Endothelial lipase: regulation and biological function.

Endothelial lipase is synthetized almost exclusively in endothelial cells and then fixed on the luminal surface of the endothelium by means of heparan sulphate proteoglycans. The enzyme is expressed in the endothelium of nearly all tissues and the degree of expression is higher in richly vascularized tissues than in the less vascularized ones. The endothelial lipase expression in tissues is upregulated by shear and cyclic stress, angiotensin II and hypertension. The plasma enzyme level is elevated by pro-inflammatory cytokines, in metabolic syndrome and obesity. Prolonged exercise reduces the plasma enzyme level in the rat. The activity of the enzyme is inhibited by: sphingomyelin, angiopoietin-like protein 3 and 4, and insulin. Endothelial lipase reduces the plasma high density lipoprotein concentration and changes its properties. The enzyme is considered to be the main regulator of the plasma high density lipoprotein concentration. The plasma endothelial lipase concentration is elevated in coronary atherosclerosis and it is inversely correlated with the plasma high density lipoprotein level. The enzyme is considered to exert mostly pro-atherogenic effects. Its action as triglyceride lipase is important in hypertriglyceridemia.

MiRNA-149 as a Candidate for Facial Clefting and Neural Crest Cell Migration.

Nonsyndromic cleft lip with or without palate (nsCL/P) ranks among the most common human birth defects and has a multifactorial etiology. Human neural crest cells (hNCC) make a substantial contribution to the formation of facial bone and cartilage and are a key cell type in terms of nsCL/P etiology. Based on increasing evidence for the role of noncoding regulatory mechanisms in nsCL/P, we investigated the role of hNCC-expressed microRNAs (miRNA) in cleft development. First, we conducted a systematic analysis of miRNAs expressed in human-induced pluripotent stem cell-derived hNCC using Affymetrix microarrays on cell lines established from 4 unaffected donors. These analyses identified 152 candidate miRNAs. Based on the hypothesis that candidate miRNA loci harbor genetic variation associated with nsCL/P risk, the genomic locations of these candidates were cross-referenced with data from a previous genome-wide association study of nsCL/P. Associated variants were reanalyzed in independent nsCL/P study populations. Jointly, the results suggest that miR-149 is implicated in nsCL/P etiology. Second, functional follow-up included in vitro overexpression and inhibition of miR-149 in hNCC and subsequent analyses at the molecular and phenotypic level. Using 3'RNA-Seq, we identified 604 differentially expressed (DE) genes in hNCC overexpressing miR-149 compared with untreated cells. These included TLR4 and JUNB, which are established targets of miR-149, and NOG, BMP4, and PAX6, which are reported nsCL/P candidate genes. Pathway analyses revealed that DE genes were enriched in pathways including regulation of cartilage development and NCC differentiation. At the cellular level, distinct hNCC migration patterns were observed in response to miR-149 overexpression. Our data suggest that miR-149 is involved in the etiology of nsCL/P via its role in hNCC migration.

Coexistence of antithrombin deficiency and suspected inferior vena cava atresia in an adolescent and his mother - case report and clinical implications.

BACKGROUND: Antithrombin deficiency (ATD) is an autosomal dominant thrombophilia presenting with varying phenotypes. In pediatric patients with ATD, thrombosis typically develops during the neonatal period or adolescence. However, to date there are no consistent recommendations on the therapeutic management of children with ATD. Inferior vena cava atresia (IVCA) belongs to a range of congenital or acquired vena cava malformations and is described as an independent risk factor for thrombosis. The present case report explores two cases of combined ATD and IVCA in an adolescent and his mother. CASE PRESENTATION: A 14-year-old male presented with extensive deep venous thromboses (DVTs) of both lower extremities as well as an IVCA. The patient had previously been diagnosed with an asymptomatic ATD without therapeutic consequences at that time. His mother was suffering from an ATD and had herself just been diagnosed with IVCA, too. The DVTs in the adolescent were treated by systemic anticoagulation and catheter-directed local thrombolysis causing favourable results. Yet, despite adequate oral anticoagulation the DVTs in both lower extremities reoccurred within 1 week after the patient was discharged from hospital. This time, thrombolysis could not be fully achieved. Surprisingly, probing and stenting of the IVCA was achieved, indicating an acquired IVCA which could have occurred after undetected thrombosis in early childhood. Genetic analyses showed the same mutation causing ATD in both son and mother: heterozygote missense mutation c.248 T > C, p.(Leu83Pro), within the heparin binding domain of antithrombin. This mutation was never reported in mutation databases before. CONCLUSIONS: To our knowledge this is the first case report discussing combined ATD and IVCA in two family members. Since ATDs present with clinical heterogeneity, taking a thorough family history is crucial for the anticipation of possible complications in affected children and decisions on targeted diagnostics and therapeutic interventions. Affected families must be educated on risk factors and clinical signs of thrombosis and need an immediate diagnostic workup in case of clinical symptoms. IVCA in patients with ATD could occur due to thrombotic occlusion at a very early age. Therefore, in case of family members with IVCA and ATD ultrasound screening in newborns should be considered.

