Personalised interventions for subgroups of children with conduct problems.

BACKGROUND: Conduct problems are a range of disruptive behaviours in childhood that are associated with long-term adverse outcomes in adolescence and adulthood, including antisocial behaviour, substance misuse, and poor academic achievement. Children with conduct problems can vary according to age of onset, comorbidities, and environmental factors, and it has been suggested that certain groups of children may have different treatment outcomes. Therefore, it is important to assess the extent to which personalised interventions for different groups of children with conduct problems may affect outcomes. To our knowledge, this is the first review to systematically identify and appraise the effectiveness of personalised interventions, adapted, or developed, for prespecified subgroups of children with conduct problems. OBJECTIVES: To assess whether personalised interventions, adapted or developed for subgroups of children with conduct problems are effective in improving outcomes. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search was 1 February 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs), in any setting, in children (aged two to 12 years) with conduct problems and within a prespecified subgroup, comparing a personalised intervention with a non-personalised intervention, waitlist control, or treatment as usual. Personalised interventions included adaptations to standard practice, such as parent-training programmes; other recommended interventions for children with conduct problems; or interventions developed specifically to target subgroups of children with conduct problems. We excluded non-personalised and non-psychological interventions (e.g. pharmacological or dietary intervention). Prespecified subgroups of children with conduct problems, however defined, were eligible for inclusion. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. child conduct problems or disruptive behaviour and 2. ADVERSE EVENTS: Our secondary outcomes were 3. personalised treatment outcomes relevant to each subgroup, 4. parenting skills and knowledge, 5. family functioning, engagement and decreased dropout, and 6. educational outcomes. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We identified 13 RCTs (858 participants). Seven studies were conducted in the USA, five in Australia, and one in Germany. Eleven studies reported their source of funding, with five studies receiving grants from the National Institute of Mental Health. In total, 15 different funders supported the studies included in the review. We separated subgroups of children with conduct problems into three broad categories: children with co-occurring conditions (e.g. emotional difficulties), parent characteristics (e.g. conflict between parents), or familial/environmental circumstances (e.g. rural families). All studies delivered a personalised intervention that was adapted or developed for a prespecified subgroup of children with conduct problems. We rated all trials at unclear or high risk of bias in most domains. Below, we report the results of improvement in child conduct problems and disruptive behaviour, personalised treatment outcomes, and parenting skills and knowledge for our main comparison: personalised versus non-personalised interventions. Improvement in child conduct problems and disruptive behaviour Compared with a non-personalised intervention, a personalised intervention may result in a slight improvement in child conduct problems or disruptive behaviour measured using the Eyberg Child Behavior Inventory (ECBI) Problem subscale in the short term (mean difference (MD) -3.04, 95% confidence interval (CI) -6.06 to -0.02; 6 studies, 278 participants; P = 0.05), but may have little to no effect on improving child conduct problems or disruptive behaviour measured by the ECBI Intensity subscale (MD -6.25, 95% CI -16.66 to 4.15; 6 studies, 278 participants; P = 0.24), or the Externalising subscale of the Child Behaviour Checklist (CBCL) (MD -2.19, 95% CI -6.97 to 2.59; 3 studies, 189 participants, P = 0.37) in the short term. We graded the certainty of evidence as very low for all three outcomes, meaning any estimate of effect is very uncertain.  Personalised treatment outcomes, relevant to each subgroup Although six studies reported personalised treatment outcomes, relevant to each subgroup, we were unable to pool the data due to differences between the measures used in the studies and the heterogeneity this would produce in analysis. The results for this outcome were inconclusive. Parenting skills and knowledge Although seven studies reported parenting skills and knowledge, we were unable to pool the data due to differences between the measures used in the studies and the heterogeneity this would produce in analysis. The results for this outcome were inconclusive.  Adverse events None of the trials reported monitoring adverse events. Summary of results In summary, there is limited evidence that personalised intervention improves child conduct problems, personalised treatment outcomes, relevant to each subgroup, or parenting skills and knowledge compared with a non-personalised intervention. AUTHORS' CONCLUSIONS: There is limited evidence for the effectiveness of personalised interventions for subgroups of children with conduct problems. The certainty of evidence for all outcomes was very low, meaning that we have very little confidence in the estimated effects and the true effects may be different to our findings, which will limit the relevance of our findings to clinical decisions. To overcome the limitations of the evidence, large-scale RCTs are needed to determine whether personalised interventions, adapted or developed, for subgroups of children with conduct problems are effective in improving outcomes. Consensus on the most appropriate measures to use in these studies is needed in order to facilitate cross-study comparisons. Persistent conduct problems predict a range of adverse long-term outcomes, so future research should investigate the medium- and long-term effects of personalised treatments. Studies are needed in low- and middle-income countries as well as studies recruiting children aged between nine and 12 years, as they were under-represented in the studies.

