Longitudinal associations between alcohol use, smoking, genetic risk scoring and symptoms of depression in the general population: a prospective 6-year cohort study.

BACKGROUND: Alcohol consumption, smoking and mood disorders are leading contributors to the global burden of disease and are highly comorbid. Yet, their interrelationships have remained elusive. The aim of this study was to examine the multi-cross-sectional and longitudinal associations between (change in) smoking and alcohol use and (change in) number of depressive symptoms. METHODS: In this prospective, longitudinal study, 6646 adults from the general population were included with follow-up measurements after 3 and 6 years. Linear mixed-effects models were used to test multi-cross-sectional and longitudinal associations, with smoking behaviour, alcohol use and genetic risk scores for smoking and alcohol use as independent variables and depressive symptoms as dependent variables. RESULTS: In the multi-cross-sectional analysis, smoking status and number of cigarettes per day were positively associated with depressive symptoms (p < 0.001). Moderate drinking was associated with less symptoms of depression compared to non-use (p = 0.011). Longitudinally, decreases in the numbers of cigarettes per day and alcoholic drinks per week as well as alcohol cessation were associated with a reduction of depressive symptoms (p = 0.001-0.028). Results of genetic risk score analyses aligned with these findings. CONCLUSIONS: While cross-sectionally smoking and moderate alcohol use show opposing associations with depressive symptoms, decreases in smoking behaviour as well as alcohol consumption are associated with improvements in depressive symptoms over time. Although we cannot infer causality, these results open avenues to further investigate interventions targeting smoking and alcohol behaviours in people suffering from depressive symptoms.

[Patient with a long history of disease in whom service dog contributed to recovery]. / Hulphond als geslaagde contextuele interventie voor herstel.

We describe a patient who reached recovery, after purchasing a dog and training it into an assistance dog. The patient has a long lasting (over 30 years) history in mental health care and was diagnosed with autism spectrum disorder, posttraumatic stress disorder and borderline personality disorder. All these years the patient did not reach symptomatic improvement or personal or social recovery. The patient suffered from severe emotional instability, feeling misunderstood, sleeping disorder because of nightmares and traumatic re-experiences, feeling unsafe and externalisation. There were repeated conflicts and periodical rejection of caregivers. A range of interventions and support options were offered. Medication intake was considerable aiming for sedation and numbness. After a second opinion an assistance dog was suggested. Two years after the purchase of the dog, her mood had improved, anxiety decreased, she slept better and stopped all medication. She feeled safe. Conflicts with others were reduced, she had some social contacts and the intensity of care had been reduced considerably.

Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders.

Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10-3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10-4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10-3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10-7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia.

Beyond Tier Three: Individualized Levels of Support During Headsprout® Early Reading Instruction for Children with Autism Spectrum Disorder.

We previously conducted a series of conceptual replications to parse out which-and to what degree-adaptations and individualized supports were needed for children to access and learn early reading skills using Headsprout®. Here we developed a systematic decision-making process for providing levels of support to individuals with autism who require additional instruction in order to access and/or advance through Headsprout®. Using a series of single-case AB, ABC, and multiple-baseline designs we examined strategies from our previous research and additional strategies iteratively developed during the study on six students with autism, all of whom demonstrated progression through Headsprout® and increased reading skills. We provide practical implications for teachers and suggestions to research these supports with other computer-based programs.

[Use of the Triangle of Care Card and its influence on the cooperation with caregivers and clients]. / Gebruik van Triadekaart en invloed op de samenwerking met naastbetrokkenen.

BACKGROUND: Although there is consensus on the importance of involving informal caregivers of people with severe mental illness, interventions are needed to support this. AIM: To explore whether the use of the 'Triangle of Care Card', an instrument developed to help strengthen the role of care-givers in their contact with workers, increases quality of cooperation and care. METHOD: Three outpatient mental health teams and twelve teams for supported housing started working with the card. Information from files and questionnaires were used to monitor change and compare this with the changes during the same year in ten other teams. RESULTS: Use of the Triangle of Care Card was sparse. When it was used, a broader range of subjects were discussed, including the needs of caregivers. Also, clients were more involved. In teams where the card was introduced, the clients' networks became more apparent and there was an increase in face-to-face meetings with members of this network. CONCLUSION: Introduction of the Triangle of Care Card leads to change in the involvement of caregivers. However, implementation is problematic and therefore the increase in quality of the cooperation with caregivers and quality of care is yet small.