'TB or not TB': the conundrum of pre-European contact tuberculosis in the Pacific.

Tuberculosis (TB) is a major global health threat, infecting one-third of the world's population. Despite this prominence, the age, origin and spread of the disease have been topics of contentious debate. Molecular studies suggest that Mycobacterium tuberculosis 'sensu stricto', the most common strain of TB infecting humans today, originated in Africa and from there spread into Europe and Asia. The M. tuberculosis strains most commonly found across the Pacific and the Americas today are most closely related to European strains, supporting a hypothesis that the disease only reached these regions relatively recently via European sailors or settlers. However, this hypothesis is inconsistent with palaeopathological evidence of TB-like lesions in human remains from across the Pacific that predate European contact. Similarly, genetic evidence from pre-European South American mummies challenges the notion of a European introduction of the disease into the Pacific. Here, we review the complex evidence for the age and origin of TB in the Pacific, and discuss key gaps in our knowledge and how these may be addressed. This article is part of the theme issue 'Insights into health and disease from ancient biomolecules'.

A systematic review and meta-analysis of dementia prevalence in seven developing countries: A STRiDE project.

The STRiDE project sets out to support the development of effective dementia policy in middle-income countries (Brazil, India, Indonesia, Jamaica, Kenya, Mexico, and South Africa). As part of this it will generate new data about the prevalence of dementia for a subset of these countries. This study aims to identify the current estimates of dementia prevalence in these countries and where the gaps lie in the current literature. A systematic review was completed on 30th April 2019 across electronic databases, identifying dementia prevalence literature originating from any of the seven countries. Four hundred and twenty-nine records were identified following de-duplication; 28 studies met the inclusion criteria and were included in the systematic review. Pooled estimates of dementia prevalence ranged from 2% to 9% based on DSM-IV criteria; these figures were generally higher in studies using other diagnostic criteria (e.g. the 10/66 algorithm). Available prevalence data varied between countries. Only Brazil, Mexico and India had data derived from studies judged as having a low risk of bias. Irrespective of country, studies often were not explicit in detailing the representativeness of their sample, or whether there was non-response bias. Further transparent and externally valid dementia prevalence research is needed across the STRiDE countries.

Non-ischemic heart preconditioning.

Ischemic heart conditioning has been shown to protect the organ against ischemia/reperfusion injury. Animal studies have revealed that the heart can also be conditioned by non-ischemic procedures, namely physical exercise and tachycardia. Long and short term endurance training, sprint training, resistance or interval training and even one bout of exercise induce cardiac preconditioning, which is manifested by a reduction in post ischemia/reperfusion infarct size, ventricular arrhythmia and improved heart function. Several factors contribute to the exercise-induced heart preconditioning, among which the most important can be: increased activity of the anti-radical defense system, opioids, interleukin-6, nitric oxide, ATP dependent potassium channels, heat shock protein 72 and sphingosine-1-phosphate. A few studies have also shown that one bout of exercise in patients with stable angina increases tolerated workload. According to some data obtained in swine and dogs, stimulated tachycardia before ischemia/reperfusion reduces the infarct size. Future studies are needed to fully clarify the mechanisms responsible for exercise- or tachycardia-induced heart preconditioning against ischemia/reperfusion. It may lead to the development of new treatment modes of the disease.

Common variants in DLG1 locus are associated with non-syndromic cleft lip with or without cleft palate.

