such as internet-delivered cognitive behavioural therapy (iCBT) programmes, in patients with cardiovascular disease (CVD) are rare. We recently reported moderate to large effect sizes on depressive symptoms in CVD outpatients following a 9-week iCBT programme compared with an online discussion forum (ODF), in favour of iCBT. In this paper, we evaluate the cost-effectiveness of this intervention. METHODS: Cost-effectiveness analysis of a randomised controlled trial. The EQ-5D-3L was used to calculate quality-adjusted life-years (QALYs). Data on healthcare costs were retrieved from healthcare registries. RESULTS: At 12-month follow-up, the QALY was significantly higher in iCBT compared with the ODF group (0.713 vs 0.598, p=0.007). The mean difference of 0.115 corresponds with 42 extra days in best imaginable health status in favour of the iCBT group over the course of 1 year. Incremental cost-effectiveness ratio (ICER) for iCBT versus ODF was €18 865 per QALY saved. The cost-effectiveness plane indicated that iCBT is a cheaper and more effective intervention in 24.5% of the cases, and in 75% a costlier and more effective intervention than ODF. Only in about 0.5% of the cases, there was an indication of a costlier, but less effective intervention compared with ODF. CONCLUSIONS: The ICER of €18 865 was lower than the cost-effectiveness threshold range of €23 400-€35 100 as proposed by the NICE guidelines, suggesting that the iCBT treatment of depressive symptoms in patients with CVD is cost-effective. TRIAL REGISTRATION NUMBER: NCT02778074; Post-results.

Waiting for kidney transplantation from deceased donors: Experiences and support needs during the waiting time -A qualitative study.

OBJECTIVES: The study aimed to explore and describe patients' experiences of the transplantation process and the support they had received during the waiting time. METHOD: Semi-structured interviews were conducted with 14 patients currently waiting for kidney transplantation from deceased donors (n = 7) or recently having received kidney transplantation (n = 7). Interviews were transcribed, anonymized and analysed inductively using thematic analysis. RESULTS: Two themes and seven sub-themes were identified. The first theme, "Swaying between hope and despair" describes patients' perceptions of waiting for transplantation as a struggle, their expectations for life after the upcoming transplantation and experienced disappointments. The second theme, "Making your way through the waiting time", describes support, strategies and behaviours used to manage the waiting time. CONCLUSION: Patients described life while waiting for kidney transplantation as challenging, involving unexpected events, not understanding the transplantation process and having unrealistic expectations on life after transplantation. They also described support, strategies and behaviours used, some of which led to unwanted consequences. PRACTICE IMPLICATIONS: Patients waiting for kidney transplantation from deceased donors need continuous and easily available education, practical and emotional support to manage the waiting time. Transplantation specific education is also needed to facilitate preparation for transplantation and adjustment to life after transplantation.

Perspectives of Policy Makers and Service Users Concerning the Implementation of eHealth in Sweden: Interview Study.

BACKGROUND: Increasing life spans of populations and a growing demand for more advanced care make effective and cost-efficient provision of health care necessary. eHealth technology is often proposed, although research on barriers to and facilitators of the implementation of eHealth technology is still scarce and fragmented. OBJECTIVE: The aim of this study is to explore the perceptions concerning barriers to and facilitators of the implementation of eHealth among policy makers and service users and explore the ways in which their perceptions converge and differ. METHODS: This study used interview data from policy makers at different levels of health care (n=7) and service users enrolled in eHealth interventions (n=25). The analysis included separate qualitative content analyses for the 2 groups and then a second qualitative content analysis to explore differences and commonalities. RESULTS: Implementation barriers perceived by policy makers were that not all service users benefit from eHealth and that there is uncertainty about the impact of eHealth on the work of health care professionals. Policy makers also perceived political decision-making as complex; this included problems related to provision of technical infrastructure and lack of extra resources for health care digitalization. Facilitators were policy makers' conviction that eHealth is what citizens want, their belief in eHealth solutions as beneficial for health care practice, and their belief in the importance of health care digitalization. Barriers for service users comprised capability limitations and varied preferences of service users and a mismatch of technology with user needs, lack of data protection, and their perception of eHealth as being more time consuming. Facilitators for service users were eHealth technology design and match with their skill set, personal feedback and staff support, a sense of privacy, a credible sender, and flexible use of time.There were several commonalities between the 2 stakeholder groups. Facilitators for both groups were the strong impetus toward technology adoption in society and expectations of time flexibility. Both groups perceived barriers in the difficulties of tailoring eHealth, and both groups expressed uncertainty about the care burden distribution. There were also differences: policy makers perceived that their decision-making was very complex and that resources for implementation were limited. Service users highlighted their need to feel that their digital data were protected and that they needed to trust the eHealth sender. CONCLUSIONS: Perceptions about barriers to and facilitators of eHealth implementation varied among stakeholders in different parts of the health care system. The study points to the need to reach an enhanced mutual understanding of priorities and overcome challenges at both the micro and macro levels of the health care system. More well-balanced decisions at the policy-maker level may lead to more effective and sustainable development and future implementation of eHealth.

