Transdiagnostic therapy for persistent physical symptoms: A mediation analysis of the PRINCE secondary trial.

The PRINCE secondary trial did not find any evidence that transdiagnostic cognitive behavioural therapy (TDT-CBT) plus standard medical care (SMC) was more efficacious than SMC for patients with Persistent Physical Symptoms (PPS) for the primary outcome Work and Social Adjustment Scale (WSAS) at final follow-up (52 weeks). There was a significant treatment effect for TDT-CBT plus CBT compared with SMC for two secondary outcomes: WSAS at the end of active treatment (20 weeks) and symptom severity (Patient Health Questionnaire, PHQ-15) at 52 weeks. To understand mechanisms that lead to effects of TDT-CBT plus SMC versus SMC we performed a planned secondary mediation analysis. We investigated whether TDT-CBT treatment effects on these two secondary outcomes at the end of the treatment could be explained by effects on variables that were targeted by TDT-CBT during the initial phase of treatment. We pre-specified mediator variables measured at mid-treatment (9 weeks). Reductions in catastrophising and symptom focusing were the strongest mediators of TDT-CBT treatment effects on WSAS at the end of treatment. Improvements in symptom focusing also mediated the effect of TDT-CBT on PHQ-15. Future developments of the TDT-CBT intervention could benefit from targeting these mediators.

Correction to: Integrated GP care for patients with persistent physical symptoms: feasibility cluster randomised trial.

An amendment to this paper has been published and can be accessed via the original article.

BMC family practice integrated GP care for patients with persistent physical symptoms: feasibility cluster randomised trial.

BACKGROUND: Patients continue to suffer from medically unexplained symptoms otherwise referred to as persistent physical symptoms (PPS). General practitioners (GPs) play a key role in the management of PPS and require further training. Patients are often frustrated with the care they receive. This study aims to assess the acceptability of an 'integrated GP care' approach which consists of offering self-help materials to patients with PPS and offering their GPs training on how to utilise cognitive behavioural skills within their consultations, as well as assessing the feasibility of conducting a future trial in primary care to evaluate its benefit. METHODS: A feasibility cluster randomised controlled trial was conducted in primary care, South London, UK. GP practices (clusters) were randomly allocated to 'integrated GP care plus treatment as usual' or 'treatment as usual'. Patients with PPS were recruited from participating GP practices before randomisation. Feasibility parameters, process variables and potential outcome measures were collected at pre-randomisation and at 12- and 24-weeks post-randomisation at cluster and individual participant level. RESULTS: Two thousand nine hundred seventy-eight patients were identified from 18 GP practices. Out of the 424 patients who responded with interest in the study, 164 fully met the eligibility criteria. One hundred sixty-one patients provided baseline data before cluster randomisation and therefore were able to participate in the study. Most feasibility parameters indicated that the intervention was acceptable and a future trial feasible. 50 GPs from 8 GP practices (randomised to intervention) attended the offer of training and provided positive feedback. Scores in GP knowledge and confidence increased post-training. Follow-up rate of patients at 24 weeks was 87%. However estimated effect sizes on potential clinical outcomes were small. CONCLUSIONS: It was feasible to identify and recruit patients with PPS. Retention rates of participants up to 24 weeks were high. A wide range of health services were used. The intervention was relatively low cost and low risk. This complex intervention should be further developed to improve patients'/GPs' utilisation of audio/visual and training resources before proceeding to a full trial evaluation. TRIAL REGISTRATION: NCT02444520  (ClinicalTrials.gov).

Correction to: Persistent physical symptoms reduction intervention: a system change and evaluation in secondary care (PRINCE secondary) - a CBT-based transdiagnostic approach: study protocol for a randomised controlled trial.

An amendment to this paper has been published and can be accessed via the original article.

Persistent physical symptoms reduction intervention: a system change and evaluation in secondary care (PRINCE secondary) - a CBT-based transdiagnostic approach: study protocol for a randomised controlled trial.