Non-syndromic cleft lip with or without cleft palate (nsCL/P) is a common craniofacial anomaly with a complex and heterogeneous aetiology. Knowledge regarding specific genetic factors underlying this birth defect is still not well understood. Therefore, we conducted an independent replication analysis for the top-associated variants located within the DLG1 locus at chromosome 3q29, which was identified as a novel cleft-susceptibility locus in our genome-wide association study (GWAS). Mega-analysis of the pooled individual data from the GWAS and replication study confirmed that common DLG1 variants are associated with the risk of nsCL/P. Two single nucleotide polymorphisms (SNPs), rs338217 and rs7649443, were statistically significant even at the genome-wide level (Ptrend = 9.70E-10 and Ptrend = 8.96E-09, respectively). Three other SNPs, rs9826379, rs6805920 and rs6583202, reached a suggestive genome-wide significance threshold (Ptrend < 1.00E-05). The location of the strongest individual SNP in the intronic sequence of the gene encoding DLG1 antisense RNA suggests that the true causal variant implicated in the risk of nsCL/P may affect the DLG1 gene expression level rather than structure of the encoded protein. In conclusion, we identified a novel cleft-susceptibility locus at chromosome 3q29 with a DLG1 as a novel candidate gene for this common craniofacial anomaly.

Candidate Genes for Nonsyndromic Cleft Palate Detected by Exome Sequencing.

Nonsyndromic cleft palate only (nsCPO) is a facial malformation that has a livebirth prevalence of 1 in 2,500. Research suggests that the etiology of nsCPO is multifactorial, with a clear genetic component. To date, genome-wide association studies have identified only 1 conclusive common variant for nsCPO, that is, a missense variant in the gene grainyhead-like-3 ( GRHL3). Thus, the underlying genetic causes of nsCPO remain largely unknown. The present study aimed at identifying rare variants that might contribute to nsCPO risk, via whole-exome sequencing (WES), in multiply affected Central European nsCPO pedigrees. WES was performed in 2 affected first-degree relatives from each family. Variants shared between both individuals were analyzed for their potential deleterious nature and a low frequency in the general population. Genes carrying promising variants were annotated for 1) reported associations with facial development, 2) multiple occurrence of variants, and 3) expression in mouse embryonic palatal shelves. This strategy resulted in the identification of a set of 26 candidate genes that were resequenced in 132 independent nsCPO cases and 623 independent controls of 2 different ethnicities, using molecular inversion probes. No rare loss-of-function mutation was identified in either WES or resequencing step. However, we identified 2 or more missense variants predicted to be deleterious in each of 3 genes ( ACACB, PTPRS, MIB1) in individuals from independent families. In addition, the analyses identified a novel variant in GRHL3 in 1 patient and a variant in CREBBP in 2 siblings. Both genes underlie different syndromic forms of CPO. A plausible hypothesis is that the apparently nonsyndromic clefts in these 3 patients might represent hypomorphic forms of the respective syndromes. In summary, the present study identified rare variants that might contribute to nsCPO risk and suggests candidate genes for further investigation.

The skeletal and heart muscle triacylglycerol lipolysis revisited.

For 40 years, the enzyme hormone sensitive lipase was considered to hydrolyze the first ester bond of the triacylglycerol moiety and thus initiate hydrolysis. However, 12 years ago a new lipolytic enzyme, termed adipose triglyceride lipase was discovered. It was further shown that the process of lipolysis of triacylglycerol to diacylglycerol and fatty acid is initiated by adipose triglyceride lipase and not by hormone sensitive lipase, responsible for hydrolysis of diacylglycerol to monoacyglycerol and fatty acid. Adipose triglyceride lipase is present in all types of cells containing neutral fat. The enzyme is activated by a protein called comparative gene identification-58 and inhibited by a protein called G0/G1 switch protein 2. It has also been discovered that perilipins, the main proteins coating lipid droplets in the cells, are involved in the process of triacylglycerol lipolysis. Five perilipins (1-5) were identified, however, up to now their role has been poorly assessed. In skeletal muscles, exercise and training affect the mRNA expression and protein content of adipose triglyceride lipase, comparative gene identification-58, G0/G1 switch protein 2, perilipin 2 and 5. The effect of exercise/training depends on exercise intensity and type of muscle fiber. An interaction between comparative gene identification-58 and adipose triglyceride lipase seems to be responsible for the enzyme activation during contractile activity. Adipose triglyceride lipase is also responsible for the activation of the first step of triacylglycerol lipolysis in the heart. There is substantial evidence that cardiac triacylglycerol metabolism affects the function of the heart. ATGL gene mutations leads to the development of neutral lipid storage diseases.