Longitudinal Outcomes of Gender Identity in Children (LOGIC): study protocol for a retrospective analysis of the characteristics and outcomes of children referred to specialist gender services in the UK and the Netherlands.

INTRODUCTION: Specialist gender services for children and young people (CYP) worldwide have experienced a significant increase in referrals in recent years. As rates of referrals increase, it is important to understand the characteristics and profile of CYP attending these services in order to inform treatment pathways and to ensure optimal outcomes. METHODS AND ANALYSIS: A retrospective observational study of clinical health records from specialist gender services for CYP in the UK and the Netherlands. The retrospective analysis will examine routinely collected clinical and outcome measures data including demographic, clinical, gender identity-related and healthcare resource use information. Data will be reported for each service and also compared between services. This study forms part of a wider programme of research investigating outcomes of gender identity in children (the Longitudinal Outcomes of Gender Identity in Children study). ETHICS AND DISSEMINATION: The proposed study has been approved by the Health Research Authority and London-Hampstead Research Ethics Committee as application 19/LO/0181. The study findings will be published in peer-reviewed journals and presented at both conferences and stakeholder events.

Longitudinal Outcomes of Gender Identity in Children (LOGIC): protocol for a prospective longitudinal cohort study of children referred to the UK gender identity development service.

INTRODUCTION: Gender identity development services (GIDS) worldwide have seen a significant increase in referrals in recent years. Many of these referrals consist of children and young people (CYP) who experience gender-related distress. This study aims to improve understanding of outcomes of CYP referred to the UK GIDS, specifically regarding gender identity, mental health, physical health and quality of life. The impact of factors such as co-occurring autism and early social transition on outcomes over time will be explored. METHODS AND ANALYSIS: This is a prospective cohort study of CYP aged 3-14 years when referred to the UK GIDS. Eligible participants will be ≤14 years at the time their referral was accepted and will be on the waitlist for the service when baseline measures are completed. Children aged under 12 years will complete the measures in an interview format with a researcher, while young people aged 12 years and over and their parents/caregivers will complete online or paper-based questionnaires. Participants will complete follow-up measures 12 months and 24 months later. The final sample size is expected to be approximately 500. Logistic regression models will be used to explore associations between prespecified explanatory variables and gender dysphoria. Appropriate regression models will also be used to investigate explanatory variables for other outcomes. Subgroup analyses based on birth-assigned gender, age at referral and co-occurring autistic traits will be explored. ETHICS AND DISSEMINATION: The study has been approved by the Health Research Authority and London - Hampstead Research Ethics Committee (reference: 19/LO/0857). The study findings will be published in peer-reviewed journals and presented at both conferences and stakeholder events. Findings will be used to inform clinical practice.

Primary Sclerosing Cholangitis and Psychological Wellbeing: A Scoping Review.

Primary sclerosing cholangitis (PSC) is a chronic liver disease resulting from the inflammation and scarring of an individual's hepatic bile ducts. With no curative treatment available and a risk of potentially severe complications and death, it is likely that those diagnosed with the illness may experience impairments in their psychological wellbeing. The aim of this scoping review is to locate, chart, and summarize all available literature on how PSC affects mental health and psychological wellbeing, as well as the factors that may or may not impact on the psychological wellbeing of those who have this diagnosis. This exercise identified five key themes within the literature: prevalence and characteristics of mental health problems, quality of life, unmet needs, medical treatment, and biomarkers. Three key recommendations for clinical practice emerge from this review.

Clinical characteristics associated with the prescribing of SSRI medication in adolescents with major unipolar depression.