BACKGROUND: Persistent physical symptoms (PPS), also known as medically unexplained symptoms (MUS), affect approximately 50% of patients in secondary care and are often associated with disability, psychological distress and increased health care costs. Cognitive behavioural therapy (CBT) has demonstrated both short- and long-term efficacy with small to medium effect sizes for PPS, with larger treatment effects for specific PPS syndromes, including non-cardiac chest pain, irritable bowel syndrome (IBS) and chronic fatigue syndrome (CFS). Research indicates that PPS conditions share similar cognitive and behavioural responses to symptoms, such as avoidance and unhelpful beliefs. This suggests that a transdiagnostic approach may be beneficial for patients with PPS. METHODS: A randomised controlled trial (RCT) will be conducted to evaluate the efficacy and cost-effectiveness of a transdiagnostic CBT-based intervention for PPS. 322 participants with PPS will be recruited from secondary care clinics. Participants stratified by clinic and disability level will be randomised to CBT plus standard medical care (SMC) versus SMC alone. The intervention consists of 8 CBT sessions delivered by a qualified therapist over a period of 20 weeks. Outcomes will be assessed at 9, 20, 40- and 52-weeks post randomisation. Efficacy will be assessed by examining the difference between arms in the primary outcome Work and Social Adjustment Scale (WSAS) at 52 weeks after randomisation. Secondary outcomes will include mood, symptom severity and clinical global impression at 9, 20, 40 and 52 weeks. Cost-effectiveness will be evaluated by combining measures of health service use, informal care, loss of working hours and financial benefits at 52 weeks. DISCUSSION: This trial will provide a powered evaluation of the efficacy and cost-effectiveness of a transdiagnostic CBT approach versus SMC for patients with PPS. It will also provide valuable information about potential healthcare pathways for patients with PPS within the National Health Service (NHS). TRIAL REGISTRATION: ClinicalTrials.gov NCT02426788. Registered 27 April 2015. Overall trial status: Ongoing; Recruitment status: No longer recruiting.

Persistent physical symptoms reduction intervention: a system change and evaluation (PRINCE)-integrated GP care for persistent physical symptoms: protocol for a feasibility and cluster randomised waiting list, controlled trial.

INTRODUCTION: Persistent physical symptoms (PPS), also known as medically unexplained symptoms are associated with profound physical disability, psychological distress and high healthcare costs. England's annual National Health Service costs of attempting to diagnose and treat PPS amounts to approximately £3 billion. Current treatment relies on a positive diagnosis, life-style advice and drug therapy. However, many patients continue to suffer from ongoing symptoms and general practitioners (GPs) are challenged to find effective treatments. Training GPs in basic cognitive behavioural skills and providing self-help materials to patients could be useful, but availability in primary care settings is limited. METHODS AND ANALYSIS: A cluster randomised waiting list, controlled trial will be conducted to assess the feasibility of an integrated approach to care in general practice. Approximately 240 patients with PPS will be recruited from 8 to 12 GP practices in London. GP practices will be randomised to 'integrated GP care plus treatment as usual' or waiting list control. Integrated GP care plus treatment as usual will include GP training in cognitive behavioural skills, GP supervision and written and audio visual materials for both GPs and participants. The primary objectives will be assessment of trial and intervention feasibility. Secondary objectives will include estimating the intracluster correlation coefficient for potential outcome measures for cluster effects in a sample size calculation. Feasibility parameters and identification of suitable primary and secondary outcomes for future trial evaluations will be assessed prerandomisation and at 12 and 24 weeks' postrandomisation, using a mixed-methods approach. ETHICS AND DISSEMINATION: Ethical approval was granted by the Camberwell St Giles Ethics Committee. Results will be disseminated via peer-reviewed publications and conference presentations. This trial will inform researchers, clinicians, patients and healthcare providers about the feasibility and potential cost-effectiveness of an integrated approach to managing PPS in primary care. TRIAL REGISTRATION NUMBER: NCT02444520; Pre-results.

Studying depression using imaging and machine learning methods.

Depression is a complex clinical entity that can pose challenges for clinicians regarding both accurate diagnosis and effective timely treatment. These challenges have prompted the development of multiple machine learning methods to help improve the management of this disease. These methods utilize anatomical and physiological data acquired from neuroimaging to create models that can identify depressed patients vs. non-depressed patients and predict treatment outcomes. This article (1) presents a background on depression, imaging, and machine learning methodologies; (2) reviews methodologies of past studies that have used imaging and machine learning to study depression; and (3) suggests directions for future depression-related studies.

Machine learning approaches for integrating clinical and imaging features in late-life depression classification and response prediction.