Childhood bullying victimization is associated with use of mental health services over five decades: a longitudinal nationally representative cohort study.

BACKGROUND: Research supports robust associations between childhood bullying victimization and mental health problems in childhood/adolescence and emerging evidence shows that the impact can persist into adulthood. We examined the impact of bullying victimization on mental health service use from childhood to midlife. METHOD: We performed secondary analysis using the National Child Development Study, the 1958 British Birth Cohort Study. We conducted analyses on 9242 participants with complete data on childhood bullying victimization and service use at midlife. We used multivariable logistic regression models to examine associations between childhood bullying victimization and mental health service use at the ages of 16, 23, 33, 42 and 50 years. We estimated incidence and persistence of mental health service use over time to the age of 50 years. RESULTS: Compared with participants who were not bullied in childhood, those who were frequently bullied were more likely to use mental health services in childhood and adolescence [odds ratio (OR) 2.53, 95% confidence interval (CI) 1.88-3.40] and also in midlife (OR 1.30, 95% CI 1.10-1.55). Disparity in service use associated with childhood bullying victimization was accounted for by both incident service use through to age 33 years by a subgroup of participants, and by persistent use up to midlife. CONCLUSIONS: Childhood bullying victimization adds to the pressure on an already stretched health care system. Policy and practice efforts providing support for victims of bullying could help contain public sector costs. Given constrained budgets and the long-term mental health impact on victims of bullying, early prevention strategies could be effective at limiting both individual distress and later costs.

Global patterns of workplace productivity for people with depression: absenteeism and presenteeism costs across eight diverse countries.

PURPOSE: Depression is a leading cause of disability worldwide. Research suggests that by far, the greatest contributor to the overall economic impact of depression is loss in productivity; however, there is very little research on the costs of depression outside of Western high-income countries. Thus, this study examines the impact of depression on workplace productivity across eight diverse countries. METHODS: We estimated the extent and costs of depression-related absenteeism and presenteeism in the workplace across eight countries: Brazil, Canada, China, Japan, South Korea, Mexico, South Africa, and the USA. We also examined the individual, workplace, and societal factors associated with lower productivity. RESULTS: To the best of our knowledge, this is the first study to examine the impact of depression on workplace productivity across a diverse set of countries, in terms of both culture and GDP. Mean annual per person costs for absenteeism were lowest in South Korea at $181 and highest in Japan ($2674). Mean presenteeism costs per person were highest in the USA ($5524) and Brazil ($5788). Costs associated with presenteeism tended to be 5-10 times higher than those associated with absenteeism. CONCLUSIONS: These findings suggest that the impact of depression in the workplace is considerable across all countries, both in absolute monetary terms and in relation to proportion of country GDP. Overall, depression is an issue deserving much greater attention, regardless of a country's economic development, national income or culture.

Cost-effectiveness of the Mental Health and Development model for schizophrenia-spectrum and bipolar disorders in rural Kenya.

BACKGROUND: The treatment gap for serious mental disorders across low-income countries is estimated to be 89%. The model for Mental Health and Development (MHD) offers community-based care for people with mental disorders in 11 low- and middle-income countries. METHOD: In Kenya, using a pre-post design, 117 consecutively enrolled participants with schizophrenia-spectrum and bipolar disorders were followed-up at 10 and 20 months. Comparison outcomes were drawn from the literature. Costs were analysed from societal and health system perspectives. RESULTS: From the societal perspective, MHD cost Int$ 594 per person in the first year and Int$ 876 over 2 years. The cost per healthy day gained was Int$ 7.96 in the first year and Int$ 1.03 over 2 years - less than the agricultural minimum wage. The cost per disability-adjusted life year averted over 2 years was Int$ 13.1 and Int$ 727 from the societal and health system perspectives, respectively, on par with antiretrovirals for HIV. CONCLUSIONS: MHD achieved increasing returns over time. The model appears cost-effective and equitable, especially over 2 years. Its affordability relies on multi-sectoral participation nationally and internationally.

MMP-9 in atrial remodeling in patients with atrial fibrillation.