Unipolar major depressions (MD) emerge markedly during adolescence. National Institute for Health and Care Excellence (NICE) UK recommends psychological therapies, with accompanying selective serotonin reuptake inhibitors (SSRIs) prescribed in severe cases only. Here, we seek to determine the extent and rationale of SSRI prescribing in adolescent MD before entering a randomised clinical trial. SSRI prescribing, together with their clinical characteristics was determined in 465 adolescent patients with MD prior to receiving a standardised psychological therapy as part of the Improving mood with psychoanalytic and cognitive therapies (IMPACT) clinical trial. Overall, 88 (19 %) had been prescribed antidepressants prior to psychological treatment. The clinical correlates varied by gender: respectively, depression severity in boys and self-harming behaviours in girls. Prescribing also differed between clinical research centres. Medical practitioners consider severity of depression in boys as an indicator for antidepressant prescribing. Self-injury in girls appears to be utilised as a prescribing aid which is inconsistent with past and current revised UK NICE guidelines.

Laminin γ2 knockout mice rescued with the human protein exhibit enamel maturation defects.

The epithelial ameloblasts are separated from the maturing enamel by an atypical basement membrane (BM) that is enriched in laminin 332 (LM-332). This heterotrimeric protein (α3, ß3 and γ2 chains) provides structural integrity to BMs and influences various epithelial cell processes including cell adhesion and differentiation. Mouse models that lack expression of individual LM-332 chains die shortly after birth. The lethal phenotype of laminin γ2 knockout mice can be rescued by human laminin γ2 (LAMC2) expressed using a doxycycline-inducible (Tet-on) cytokeratin 14 promoter-rtTA. These otherwise normal-looking rescued mice exhibit white spot lesions on incisors. We therefore investigated the effect of rescue with human LAMC2 on enamel maturation and structuring of the atypical BM. The maturation stage enamel organ in transgenic mice was severely altered as compared to wild type controls, a structured BM was no longer discernible, dystrophic matrix appeared in the maturing enamel layer, and there was residual enamel matrix late into the maturation stage. Microtomographic scans revealed excessive wear of occlusal surfaces on molars, chipping of enamel on incisor tips, and hypomineralization of the enamel layer. No structural alterations were observed at other epithelial sites, such as skin, palate and tongue. These results indicate that while this humanized mouse model is capable of rescue in various epithelial tissues, it is unable to sustain structuring of a proper BM at the interface between ameloblasts and maturing enamel. This failure may be related to the atypical composition of the BM in the maturation stage and reaffirms that the atypical BM is essential for enamel maturation.

Rationale and Design of the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) Study. Sarcoidosis Protocol.

Sarcoidosis is a systemic disease characterized by noncaseating granulomatous inflammation with tremendous clinical heterogeneity and uncertain pathobiology and lacking in clinically useful biomarkers. The Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study is an observational cohort study designed to explore the role of the lung microbiome and genome in these two diseases. This article describes the design and rationale for the GRADS study sarcoidosis protocol. The study addresses the hypothesis that distinct patterns in the lung microbiome are characteristic of sarcoidosis phenotypes and are reflected in changes in systemic inflammatory responses as measured by peripheral blood changes in gene transcription. The goal is to enroll 400 participants, with a minimum of 35 in each of 9 clinical phenotype subgroups prioritized by their clinical relevance to understanding of the pathobiology and clinical heterogeneity of sarcoidosis. Participants with a confirmed diagnosis of sarcoidosis undergo a baseline visit with self-administered questionnaires, chest computed tomography, pulmonary function tests, and blood and urine testing. A research or clinical bronchoscopy with a research bronchoalveolar lavage will be performed to obtain samples for genomic and microbiome analyses. Comparisons will be made by blood genomic analysis and with clinical phenotypic variables. A 6-month follow-up visit is planned to assess each participant's clinical course. By the use of an integrative approach to the analysis of the microbiome and genome in selected clinical phenotypes, the GRADS study is powerfully positioned to inform and direct studies on the pathobiology of sarcoidosis, identify diagnostic or prognostic biomarkers, and provide novel molecular phenotypes that could lead to improved personalized approaches to therapy for sarcoidosis.