OBJECTIVE: Currently, depression diagnosis relies primarily on behavioral symptoms and signs, and treatment is guided by trial and error instead of evaluating associated underlying brain characteristics. Unlike past studies, we attempted to estimate accurate prediction models for late-life depression diagnosis and treatment response using multiple machine learning methods with inputs of multi-modal imaging and non-imaging whole brain and network-based features. METHODS: Late-life depression patients (medicated post-recruitment) (n = 33) and older non-depressed individuals (n = 35) were recruited. Their demographics and cognitive ability scores were recorded, and brain characteristics were acquired using multi-modal magnetic resonance imaging pretreatment. Linear and nonlinear learning methods were tested for estimating accurate prediction models. RESULTS: A learning method called alternating decision trees estimated the most accurate prediction models for late-life depression diagnosis (87.27% accuracy) and treatment response (89.47% accuracy). The diagnosis model included measures of age, Mini-mental state examination score, and structural imaging (e.g. whole brain atrophy and global white mater hyperintensity burden). The treatment response model included measures of structural and functional connectivity. CONCLUSIONS: Combinations of multi-modal imaging and/or non-imaging measures may help better predict late-life depression diagnosis and treatment response. As a preliminary observation, we speculate that the results may also suggest that different underlying brain characteristics defined by multi-modal imaging measures-rather than region-based differences-are associated with depression versus depression recovery because to our knowledge this is the first depression study to accurately predict both using the same approach. These findings may help better understand late-life depression and identify preliminary steps toward personalized late-life depression treatment.

Resting state functional connectivity and treatment response in late-life depression.

Indices of functional connectivity in the default mode network (DMN) are promising neural markers of treatment response in late-life depression. We examined the differences in DMN functional connectivity between treatment-responsive and treatment-resistant depressed older adults. Forty-seven depressed older adults underwent MRI scanning pre- and post-pharmacotherapy. Forty-six never depressed older adults underwent MR scanning as comparison subjects. Treatment response was defined as achieving a Hamilton Depression Rating Scale of 10 or less post-treatment. We analyzed resting state functional connectivity using the posterior cingulate cortex as the seed region-of-interest. The resulting correlation maps were employed to investigate between-group differences. Additionally we examined the association between white matter hyperintensity burden and functional connectivity results. Comparison of pre- and post-treatment scans of depressed participants revealed greater post-treatment functional connectivity in the frontal precentral gyrus. Relative to treatment-responsive participants, treatment-resistant participants had increased functional connectivity in the left striatum. When adjusting for white matter hyperintensity burden, the observed differences lost significance for the PCC-prefrontal functional connectivity, but not for the PCC-striatum functional connectivity. The post-treatment "frontalization" of the DMN connectivity suggests a normalizing effect of antidepressant treatment. Moreover, our study confirms the central role of white matter lesions in disrupting brain functional connectivity.

Association of small vessel ischemic white matter changes with BOLD fMRI imaging in the elderly.

White matter hyperintensities (WMHs) are often identified on T2-weighted magnetic resonance (MR) images in the elderly. The WMHs are generally associated with small vessel ischemic or pre-ischemic changes. However, the association of WMHs with blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal is understudied. In this study, we evaluate how the BOLD signal change is related to the presence of WMHs in the elderly. Data were acquired as part of a study of late-life depression and included elderly individuals with and without major depression. The subjects were pooled because the presence of depression was not significantly associated with task-related BOLD changes, task performance, and WMH distribution. A whole brain voxel-wise regression analysis revealed a significant negative correlation between WMH burden and BOLD signal change during finger-tapping in the parietal white matter. Our observation that WMHs are associated with a significant diminution of the BOLD signal change underscores the importance of considering cerebrovascular burden when interpreting fMRI studies in the elderly. The mechanism underlying the association of WMH and BOLD signal change remains unclear: the association may be mediated by changes in neural activation, changes in coupling between neuronal activity and hemodynamics, or, perhaps, secondary to the effect of the ischemic changes on the sensitivity of the T2* BOLD MR signal.

fMRI correlates of white matter hyperintensities in late-life depression.