INTRODUCTION: Atrial fibrillation (AF) is the most common arrhythmia and is associated with significant morbidity and mortality. The impact of matrix metalloproteinases (MMPs) on structural atrial remodeling and sustainment of AF in patients with persistent and permanent AF is unresolved. OBJECTIVES: The aim was to evaluate MMP-9 and its tissue inhibitor-1 (TIMP-1) as markers of atrial remodeling in patients with persistent AF (PAF) who underwent electrical cardioversion (ECV) and in patients with permanent AF (continuous AF, CAF). PATIENTS AND METHODS: Plasma levels of MMP-9 and TIMP-1, clinical findings, and echocardiographic parameters were evaluated in 39 patients with AF and in 14 controls with sinus rhythm. RESULTS: The concentrations of MMP-9 were significantly higher in patients with PAF and CAF compared to controls. There was a significant increase of MMP-9 after ECV in the persistent AF group. The values of TIMP-1 were not significantly different between the groups. In patients with AF, MMP-9 levels were positively related to posterior wall thickness of the LV (r=0.356, P=0.049) and body mass index (r=0.367, P=0.046). CONCLUSION: Elevated levels of MMP-9 were related to the occurrence and maintenance of AF. This suggests that MMP-9 can be a marker of atrial remodeling in patients with AF. Regulation of the extracellular collagen matrix might be a potential therapeutic target in AF.

Perinatal depression and child development: exploring the economic consequences from a South London cohort.

BACKGROUND: Depression in mothers during pregnancy and in the postnatal period has been recognized to have wide-ranging adverse impacts on offspring. Our study examines some of the outcomes and long-term economic implications experienced by offspring who have been exposed to perinatal depression. METHOD: We analysed the effects of perinatal depression on child development outcomes of children at ages 11 and 16 years from the community-based South London Child Development Study. Economic consequences were attached to those outcomes through simple decision-analytic techniques, building on evidence from studies of epidemiology, health-related quality of life, public sector costs and employment. The economic analysis takes a life-course perspective from the viewpoints of the public sector, individual and society. RESULTS: Additional risks that children exposed to perinatal depression develop emotional, behavioural or cognitive problems ranged from 5% to 21%. In addition, there was a high risk (24%) that children would have special educational needs. We present results in the form of cost consequences attached to adverse child outcomes. For each child exposed to perinatal depression, public sector costs exceeded £3030, costs due to reduced earnings were £1400 and health-related quality of life loss was valued at £3760. CONCLUSIONS: Action to prevent or treat mothers' depression during pregnancy and after birth is likely to reduce public sector costs, increase earnings and improve quality of life for children who were exposed to the condition.

The state of the art in European research on reducing social exclusion and stigma related to mental health: a systematic mapping of the literature.

Stigma and social exclusion related to mental health are of substantial public health importance for Europe. As part of ROAMER (ROAdmap for MEntal health Research in Europe), we used systematic mapping techniques to describe the current state of research on stigma and social exclusion across Europe. Findings demonstrate growing interest in this field between 2007 and 2012. Most studies were descriptive (60%), focused on adults of working age (60%) and were performed in Northwest Europe-primarily in the UK (32%), Finland (8%), Sweden (8%) and Germany (7%). In terms of mental health characteristics, the largest proportion of studies investigated general mental health (20%), common mental disorders (16%), schizophrenia (16%) or depression (14%). There is a paucity of research looking at mechanisms to reduce stigma and promote social inclusion, or at factors that might promote resilience or protect against stigma/social exclusion across the life course. Evidence is also limited in relation to evaluations of interventions. Increasing incentives for cross-country research collaborations, especially with new EU Member States and collaboration across European professional organizations and disciplines, could improve understanding of the range of underpinning social and cultural factors which promote inclusion or contribute toward lower levels of stigma, especially during times of hardship.

Strong association of variants around FOXE1 and orofacial clefting.

Nonsyndromic orofacial clefting (nsOFC) is a common, complex congenital disorder. The most frequent forms are nonsyndromic cleft lip with or without cleft palate (nsCL/P) and nonsyndromic cleft palate only (nsCPO). Although they are generally considered distinct entities, a recent study has implicated a region around the FOXE1 gene in both nsCL/P and nsCPO. To investigate this hypothesis, we analyzed the 2 most strongly associated markers (rs3758249 and rs4460498) in 2 independent samples of differing ethnicities: Central European (949 nsCL/P cases, 155 nsCPO cases, 1163 controls) and Mayan Mesoamerican (156 nsCL/P cases, 10 nsCPO cases, 338 controls). While highly significant associations for both single-nucleotide polymorphisms were obtained in nsCL/P (rs4460498: p Europe = 6.50 × 10(-06), p Mayan = .0151; rs3758249: p Europe = 2.41 × 10(-05), p Mayan = .0299), no association was found in nsCPO (p > .05). Genotyping of rs4460498 in 472 independent European trios revealed significant associations for nsCL/P (p = .016) and nsCPO (p = .043). A meta-analysis of all data revealed a genomewide significant result for nsCL/P (p = 1.31 × 10(-08)), which became more significant when nsCPO cases were added (p nsOFC = 1.56 × 10(-09)). These results strongly support the FOXE1 locus as a risk factor for nsOFC. With the data of the initial study, there is now considerable evidence that this locus is the first conclusive risk factor shared between nsCL/P and nsCPO.