Rationale and Design of the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis Study. Alpha-1 Protocol.

Severe deficiency of alpha-1 antitrypsin has a highly variable clinical presentation. The Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis α1 Study is a prospective, multicenter, cross-sectional study of adults older than age 35 years with PiZZ or PiMZ alpha-1 antitrypsin genotypes. It is designed to better understand if microbial factors influence this heterogeneity. Clinical symptoms, pulmonary function testing, computed chest tomography, exercise capacity, and bronchoalveolar lavage (BAL) will be used to define chronic obstructive pulmonary disease (COPD) phenotypes that can be studied with an integrated systems biology approach that includes plasma proteomics; mouth, BAL, and stool microbiome and virome analysis; and blood microRNA and blood mononuclear cell RNA and DNA profiling. We will rely on global genome, transcriptome, proteome, and metabolome datasets. Matched cohorts of PiZZ participants on or off alpha-1 antitrypsin augmentation therapy, PiMZ participants not on augmentation therapy, and control participants from the Subpopulations and Intermediate Outcome Measures in COPD Study who match on FEV1 and age will be compared. In the primary analysis, we will determine if the PiZZ individuals on augmentation therapy have a difference in lower respiratory tract microbes identified compared with matched PiZZ individuals who are not on augmentation therapy. By characterizing the microbiome in alpha-1 antitrypsin deficiency (AATD), we hope to define new phenotypes of COPD that explain some of the diversity of clinical presentations. As a unique genetic cause of COPD, AATD may inform typical COPD pathogenesis, and better understanding of it may illuminate the complex interplay between environment and genetics. Although the biologic approaches are hypothesis generating, the results may lead to development of novel biomarkers, better understanding of COPD phenotypes, and development of novel diagnostic and therapeutic trials in AATD and COPD. Clinical trial registered with www.clinicaltrials.gov (NCT01832220).

Matrix metalloproteinase-9 activates TGF-ß and stimulates fibroblast contraction of collagen gels.

Matrix metalloproteinase-9 (MMP-9) is a matrix-degrading enzyme implicated in many biological processes, including inflammation. It is produced by many cells, including fibroblasts. When cultured in three-dimensional (3D) collagen gels, fibroblasts contract the surrounding matrix, a function that is thought to model the contraction that characterizes both normal wound repair and fibrosis. The current study was designed to evaluate the role of endogenously produced MMP-9 in fibroblast contraction of 3D collagen gels. Fibroblasts from mice lacking expression of MMP-9 and human lung fibroblasts (HFL-1) transfected with MMP-9 small-interfering RNA (siRNA) were used. Fibroblasts were cast into type I collagen gels and floated in culture medium with or without transforming growth factor (TGF)-ß1 for 5 days. Gel size was determined daily using an image analysis system. Gels made from MMP-9 siRNA-treated human fibroblasts contracted less than control fibroblasts, as did fibroblasts incubated with a nonspecific MMP inhibitor. Similarly, fibroblasts cultured from MMP-9-deficient mice contracted gels less than did fibroblasts from control mice. Transfection of the MMP-9-deficient murine fibroblasts with a vector expressing murine MMP-9 restored contractile activity to MMP-9-deficient fibroblasts. Inhibition of MMP-9 reduced active TGF-ß1 and reduced several TGF-ß1-driven responses, including activity of a Smad3 reporter gene and production of fibronectin. Because TGF-ß1 also drives fibroblast gel contraction, this suggests the mechanism for MMP-9 regulation of contraction is through the generation of active TGF-ß1. This study provides direct evidence that endogenously produced MMP-9 has a role in regulation of tissue contraction of 3D collagen gels mediated by fibroblasts.

The role of the lung microbiome in health and disease. A National Heart, Lung, and Blood Institute workshop report.