Public perception and awareness of waste management from Benin City.

Poor waste management is increasingly becoming a major challenge for municipalities, globally. Unlike previous waste management studies in Nigeria, this study examines the implications of waste management to regional greenhouse gas emissions based on awareness levels and perception of urban inhabitants. Benin City was divided into four residential zones: core, intermediate, suburban, and planned estates. Blocking was utilized to collect data from a total of 2720 randomly selected inhabitants through a self-administered survey. Results reveals low awareness level in terms of indiscrimination dumping of waste, thereby promoting sustainable mitigation and adaptation measures region-wide. It is imperative to integrate various aspects of regional government services such as infrastructure, urban planning and development, socioeconomics, public health, and regulation enforcement. Waste management policy is strengthened via working groups, community, and regional authorities.

Resuscitation with an AED: putting the data to use.

The increased use of the automated external defibrillator (AED) contributes to the rising survival rate after sudden cardiac arrest in the Netherlands. When used, the AED records the unconscious person's medical data (heart rhythm and information about cardiopulmonary resuscitation), which may be important for further diagnosis and treatment. In practice, ethical and legal questions arise about what can and should be done with these 'AED data'. In this article, the authors advocate the development of national guidelines on the handling of AED data. These guidelines should serve two purposes: (1) to safeguard that data are handled carefully in accordance with data protection principles and the rules of medical confidentiality; and (2) to ensure nationwide availability of data for care of patients who survive resuscitation, as well as for quality monitoring of this care and for related scientific research. Given the medical ethical duties of beneficence and fairness, existing (sometimes lifesaving) information about AED use ought to be made available to clinicians and researchers on a structural basis. Creating a national AED data infrastructure, however, requires overcoming practical and organisational barriers. In addition, further legal study is warranted.

Tumor repolarization by an advanced liposomal drug delivery system provides a potent new approach for chemo-immunotherapy.

Immunosuppressive cells in the tumor microenvironment allow cancer cells to escape immune recognition and support cancer progression and dissemination. To improve therapeutic efficacy, we designed a liposomal oxaliplatin formulation (PCL8-U75) that elicits cytotoxic effects toward both cancer and immunosuppressive cells via protease-mediated, intratumoral liposome activation. The PCL8-U75 liposomes displayed superior therapeutic efficacy across all syngeneic cancer models in comparison to free-drug and liposomal controls. The PCL8-U75 depleted myeloid-derived suppressor cells and tumor-associated macrophages in the tumor microenvironment. The combination of improved cancer cell cytotoxicity and depletion of immunosuppressive populations of immune cells is attractive for combination with immune-activating therapy. Combining the PCL8-U75 liposomes with a TLR7 agonist induced immunological rejection of established tumors. This combination therapy increased intratumoral numbers of cancer antigen-specific cytotoxic T cells and Foxp3- T helper cells. These results are encouraging toward advancing liposomal drug delivery systems with anticancer and immune-modulating properties into clinical cancer therapy.

Implementing early intensive behavioral intervention in community settings.

LAY ABSTRACT: Although research shows early intensive behavioral intervention can be very beneficial for children with autism spectrum disorder when delivered in university or private intervention centers, little is known about the best way to provide early intensive behavioral intervention within the broader community. The Michigan State University Early Learning Institute was developed to address challenges with providing early intensive behavioral intervention in community settings, with an emphasis on serving children and families on Medicaid. This short report describes the approach taken by the Early Learning Institute and reports data regarding enrollment and utilization among Medicaid families. Results suggest the model has potential to be used within community settings and that children on Medicaid are likely to consistently attend their treatment sessions.

Analysis of microRNA expression in brush cytology specimens improves the diagnosis of pancreatobiliary cancer.