Usefulness of automatic measurement of contrast flow intensity: an innovative tool in contrast-enhanced ultrasound imaging of atherosclerotic carotid plaque neovascularization. A pilot study.

AIM: Contrast-enhanced ultrasound imaging of the carotid arteries (CECU) permits direct, real-time visualization of neovascularization in atherosclerotic plaques and is a confirmed predictor of unstable atheromatous lesions. The aim of the study was the assessment of a new, automatically measured index of intensity in quantitative estimation of the contrast flow through the carotid plaque (till now assessed only visually). METHODS: Forty-four patients (mean age 70.4±11.4) with ultrasound diagnosed significant stenosis of internal carotid artery (ICA), after cerebrovascular or cardiovascular events, qualified for carotid artery stenting (CAS) were examined. The carotid ultrasound examinations with contrast agent Sonovue were performed. RESULTS: Visually in 22 patients (50%) contrast flow through the atherosclerotic plaques was found. In 17 patients (38.6%) massive, calcified atherosclerotic plaques were present. Patients with preserved contrast flow through the plaque more frequently had a history of cerebral stroke (P=0.04). Massive calcifications of atherosclerotic plaques correlated with a previous MI (P=0.03) and the degree of advancement of coronary artery disease (P=0.04), but not with a previous cerebral stroke. Contrast flow through the atherosclerotic plaque positively correlated with values of the index of intensity (r=0.69, P<0.00001). In patients with preserved contrast flow the mean value of the index of intensity was 22.24±3.55 dB as compared with 12.37±7.67 dB - a value present in patients without preserved contrast flow. No significant relation for the degree of calcifications and the value of the index of intensity was found. CONCLUSION: The assessment of the index of intensity is a novel, simple and automatic method to estimate the degree of contrast flow through the carotid plaque. The values of the index of intensity correlate with the contrast flow through the atherosclerotic plaque, but not with its calcification.

The impact of non-adherence to medication in patients with schizophrenia on health, social care and societal costs. Analysis of the QUATRO study.

Aims. For people with schizophrenia, non-adherence to antipsychotic medications may result in high use of health and other services. The objective of our research was to examine the economic consequences of non-adherence in patients with schizophrenia taking antipsychotic medication. Methods. Data were taken from QUATRO, a randomized controlled trial that drew a sample of adults with schizophrenia receiving psychiatric services in four European cities: Amsterdam, Leipzig, London and Verona. Trial inclusion criteria were a clinical diagnosis of schizophrenia, requiring on-going antipsychotic medication for at least 1-year following baseline assessment, and exhibiting evidence of clinical instability in the year prior to baseline. The patient-completed Medication Adherence Questionnaire (MAQ) was used to calculate the 5-point Morisky index of adherence. Generalized linear models (GLM) were developed to determine the effect of adherence on (i) health and social care and (ii) societal costs before and after treatment, taking into account other potential cost-influencing factors. Results. The effect of non-adherence on costs was mixed. For different groups of services, and according to treatment group assignment, non-adherence was both negatively and positively associated with costs. Conclusions. The impact of non-adherence on costs varies across the types of services used by individuals with schizophrenia.

Impact of initial treatment outcome on long-term costs of depression: a 3-year nationwide follow-up study in Taiwan.