Study of the human lung microbiome in the context of pulmonary health and disease is an area of emerging research interest that is being driven by several contributing factors. These factors include increased recognition of the diversity of human-associated microbiota, their roles in health and in diseases associated with chronic inflammation, and advancements in technologies and tools that have facilitated such discoveries about the microbiota in organ systems outside of the lung. Therefore, the overarching goals of lung microbiome research are: to identify and characterize microbial populations associated with the respiratory tract and lungs; to understand their roles in lung health and disease; and, we hope, to allow the development of improved approaches for diagnosing and treating chronic respiratory diseases in which the microbiome has a role. Recent studies of the lung microbiome have yielded a number of interesting findings but also highlighted questions and challenges for researchers and clinicians. In December 2011, the National Heart, Lung, and Blood Institute convened a workshop to identify key issues and areas for further attention or development to advance research on the lung microbiome. Current knowledge and the state of research on the lung and related areas of human microbiome investigation were reviewed and discussed.

Accurate measurement of small airways on low-dose thoracic CT scans in smokers.

BACKGROUND: Partial volume averaging and tilt relative to the scan plane on transverse images limit the accuracy of airway wall thickness measurements on CT scan, confounding assessment of the relationship between airway remodeling and clinical status in COPD. The purpose of this study was to assess the effect of partial volume averaging and tilt corrections on airway wall thickness measurement accuracy and on relationships between airway wall thickening and clinical status in COPD. METHODS: Airway wall thickness measurements in 80 heavy smokers were obtained on transverse images from low-dose CT scan using the open-source program Airway Inspector. Measurements were corrected for partial volume averaging and tilt effects using an attenuation- and geometry-based algorithm and compared with functional status. RESULTS: The algorithm reduced wall thickness measurements of smaller airways to a greater degree than larger airways, increasing the overall range. When restricted to analyses of airways with an inner diameter < 3.0 mm, for a theoretical airway of 2.0 mm inner diameter, the wall thickness decreased from 1.07 ± 0.07 to 0.29 ± 0.10 mm, and the square root of the wall area decreased from 3.34 ± 0.15 to 1.58 ± 0.29 mm, comparable to histologic measurement studies. Corrected measurements had higher correlation with FEV1, differed more between BMI, airflow obstruction, dyspnea, and exercise capacity (BODE) index scores, and explained a greater proportion of FEV1 variability in multivariate models. CONCLUSIONS: Correcting for partial volume averaging improves accuracy of airway wall thickness estimation, allowing direct measurement of the small airways to better define their role in COPD.

Keratinocyte-targeted expression of human laminin γ2 rescues skin blistering and early lethality of laminin γ2 deficient mice.

Laminin-332 is a heterotrimeric basement membrane component comprised of the α3, ß3, and γ2 laminin chains. Laminin-332 modulates epithelial cell processes, such as adhesion, migration, and differentiation and is prominent in many embryonic and adult tissues. In skin, laminin-332 is secreted by keratinocytes and is a key component of hemidesmosomes connecting the keratinocytes to the underlying dermis. In mice, lack of expression of any of the three Laminin-332 chains result in impaired anchorage and detachment of the epidermis, similar to that seen in human junctional epidermolysis bullosa, and death occurs within a few days after birth. To bypass the early lethality of laminin-332 deficiency caused by the knockout of the mouse laminin γ2 chain, we expressed a dox-controllable human laminin γ2 transgene under a keratinocyte-specific promoter on the laminin γ2 (Lamc2) knockout background. These mice appear similar to their wild-type littermates, do not develop skin blisters, are fertile, and survive >1.5 years. Immunofluorescence analyses of the skin showed that human laminin γ2 colocalized with mouse laminin α3 and ß3 in the basement membrane zone underlying the epidermis. Furthermore, the presence of "humanized" laminin-332 in the epidermal basement membrane zone rescued the alterations in the deposition of hemidesmosomal components, such as plectin, collagen type XVII/BP180, and integrin α6 and ß4 chains, seen in conventional Lamc2 knockout mice, leading to restored formation of hemidesmosomes. These mice will be a valuable tool for studies of organs deficient in laminin-332 and the role of laminin-332 in skin, including wound healing.

Functional consequences of cell type-restricted expression of laminin α5 in mouse placental labyrinth and kidney glomerular capillaries.

