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.

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.

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.

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.

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.

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.

Evidence for a polygenic contribution to androgenetic alopecia.

BACKGROUND: Male pattern baldness (androgenetic alopecia, AGA) is a highly heritable trait and the most common form of hair loss in humans. Eight genome-wide significant risk loci for AGA have been identified. OBJECTIVES: To determine whether a polygenic component contributes to the genetic risk for AGA. METHODS: This study used a German case-control sample for AGA, which comprised 581 severely affected patients and 617 controls, to determine the contribution of polygenic variance to AGA risk. The sample was divided evenly into discovery and test samples. An additive polygenic risk score was calculated from risk alleles with increasingly liberal P-values in the discovery dataset, which was then used to test for the enrichment of AGA risk score alleles in the independent test samples. RESULTS: The polygenic score analysis provided significant evidence for a polygenic contribution to AGA where the amount of variance explained was 1·4-4·5%. CONCLUSION: This study provides evidence for the specific contribution of a polygenic component to the overall heritable risk for AGA. To some degree, the polygenic architecture of AGA might reflect the complexity of the biological pathways involved. Further analyses and strategies that complement conventional genome-wide association studies are needed to identify these factors. These may include pathway-based analyses, the analysis of functional candidate genes and tests for epistatic effects with known loci.

Mapping of the gene for autosomal recessive polycystic kidney disease (ARPKD) to chromosome 6p21-cen.

Autosomal recessive polycystic kidney disease (ARPKD) is one of the major hereditary nephropathies in children predominantly presenting in early childhood. The clinical picture is variable but there is a fatal outcome in many cases. We have performed linkage analysis in 16 ARPKD families and localized the ARPKD gene to chromosomal region 6p21-cen with no evidence for genetic heterogeneity among different clinical phenotypes. Linkage was confirmed using six adjacent microsatellite markers and the highest lod score of 7.42 was obtained with D6S272 at theta = 0.00. Our findings should lead to more accurate forms of prenatal diagnosis than those currently available using ultrasound.

The potential of case management for people with dementia: a commentary.

BACKGROUND: A recent review of studies of case management in dementia argues that lack of evidence of cost-effectiveness should discourage the use of this approach to care. We argue that that this is too conservative a stance, given the urgent need throughout the world to improve the quality of care for people with dementia and their caregivers. We propose a research agenda on case management for people with dementia. METHOD: A critical comparison was made of the studies identified in two systematic reviews of trials of case management for dementia, with selective inclusion of non-trial studies and economic evaluations. RESULTS: Our interpretation of the literature leads us to four provisional conclusions. First, studies with long follow-up periods tend to show delayed relocation of people with dementia to care homes. Second, the quality of life of people with dementia and their caregivers may also influence the likelihood of relocation. Third, different understandings of what constitutes case management make interpretation of studies difficult. Fourth, we agree that the population most likely to benefit from case management needs to be characterised. Earlier intervention may be more beneficial than intervening when the condition has progressed and the individual's situation is highly complex. However, this runs counter to some definitions of case management as an administrative, professional, and systemic focus on people with high needs and where expensive support is accessed or in prospect. CONCLUSIONS: More work needs to be carried out in a more focused way in order to establish the value of case management for people with dementia. Since care home residence is such a sizeable contributor to the costs of dementia care, studies need to be long enough to capture possible postponed relocation. However, case management studies with shorter follow-up periods can still contribute to our understanding, since they can demonstrate improved quality of life. Future research should be built around a common, agreed definition of types of case management.

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.

Structural description of the macroscopic piezo- and ferroelectric properties of lead zirconate titanate.

An in situ structural description of the origin of the ferroelectric properties as a function of the applied electric field E was obtained by synchrotron x-ray diffraction. A setup was used to average the effects of the preferred orientation induced by the strong piezoelectric strain and solve in situ the crystal structure as a function of the applied electric field. Hence, we were able to describe the microscopic origin of the macroscopic ferro- and piezoelectric properties of the most widely used ferroelectric material, lead zirconate titanate.

Host plant resistance among tomato accessions to the spider mite Tetranychus evansi in Kenya.

The spider mite Tetranychus evansi has a broad range of host plants. Control of T. evansi has been a big challenge to tomato farmers due to its fast rate of reproduction, development of resistance to chemical pesticides and its ability to use weeds as alternative hosts when the tomato plants are not available. The aim of the current study was to determine the host plant acceptance and the relative contributions of trichomes in the control of the red spider mite by comparing the survival, development and oviposition rates of the red spider mite on eight tomato accessions. Leaflets from eight tomato varieties were assayed with the spider mites to determine the egg laying capacity and developmental time of the spider mites on the tomato accessions as well as the trichome densities. Densities of trichome types I, IV, V and VI varied among the tomato accessions. Variation in types I, IV and VI accounted for most of the variation in mite responses. The varieties with high densities of types IV and VI had the highest fecundity and mite development did not go beyond the larval stage. The developmental time varied significantly among the tomato accessions. The results indicated that the higher the density of trichome type I the lower the adult survival. The findings indicated possible resistance of some of the tested tomato accessions against T. evansi which is partially associated with trichomes types and density.