OBJECTIVE: This study tests whether or not the structural white matter lesions that are characteristic of late-life depression are associated with alterations in the functional affective circuits of late-life depression. This study used an emotional faces paradigm that has been shown to engage the affective limbic brain regions. METHOD: Thirty-three elderly depressed patients and 27 nondepressed comparison subjects participated in this study. The patients were recruited through the NIMH-sponsored Advanced Center for Interventions and Services Research for the Study of Late-Life Mood Disorders at the University of Pittsburgh Center for Bioethics and Health Law. Structural and functional MRI was used to assess white matter hyperintensity (WMH) burden and functional magnetic resonance imaging (fMRI) blood-oxygen-level-dependent (BOLD) response on a facial expression affective-reactivity task in both elderly participants with nonpsychotic and nonbipolar major depression (unmedicated) and nondepressed elderly comparison subjects. RESULTS: As expected, greater subgenual cingulate activity was observed in the depressed patients relative to the nondepressed comparison subjects. This same region showed greater task-related activity associated with a greater burden of cerebrovascular white matter change in the depressed group. Moreover, the depressed group showed a significantly greater interaction of WMH by fMRI activity effect than the nondepressed group. CONCLUSIONS: The observation that high WMH burden in late-life depression is associated with greater BOLD response on the affective-reactivity task supports the model that white matter ischemia in elderly depressed patients disrupts brain mechanisms of affective regulation and leads to limbic hyperactivation.

Ethyl-cyanoacrylate is acutely nontoxic and provides sufficient bond strength for anastomosis of peripheral nerves.

Anastomosis is a common technique for the union of severed nerve trunks. This is commonly performed with sutures, a process that can be both time consuming and injurious to tissue. One promising alternative to suturing is the use of adhesives to join the severed segments. Cyanoacrylate-based glues have been used clinically as a surgical adhesive for soft tissues. However, the acute effects of these glues on nerve electrophysiology and the tensile strength of the rejoined tissues have not been evaluated. Using a guinea pig model, we analyzed the mechanical properties of transected sciatic nerves repaired with epineural application of ethyl-cyanoacrylate and the short term consequences of cyanoacrylate application on impulse conduction. Results showed that nerves coapted with ethyl-cyanoacrylate were capable of bearing in vivo forces. Additionally, no acute effects on conduction were observed in uninjured sciatic nerves exposed to ethyl-cyanoacrylate. In conjunction with long term in vivo reports from literature, the current results support the use of cyanoacrylates in nerve repair.

PTC124 targets genetic disorders caused by nonsense mutations.

Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.

Cleavage of pre-tRNAs by the splicing endonuclease requires a composite active site.

Splicing is required for the removal of introns from a subset of transfer RNAs in all eukaryotic organisms. The first step of splicing, intron recognition and cleavage, is performed by the tRNA-splicing endonuclease, a tetrameric enzyme composed of the protein subunits Sen54, Sen2, Sen34 and Sen15. It has previously been demonstrated that the active sites for cleavage at the 5' and 3' splice sites of precursor tRNA are contained within Sen2 and Sen34, respectively. A recent structure of an archaeal endonuclease complexed with a bulge-helix-bulge RNA has led to the unexpected hypothesis that catalysis requires a critical 'cation-pi sandwich' composed of two arginine residues that serve to position the RNA substrate within the active site. This motif is derived from a cross-subunit interaction between the two catalytic subunits. Here we test the role of this interaction within the eukaryotic endonuclease and show that catalysis at the 5' splice site requires the conserved cation-pi sandwich derived from the Sen34 subunit in addition to the catalytic triad of Sen2. The catalysis of pre-tRNA by the eukaryotic tRNA-splicing endonuclease therefore requires a previously unrecognized composite active site.

Identification of a human endonuclease complex reveals a link between tRNA splicing and pre-mRNA 3' end formation.

tRNA splicing is a fundamental process required for cell growth and division. The first step in tRNA splicing is the removal of introns catalyzed in yeast by the tRNA splicing endonuclease. The enzyme responsible for intron removal in mammalian cells is unknown. We present the identification and characterization of the human tRNA splicing endonuclease. This enzyme consists of HsSen2, HsSen34, HsSen15, and HsSen54, homologs of the yeast tRNA endonuclease subunits. Additionally, we identified an alternatively spliced isoform of SEN2 that is part of a complex with unique RNA endonuclease activity. Surprisingly, both human endonuclease complexes are associated with pre-mRNA 3' end processing factors. Furthermore, siRNA-mediated depletion of SEN2 exhibited defects in maturation of both pre-tRNA and pre-mRNA. These findings demonstrate a link between pre-tRNA splicing and pre-mRNA 3' end formation, suggesting that the endonuclease subunits function in multiple RNA-processing events.