BACKGROUND: The impact of initial treatment outcome on long-term healthcare costs in depression remains to be determined. We aimed to identify demographic and clinical characteristics associated with initial treatment outcomes and to test whether and how these outcomes influence total healthcare costs over the subsequent 3 years. METHOD: In this secondary analysis of a large healthcare database, a national cohort of adult patients (n = 126,471) who received antidepressant treatment for depression was identified and factors associated with initial outcomes were examined. Potential predictors of total healthcare costs in the subsequent years were assessed using generalized linear modeling, with a particular focus on initial outcome status after antidepressant treatment and co-morbidities. RESULTS: Depression type and co-morbid painful physical symptoms (PPS) or mental illnesses were found to be associated with initial outcome status. Having sustained treatment-free status after initial treatment was shown to be associated with a 22-33% reduction in total healthcare costs in the second and third years (compared to those with late recontacts). Although the presence of co-morbid PPS was associated with higher healthcare costs, having certain co-morbid anxiety disorders was associated with lower costs over the 3 years. CONCLUSIONS: Initial outcome status after antidepressant treatment has a sustained impact on individuals' total healthcare costs over the following 3 years. Future efforts to improve initial treatment outcome of depression are warranted.

A cluster randomised controlled trial and economic evaluation of a structured training programme for caregivers of inpatients after stroke: the TRACS trial.

BACKGROUND: The majority of stroke patients are discharged home dependent on informal caregivers, usually family members, to provide assistance with activities of daily living (ADL), including bathing, dressing and toileting. Many caregivers feel unprepared for this role and this may have a detrimental effect on both the patient and caregiver. OBJECTIVE: To evaluate whether or not a structured, competency-based training programme for caregivers [the London Stroke Carer Training Course (LSCTC)] improved physical and psychological outcomes for patients and their caregivers after disabling stroke, and to determine if such a training programme is cost-effective. DESIGN: A pragmatic, multicentre, cluster randomised controlled trial. SETTING: Stratified randomisation of 36 stroke rehabilitation units (SRUs) to the intervention or control group by geographical region and quality of care. PARTICIPANTS: A total of 930 stroke patient and caregiver dyads were recruited. Patients were eligible if they had a confirmed diagnosis of stroke, were medically stable, were likely to return home with residual disability at the time of discharge and had a caregiver available, willing and able to provide support after discharge. The caregiver was defined as the main person--other than health, social or voluntary care provider--helping with ADL and/or advocating on behalf of the patient. INTERVENTION: The intervention (the LSCTC) comprised a number of caregiver training sessions and competency assessment delivered by SRU staff while the patient was in the SRU and one recommended follow-up session after discharge. The control group continued to provide usual care according to national guidelines. Recruitment was completed by independent researchers and participants were unaware of the SRUs' allocation. MAIN OUTCOME MEASURES: The primary outcomes were self-reported extended ADL for the patient and caregiver burden measured at 6 months after recruitment. Secondary outcomes included quality of life, mood and cost-effectiveness, with final follow-up at 12 months. RESULTS: No differences in primary outcomes were found between the groups at 6 months. Adjusted mean differences were -0.2 points [95% confidence interval (CI) -3.0 to 2.5 points; p = 0.866; intracluster correlation coefficient (ICC) = 0.027] for the patient Nottingham Extended Activities of Daily Living score and 0.5 points (95% CI -1.7 to 2.7 points; p = 0.660; ICC = 0.013) for the Caregiver Burden Scale. Furthermore, no differences were detected in any of the secondary outcomes. Intervention compliance varied across the units. Half of the participating centres had a compliance rating of > 60%. Analysis showed no evidence of higher levels of patient independence or lower levels of caregiver burden in the SRUs with better levels of intervention compliance. The economic evaluation suggests that from a patient and caregiver perspective, health and social care costs, societal costs and outcomes are similar for the intervention and control groups at 6 months, 12 months and over 1 year. CONCLUSIONS: We have conducted a robust multicentre, cluster randomised trial, demonstrating for the first time that this methodology is feasible in stroke rehabilitation research. There was no difference between the LSCTC and usual care with respect to improving stroke patients' recovery, reducing caregivers' burden, or improving other physical and psychological outcomes, nor was it cost-effective compared with usual care. Compliance with the intervention varied, but analysis indicated that a dose effect was unlikely. It is possible that the immediate post-stroke period may not be the ideal time for the delivery of structured training. The intervention approach might be more relevant if delivered after discharge by community-based teams. TRIAL REGISTRATION: Current Controlled Trials ISRCTN49208824. FUNDING: This project was funded by the MRC and is managed by the NIHR (project number 09/800/10) on behalf of the MRC-NIHR partnership, and will be published in full in Health Technology Assessment; Vol. 17, No. 46. See the NIHR Journals Library website for further project information.