The labyrinth is the highly vascularized part of the rodent placenta that allows efficient transfer of gases, nutrients, wastes, and other molecules between the maternal and embryonic circulations. These two blood compartments are separated by blastocyst-derived trophoblasts and endothelial cells with an intervening basement membrane that contains laminin and other typical basement membrane components. Previously we reported that the labyrinth of laminin α5 knockout (LMα5-/-) embryos exhibits reduced vascularization and detachment of endothelial cells from the basement membrane, which normally contains LMα5. As very little is known about the origin of this vascular basement membrane, we investigated the cellular requirements for LMα5 expression in the mouse placental labyrinth. By fluorescence-activated cell sorting and RT-PCR we confirmed that both endothelial cells and trophoblasts normally express LMα5. Using Cre-loxP technology and doxycycline-mediated gene expression, we generated genetically mosaic placentas in which either the trophoblasts or the endothelial cells, but not both, expressed LMα5. We found that the overall architecture of the labyrinth was normal as long as one of these two cell types expressed LMα5, even if it was transgene-derived human laminin α5. These results suggest that laminin trimers containing α5 that are synthesized and secreted by endothelium or by trophoblasts are capable of integrating into the basement membrane and promoting normal vascularization of the placenta. Additional studies showed that endothelium-expressed human LMα5 can support vascularization of the kidney glomerulus, consistent with previous studies using a tissue grafting approach.

Neutrophil elastase cleaves the murine hemidesmosomal protein BP180/type XVII collagen and generates degradation products that modulate experimental bullous pemphigoid.

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease associated with autoantibodies against the hemidesmosomal proteins BP180 and BP230. In the IgG passive transfer model of BP, blister formation is triggered by anti-BP180 IgG and depends on complement activation, mast cell degranulation, and neutrophil recruitment. Mice lacking neutrophil elastase (NE) do not develop experimental BP. Here, we demonstrated that NE degrades recombinant mouse BP180 within the immunodominant extracellular domain at amino acid positions 506 and 561, generating peptide p561 and peptide p506. Peptide p561 is chemotactic for neutrophils both in vitro and in vivo. Local injection of NE into B6 mice recruits neutrophils to the skin, and neutrophil infiltration is completely blocked by co-injection with the NE inhibitor α1-proteinase inhibitor. More importantly, NE directly cleaves BP180 in mouse and human skin, as well as the native human BP180 trimer molecule. These results demonstrate that (i) NE directly damages the extracellular matrix and (ii) NE degradation of mouse BP180 generates neutrophil chemotactic peptides that amplify disease severity at the early stage of the disease.

In vivo detection of acinar microstructural changes in early emphysema with (3)He lung morphometry.

PURPOSE: To quantitatively characterize early emphysematous changes in the lung microstructure of current and former smokers with noninvasive helium 3 ((3)He) lung morphometry and to compare these results with the clinical standards, pulmonary function testing (PFT) and low-dose computed tomography (CT). MATERIALS AND METHODS: This study was approved by the local institutional review board, and all subjects provided informed consent. Thirty current and former smokers, each with a minimum 30-pack-year smoking history and mild or no abnormalities at PFT, underwent (3)He lung morphometry. This technique is based on diffusion MR imaging with hyperpolarized (3)He gas and yields quantitative localized in vivo measurements of acinar airway geometric parameters, such as airway radii, alveolar depth, and number of alveoli per unit lung volume. These measurements enable calculation of standard morphometric characteristics, such as mean linear intercept and surface-to-volume ratio. RESULTS: Noninvasive (3)He lung morphometry was used to detect alterations in acinar structure in smokers with normal PFT findings. When compared with smokers with the largest forced expiratory volume in 1 second (FEV(1)) to forced vital capacity (FVC) ratio, those with chronic obstructive pulmonary disease had significantly reduced alveolar depth (0.07 mm vs 0.13 mm) and enlarged acinar ducts (0.36 mm vs 0.3 mm). The mean alveolar geometry measurements in the healthiest subjects were in excellent quantitative agreement with literature values obtained by using invasive techniques (acinar duct radius, 0.3 mm; alveolar depth, 0.14 mm at 1 L above functional residual capacity). (3)He lung morphometry depicted greater abnormalities than did PFT and CT. No adverse events were associated with inhalation of (3)He gas. CONCLUSION: (3)He lung morphometry yields valuable noninvasive insight into early emphysematous changes in alveolar geometry with increased sensitivity compared with conventional techniques.

