PRegnancy Outcomes after a Maternity Intervention for Stressful EmotionS (PROMISES): study protocol for a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>There is ample evidence from observational prospective studies that maternal depression or anxiety during pregnancy is a risk factor for adverse psychosocial outcomes in the offspring. However, to date no previous study has demonstrated that treatment of depressive or anxious symptoms in pregnancy actually could prevent psychosocial problems in children. Preventing psychosocial problems in children will eventually bring down the huge public health burden of mental disease. The main objective of this study is to assess the effects of cognitive behavioural therapy in pregnant women with symptoms of anxiety or depression on the child's development as well as behavioural and emotional problems. In addition, we aim to study its effects on the child's development, maternal mental health, and neonatal outcomes, as well as the cost-effectiveness of cognitive behavioural therapy relative to usual care.</p> <p>Methods/design</p> <p>We will include 300 women with at least moderate levels of anxiety or depression at the end of the first trimester of pregnancy. By including 300 women we will be able to demonstrate effect sizes of 0.35 or over on the total problems scale of the child behavioural checklist 1.5-5 with alpha 5% and power (1-beta) 80%.</p> <p>Women in the intervention arm are offered 10-14 individual cognitive behavioural therapy sessions, 6-10 sessions during pregnancy and 4-8 sessions after delivery (once a week). Women in the control group receive care as usual.</p> <p>Primary outcome is behavioural/emotional problems at 1.5 years of age as assessed by the total problems scale of the child behaviour checklist 1.5 - 5 years.</p> <p>Secondary outcomes will be mental, psychomotor and behavioural development of the child at age 18 months according to the Bayley scales, maternal anxiety and depression during pregnancy and postpartum, and neonatal outcomes such as birth weight, gestational age and Apgar score, health care consumption and general health status (economic evaluation).</p> <p>Trial Registration</p> <p>Netherlands Trial Register (NTR): <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2242">NTR2242</a></p

Functional Characterization of Human Cancer-Derived TRKB Mutations

Cancer originates from cells that have acquired mutations in genes critical for controlling cell proliferation, survival and differentiation. Often, tumors continue to depend on these so-called driver mutations, providing the rationale for targeted anticancer therapies. To date, large-scale sequencing analyses have revealed hundreds of mutations in human tumors. However, without their functional validation it remains unclear which mutations correspond to driver, or rather bystander, mutations and, therefore, whether the mutated gene represents a target for therapeutic intervention. In human colorectal tumors, the neurotrophic receptor TRKB has been found mutated on two different sites in its kinase domain (TRKBT695I and TRKBD751N). Another site, in the extracellular part of TRKB, is mutated in a human lung adenocarcinoma cell line (TRKBL138F). Lastly, our own analysis has identified one additional TRKB point mutation proximal to the kinase domain (TRKBP507L) in a human melanoma cell line. The functional consequences of all these point mutations, however, have so far remained elusive. Previously, we have shown that TRKB is a potent suppressor of anoikis and that TRKB-expressing cells form highly invasive and metastatic tumors in nude mice. To assess the functional consequences of these four TRKB mutations, we determined their potential to suppress anoikis and to form tumors in nude mice. Unexpectedly, both colon cancer-derived mutants, TRKBT695I and TRKBD751N, displayed reduced activity compared to that of wild-type TRKB. Consistently, upon stimulation with the TRKB ligand BDNF, these mutants were impaired in activating TRKB and its downstream effectors AKT and ERK. The two mutants derived from human tumor cell lines (TRKBL138F and TRKBP507L) were functionally indistinguishable from wild-type TRKB in both in-vitro and in-vivo assays. In conclusion, we fail to detect any gain-of-function of four cancer-derived TRKB point mutations

Aggravation of Chronic Stress Effects on Hippocampal Neurogenesis and Spatial Memory in LPA1 Receptor Knockout Mice

The lysophosphatidic acid LPA₁ receptor regulates plasticity and neurogenesis in the adult hippocampus. Here, we studied whether absence of the LPA₁ receptor modulated the detrimental effects of chronic stress on hippocampal neurogenesis and spatial memory.Male LPA₁-null (NULL) and wild-type (WT) mice were assigned to control or chronic stress conditions (21 days of restraint, 3 h/day). Immunohistochemistry for bromodeoxyuridine and endogenous markers was performed to examine hippocampal cell proliferation, survival, number and maturation of young neurons, hippocampal structure and apoptosis in the hippocampus. Corticosterone levels were measured in another a separate cohort of mice. Finally, the hole-board test assessed spatial reference and working memory. Under control conditions, NULL mice showed reduced cell proliferation, a defective population of young neurons, reduced hippocampal volume and moderate spatial memory deficits. However, the primary result is that chronic stress impaired hippocampal neurogenesis in NULLs more severely than in WT mice in terms of cell proliferation; apoptosis; the number and maturation of young neurons; and both the volume and neuronal density in the granular zone. Only stressed NULLs presented hypocortisolemia. Moreover, a dramatic deficit in spatial reference memory consolidation was observed in chronically stressed NULL mice, which was in contrast to the minor effect observed in stressed WT mice.These results reveal that the absence of the LPA₁ receptor aggravates the chronic stress-induced impairment to hippocampal neurogenesis and its dependent functions. Thus, modulation of the LPA₁ receptor pathway may be of interest with respect to the treatment of stress-induced hippocampal pathology