Effects of Internet-delivered cognitive behavioural therapy adapted for patients with cardiovascular disease and depression: a long-term follow-up of a randomized controlled trial at 6 and 12 months posttreatment.

BACKGROUND: Internet-based cognitive behavioural treatment (iCBT) has shown positive short-term effects on depression in patients with cardiovascular disease (CVD). However, knowledge regarding long-term effects and factors that may impact the effect of iCBT is lacking. AIMS: This study therefore sought (i) to evaluate the effect of iCBT on depression in CVD patients at 6- and 12-month follow-ups and (ii) to explore factors that might impact on the effect of iCBT on change in depression at 12-month follow-up. METHODS AND RESULTS: A longitudinal follow-up study of a randomized controlled trial evaluating the effects of a 9-week iCBT programme compared to an online discussion forum (ODF) on depression in CVD patients (n = 144). After 9 weeks, those in the ODF group were offered the chance to take part in the iCBT programme. The Patient Health Questionnaire (PHQ-9) and the Montgomery-Åsberg Depression Rating Scale-self-rated version (MADRS-S) measured depression at baseline, 9 weeks, 6 months, and 12 months. Linear mixed model and multiple regression analysis were used for statistical computing. The iCBT programme significantly improved depression at 9-week follow-up and this was stable at 6- and 12-month follow-ups (PHQ-9 P = 0.001, MADRS-S P = 0.001). Higher levels of depression at baseline and a diagnosis of heart failure were factors found to impact the effect of iCBT on the change in depression. CONCLUSION: A 9-week iCBT programme in CVD patients led to long-term improvement in depression. Higher levels of depression scores at baseline were associated with improvement in depression, whereas heart failure had opposite effect. CLINICAL TRIAL: The trial is registered at ClinicalTrials.gov, NCT02778074.

Novel imaging findings in pyruvate dehydrogenase complex (PDHc) deficiency-Results from a nationwide population-based study.

The vast clinical and radiological spectrum of pyruvate dehydrogenase complex (PDHc) deficiency continues to pose challenges both in diagnostics and disease monitoring. Prompt diagnosis is important to enable early initiation of ketogenic diet. The patients were recruited from an ongoing population-based study in Sweden. All patients with a genetically confirmed diagnosis who had been investigated with an MRI of the brain were included. Repeated investigations were assessed to study the evolution of the MRI changes. Sixty-two MRI investigations had been performed in 34 patients (23 females). The genetic cause was mutations in PDHA1 in 29, PDHX and DLAT in 2 each, and PDHB in 1. The lesions were prenatal developmental in 16, prenatal clastic in 18, and postnatal clastic in 15 individuals. Leigh-like lesions with predominant involvement of globus pallidus were present in 12, while leukoencephalopathy was present in 6 and stroke-like lesions in 3 individuals. A combination of prenatal developmental and clastic lesions was present in 15 individuals. In addition, one male with PDHA1 also had postnatal clastic lesions. The most common lesions found in our study were agenesis or hypoplasia of corpus callosum, ventriculomegaly, or Leigh-like lesions. Furthermore, we describe a broad spectrum of other MRI changes that include leukoencephalopathy and stroke-like lesions. We argue that a novel important clue, suggesting the possibility of PDHc deficiency on MRI scans, is the simultaneous presence of multiple lesions on MRI that have occurred during different phases of brain development.