Improving mood with psychoanalytic and cognitive therapies (IMPACT): a pragmatic effectiveness superiority trial to investigate whether specialised psychological treatment reduces the risk for relapse in adolescents with moderate to severe unipolar depression: study protocol for a randomised controlled trial.

BACKGROUND: Up to 70% of adolescents with moderate to severe unipolar major depression respond to psychological treatment plus Fluoxetine (20-50 mg) with symptom reduction and improved social function reported by 24 weeks after beginning treatment. Around 20% of non responders appear treatment resistant and 30% of responders relapse within 2 years. The specific efficacy of different psychological therapies and the moderators and mediators that influence risk for relapse are unclear. The cost-effectiveness and safety of psychological treatments remain poorly evaluated. METHODS/DESIGN: Improving Mood with Psychoanalytic and Cognitive Therapies, the IMPACT Study, will determine whether Cognitive Behavioural Therapy or Short Term Psychoanalytic Therapy is superior in reducing relapse compared with Specialist Clinical Care. The study is a multicentre pragmatic effectiveness superiority randomised clinical trial: Cognitive Behavioural Therapy consists of 20 sessions over 30 weeks, Short Term Psychoanalytic Psychotherapy 30 sessions over 30 weeks and Specialist Clinical Care 12 sessions over 20 weeks. We will recruit 540 patients with 180 randomised to each arm. Patients will be reassessed at 6, 12, 36, 52 and 86 weeks. Methodological aspects of the study are systematic recruitment, explicit inclusion criteria, reliability checks of assessments with control for rater shift, research assessors independent of treatment team and blind to randomization, analysis by intention to treat, data management using remote data entry, measures of quality assurance, advanced statistical analysis, manualised treatment protocols, checks of adherence and competence of therapists and assessment of cost-effectiveness. We will also determine whether time to recovery and/or relapse are moderated by variations in brain structure and function and selected genetic and hormone biomarkers taken at entry. DISCUSSION: The objective of this clinical trial is to determine whether there are specific effects of specialist psychotherapy that reduce relapse in unipolar major depression in adolescents and thereby costs of treatment to society. We also anticipate being able to utilise psychotherapy experience, neuroimaging, genetic and hormone measures to reveal what techniques and their protocols may work best for which patients. TRIAL REGISTRATION: Current Controlled Trials ISRCTN83033550.

The role of matrix metalloproteinase-9 in cigarette smoke-induced emphysema.

RATIONALE: Matrix metalloprotease (MMP)-9 is an elastolytic endopeptidase produced by activated macrophages that may be involved in the development of human pulmonary emphysema and could be inhibited with existing compounds. Mouse models have demonstrated that excess MMP-9 production can result in permanent alveolar destruction. OBJECTIVES: To determine if MMP-9 causes cigarette smoke-induced emphysema using MMP-9 knockout mice and human samples. METHODS: Mouse lungs were analyzed for inflammation and airspace enlargement using a mainstream smoke-exposure model. Human macrophage mRNA was isolated from subjects with emphysema by laser capture microdissection. Human blood monocyte mRNA was isolated from subjects with greater than 30 pack-year smoking history. Human gene expression was determined by quantitative polymerase chain reaction and compared with emphysema severity determined by automated computed tomography analysis. Plasma Clara cell secretory protein and surfactant protein-D were quantified to measure ongoing lung injury. MEASUREMENTS AND MAIN RESULTS: Mice deficient in MMP-9 develop the same degree of cigarette smoke-induced inflammation and airspace enlargement as strain-matched controls. Macrophages are the predominant source of MMP-9 production in human emphysema specimens and similar quantities of macrophage MMP-9 mRNA is present in areas of lung with and without emphysema. Circulating monocytes produce more MMP-9 in individuals with advanced emphysema severity despite no correlation of MMP-9 with markers of ongoing lung damage. CONCLUSIONS: These results suggest that MMP-9 in humans who smoke is similar to smoke-exposed mice, where MMP-9 is present in emphysematous lung but not correlated with the emphysema. To the degree that the mechanisms of emphysema in humans who smoke resemble the mouse model, these data suggest specific inhibition of MMP-9 is unlikely to be an effective therapy for cigarette smoke-induced emphysema. Clinical trial registered with www.clinicaltrials.gov (NCT 00757120).