Ultrasound for Distal Forearm Fracture:A Systematic Review and Diagnostic Meta-Analysis

STUDY OBJECTIVE:To determine the diagnostic accuracy of ultrasound for detecting distal forearm fractures. METHODS:A systematic review and diagnostic meta-analysis was performed according to the PRISMA statement. We searched MEDLINE, Web of Science and the Cochrane Library from inception to September 2015. All prospective studies of the diagnostic accuracy of ultrasound versus radiography as the reference standard were included. We excluded studies with a retrospective design and those with evidence of verification bias. We assessed the methodological quality of the included studies with the QUADAS-2 tool. We performed a meta-analysis of studies evaluating ultrasound to calculate the pooled sensitivity and specificity with 95% confidence intervals (CI95%) using a bivariate model with random effects. Subgroup and sensitivity analysis were used to examine the effect of methodological differences and other study characteristics. RESULTS:Out of 867 publications we included 16 studies with 1,204 patients and 641 fractures. The pooled test characteristics for ultrasound were: sensitivity 97% (CI95% 93-99%), specificity 95% (CI95% 89-98%), positive likelihood ratio (LR) 20.0 (8.5-47.2) and negative LR 0.03 (0.01-0.08). The corresponding pooled diagnostic odds ratio (DOR) was 667 (142-3,133). Apparent differences were shown for method of viewing, with the 6-view method showing higher specificity, positive LR, and DOR, compared to the 4-view method. CONCLUSION:The present meta-analysis showed that ultrasound has a high accuracy for the diagnosis of distal forearm fractures in children when used by proper viewing method. Based on this, ultrasound should be considered a reliable alternative, which has the advantages of being radiation free

The mental health of young children with intellectual disabilities or borderline intellectual functioning

Objective To determine within a nationally representative sample of young Australian children: (1) the association amongst intellectual disability, borderline intellectual functioning and the prevalence of possible mental health problems; (2) the association amongst intellectual disability, borderline intellectual functioning and exposure to social disadvantage; (3) the extent to which any between-group differences in the relative risk of possible mental health problems may be attributable to differences in exposure to disadvantageous social circumstances. Methods The study included a secondary analysis of a population-based child cohort of 4,337 children, aged 4/5 years, followed up at age 6/7 years. The main outcome measure was the scoring within the ‘abnormal’ range at age 6/7 years on the parent-completed Strengths and Difficulties Questionnaire. Results When compared to typically developing children, children identified at age 4/5 years as having intellectual disability or borderline intellectual functioning: (1) showed significantly higher rates of possible mental health problems for total difficulties and on all five SDQ subscales at age 6/7 years (OR 1.98–5.58); (2) were significantly more likely to be exposed to socio-economic disadvantage at age 4/5 and 6/7 years. Controlling for the possible confounding effects of exposure to socio-economic disadvantage (and child gender) significantly reduced, but did not eliminate, between-group differences in prevalence. Conclusions Children with limited intellectual functioning make a disproportionate contribution to overall child psychiatric morbidity. Public health and child and adolescent mental health services need to ensure that services and interventions fit to the purpose and are effective for children with limited intellectual functioning, and especially those living in poverty, as they are for other children

Effects of prescribed antihypertensives and other cardiovascular drugs on mortality in patients with atrial fibrillation and hypertension: a cohort study from Sweden.

Although antihypertensive drugs are known to reduce mortality in individuals with hypertension, the effects of different cardiovascular pharmacotherapies on mortality among patients with hypertension and atrial fibrillation (AF) have been less thoroughly explored. To study mortality rates in men and women separately with hypertension and AF prescribed different cardiovascular pharmacotherapies. A cohort of men (n=2809) and women (n=2793) aged >45 years diagnosed with hypertension and AF were selected using patient records. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox regression, with all-cause mortality as the outcome. Analysis was performed on the whole population and after stratification by age and sex. Independent factors were prescribed pharmacotherapies. Adjustments were made for a propensity score comprising age, comorbidities, education and marital status. The higher the number of antihypertensive drugs prescribed, the lower the mortality rate (P-value for trend 0.005). Individuals prescribed 4-5 antihypertensive drugs had a lower risk of mortality than those prescribed 0-1 drugs (HR: 0.62; 95% CI: 0.45-0.86). The HRs for the following drug classes were: loop diuretics 1.39 (95% CI: 1.08-1.78), non-selective β-blockers 0.68 (95% CI: 0.53-0.88), angiotensin receptor blockers 0.75 (95% CI: 0.56-0.99) and statins 0.68 (95% CI: 0.53-0.88). AF patients with hypertension prescribed statins, non-selective β-blockers and angiotensin receptor blockers had low relative mortality risks, suggesting that these prescribed pharmacotherapies were beneficial. This needs to be further explored in other clinical settings.Hypertension Research advance online publication, 6 March 2014; doi:10.1038/hr.2014.32