Dismantling, optimising, and personalising internet cognitive behavioural therapy for depression: a systematic review and component network meta-analysis using individual participant data.

BACKGROUND: Internet cognitive behavioural therapy (iCBT) is a viable delivery format of CBT for depression. However, iCBT programmes include training in a wide array of cognitive and behavioural skills via different delivery methods, and it remains unclear which of these components are more efficacious and for whom. METHODS: We did a systematic review and individual participant data component network meta-analysis (cNMA) of iCBT trials for depression. We searched PubMed, PsycINFO, Embase, and the Cochrane Library for randomised controlled trials (RCTs) published from database inception to Jan 1, 2019, that compared any form of iCBT against another or a control condition in the acute treatment of adults (aged ≥18 years) with depression. Studies with inpatients or patients with bipolar depression were excluded. We sought individual participant data from the original authors. When these data were unavailable, we used aggregate data. Two independent researchers identified the included components. The primary outcome was depression severity, expressed as incremental mean difference (iMD) in the Patient Health Questionnaire-9 (PHQ-9) scores when a component is added to a treatment. We developed a web app that estimates relative efficacies between any two combinations of components, given baseline patient characteristics. This study is registered in PROSPERO, CRD42018104683. FINDINGS: We identified 76 RCTs, including 48 trials contributing individual participant data (11 704 participants) and 28 trials with aggregate data (6474 participants). The participants' weighted mean age was 42·0 years and 12 406 (71%) of 17 521 reported were women. There was suggestive evidence that behavioural activation might be beneficial (iMD -1·83 [95% credible interval (CrI) -2·90 to -0·80]) and that relaxation might be harmful (1·20 [95% CrI 0·17 to 2·27]). Baseline severity emerged as the strongest prognostic factor for endpoint depression. Combining human and automated encouragement reduced dropouts from treatment (incremental odds ratio, 0·32 [95% CrI 0·13 to 0·93]). The risk of bias was low for the randomisation process, missing outcome data, or selection of reported results in most of the included studies, uncertain for deviation from intended interventions, and high for measurement of outcomes. There was moderate to high heterogeneity among the studies and their components. INTERPRETATION: The individual patient data cNMA revealed potentially helpful, less helpful, or harmful components and delivery formats for iCBT packages. iCBT packages aiming to be effective and efficient might choose to include beneficial components and exclude ones that are potentially detrimental. Our web app can facilitate shared decision making by therapist and patient in choosing their preferred iCBT package. FUNDING: Japan Society for the Promotion of Science.

Trajectories and associations between depression and physical activity in patients with cardiovascular disease during participation in an internet-based cognitive behavioural therapy programme.

BACKGROUND: There is a lack of knowledge about internet-based cognitive behavioural therapy in patients with cardiovascular disease, and its effects on depressive symptoms and physical activity. AIM: To examine trajectories of depressive symptoms and physical activity, and to explore if these trajectories are linked with the delivery of internet-based cognitive behavioural therapy. METHODS: A secondary-analysis of data collected in a randomised controlled trial that evaluated the effects of a 9-week internet-based cognitive behavioural therapy programme compared to an online discussion forum on depressive symptoms in cardiovascular disease patients. Data were collected at baseline, once weekly during the 9-week intervention period and at the 9-week follow-up. The Montgomery Åsberg depression rating scale - self-rating (MADRS-S) was used to measure depressive symptoms. Two modified items from the physical activity questionnaire measuring frequency and length of physical activity were merged to form a physical activity factor. RESULTS: After 2 weeks the internet-based cognitive behavioural therapy group had a temporary worsening in depressive symptoms. At 9-week follow-up, depressive symptoms (P<0.001) and physical activity (P=0.02) had improved more in the internet-based cognitive behavioural therapy group. Only in the internet-based cognitive behavioural therapy group, was a significant correlation (r=-0.39, P=0.002) between changes in depressive symptoms and changes in physical activity found. Structural equation analyses revealed that internet-based cognitive behavioural therapy decreased depressive symptoms, and that a decrease in depression, in turn, resulted in an increase in physical activity. CONCLUSIONS: Internet-based cognitive behavioural therapy was more effective than an online discussion forum to decrease depressive symptoms and increase physical activity. Importantly, a decrease in depressive symptoms needs to precede an increase in physical activity.