A phantom extinction? New insights into extinction dynamics of the Don-hare Lepus tanaiticus.

The Pleistocene to Holocene transition was accompanied by a worldwide extinction event affecting numerous mammalian species. Several species such as the woolly mammoth and the giant deer survived this extinction wave, only to go extinct a few thousand years later during the Holocene. Another example for such a Holocene extinction is the Don-hare, Lepus tanaiticus, which inhabited the Russian plains during the late glacial. After being slowly replaced by the extant mountain hare (Lepus timidus), it eventually went extinct during the middle Holocene. Here, we report the phylogenetic relationship of L. tanaiticus and L. timidus based on a 339-basepair (bp) fragment of the mitochondrial D-loop. Phylogenetic tree- and network reconstructions do not support L. tanaiticus and L. timidus being different species. Rather, we suggest that the two taxa represent different morphotypes of a single species and the extinction of 'L. tanaiticus' represents the disappearance of a local morphotype rather than the extinction of a species.

Overcoming the barriers experienced in conducting a medication trial in adults with aggressive challenging behaviour and intellectual disabilities.

BACKGROUND: Aggressive challenging behaviour in people with intellectual disability (ID) is frequently treated with antipsychotic drugs, despite a limited evidence base. METHOD: A multi-centre randomised controlled trial was undertaken to investigate the efficacy, adverse effects and costs of two commonly prescribed antipsychotic drugs (risperidone and haloperidol) and placebo. RESULTS: The trial faced significant problems in recruitment. The intent was to recruit 120 patients over 2 years in three centres and to use a validated aggression scale (Modified Overt Aggression Scale) score as the primary outcome. Despite doubling the period of recruitment, only 86 patients were ultimately recruited. CONCLUSIONS: Variation in beliefs over the efficacy of drug treatment, difficulties within multidisciplinary teams and perceived ethical concerns over medication trials in this population all contributed to poor recruitment. Where appropriate to the research question cluster randomised trials represent an ethically and logistically feasible alternative to individually randomised trials.

Reproductive performance of seven strains of the tomato red spider mite Tetranychus evansi (Acari: Tetranychidae) at five temperatures.

The tomato red spider mite Tetranychus evansi Baker et Pritchard occurs on solanaceous plants, and causes serious damage to a variety of crops in Africa and Europe. In 2001 this species was also found in Japan, on nightshade (Solanum nigrum L.), and its invasion to solanaceous of agricultural importance is feasible. To evaluate its potential severity as a pest, the present study assessed the life-history parameters, such as the rate of development and the intrinsic rate of natural increase (r(m)), on S. nigrum for T. evansi collected on seven sites worldwide. Increasing temperatures between 15 and 32.5°C significantly increased the developmental rate of the seven strains while immature developmental duration was about the same at 32.5-40°C. The rate of egg-to-adult development [(% hatch) × (% survival)] exceeded 88% at temperatures between 15 and 37.5°C. The lower thermal thresholds (LT) were 11.9-12.5°C for both egg-to-adult and egg-to-egg development. The optimum developmental temperatures ranged from 36.7 to 43.8°C and the upper developmental threshold (UT) ranged from 45.2 to 59.4°C. The r (m)-values became higher with temperature increasing from 15 to 35°C. The r (m)-values at 25°C ranged from 0.265 to 0.277 which are relatively high for species of the genus Tetranychus. These results indicate that T. evansi after invasion into Japan has the potential to become a serious pest on solanaceous crops, just the same as in Africa and Europe.

'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.

Phase II trial of thalidomide, irinotecan and gemcitabine in chemonaive patients with advanced non-small cell lung cancer.

This study aim was to determine the efficacy and safety of the combination of Gemcitabine 1000 mg/m(2) day 1 & 8 and Irinotecan 100 mg/m(2) day 1 & 8 with escalating dose of thalidomide in chemonaive patients with advanced non-small cell lung cancer. Among the 20 patients who met eligibility criteria and received treatment, two patients (10%) experienced partial response and 14 (70%) experienced stable disease. The median time to disease progression was 4 months (95% CI: 2.8-6.6). The 1 year and 2 year survival rates were 36% and 27%, respectively. This combination is active in advanced NSCLC with manageable toxicity profile.