BACKGROUND/OBJECTIVES: Malignant pancreatobiliary strictures are in many cases clinically indistinguishable and present a major problem to endoscopy specialists. Intraductal sampling procedures such as brush cytology are commonly used for diagnosis with a sensitivity that is low for a diagnostic test used in daily clinical practice. MicroRNA (miR) alterations detected in many cancers are disease-specific, which can be utilized in clinical applications. The aim of the present study was to analyze whether determination of miR expression levels in intraductal brush cytology specimens is a feasible approach to improve the diagnosis of pancreatobiliary cancer. METHODS: Brush cytology specimens have been collected during endoscopic retrograde cholangio-pancreatography (ERCP) and analyzed by routine cytology and ancillary miR assays. Total RNA was extracted using the miRNeasy Mini Kit and the expression of miRs frequently dysregulated in pancreatobiliary cancer (miR-16, miR-21, miR-196a, miR-221) were analyzed by quantitative real-time PCR using RNU6B as internal control. RESULTS: Routine cytology resulted in no false positive diagnoses, however, the combined sensitivity remained at 53.8%. Expression (ΔCt values) of miR-16 (p = 0.0039), miR-196a (p = 0.0003) and miR-221 (p = 0.0049) showed a clear statistical significance between malignant and benign pancreatobiliary specimens (n = 35). Malignancy could be detected combining routine cytology and the miR-196a single marker expression levels with a sensitivity of 84.6% (92.9% in biliary strictures) with no false positives. CONCLUSIONS: The results offer the first direct demonstration that microRNAs are readily detectable in brush cytology specimens obtained during ERCP, and have the potential to help the cytological diagnosis of pancreatobiliary malignancy.

A Pilot Evaluation of a Treatment Package to Teach Social Conversation via Video-Chat.

By engaging with family members through video-chat technology, children with autism spectrum disorder (ASD) may access additional opportunities to develop social connections to build familial cohesion and access emotional support. The purpose of this study was to evaluate a behavioral intervention package in teaching social conversation via video-chat. Using a non-concurrent multiple-baseline across participants with an embedded alternating treatments design, three seven-year-old males with ASD were taught two variations of a social conversation. Their conversation skills generalized to unfamiliar adults, some of whom had no prior experience with children with ASD. When visual supports were removed, participants appropriately varied their social conversations. Social conversations continued to occur 2 weeks following the completion of the study. Results and implications are discussed.

Effects of Joint Video Modeling on Unscripted Play Behavior of Children with Autism Spectrum Disorder.

Preschool aged children with autism spectrum disorder (ASD) have marked deficits in pretend play that impede interactions with typically developing peers in inclusive early childhood settings. This study aimed to teach three young children with ASD to engage in pretend play behaviors with their peers. A multiple probe across participants experimental design was used to evaluate the effects of joint video modeling on scripted and unscripted verbalizations and scripted and unscripted play actions of children with ASD. The participants showed improvement on unscripted verbalizations during pretend play with typically developing peers in an inclusive early childhood setting.

No differences in olanzapine- and risperidone-related weight gain between women and men: a meta-analysis of short- and middle-term treatment.

OBJECTIVE: A plethora of data deriving from single studies as well as meta-analyses demonstrates that weight gain is associated with the exposure to the majority of antipsychotics (AP). However, potential sex differences have widely evaded the attention of AP treatment trials. It is hypothesised that female patients gain more weight compared with male patients due to their enhanced susceptibility to adverse drug reactions. METHOD: A meta-analysis was conducted using clinical trials of AP that reported weight change separately for female and male patients. Duration of AP use was stratified in four categories: <6 weeks, 6-16 weeks, 16-38 weeks and >38 weeks. Forest plots were generated for men and women separately, stratified by AP as well as by duration of use. Sex differences were tested by performing meta-regression. RESULTS: Data of 26 studies were used in the present analysis because sufficient data were available only for olanzapine, risperidone and the no-medication group. Both female and male patients showed considerable weight gain after switch or initiate of olanzapine or risperidone, but meta-regression analyses did not show significant sex differences. CONCLUSION: The present meta-analysis revealed that sex differences in AP-related weight gain have been under investigated hampering the detection of sex-specific patterns. In chronic patients switching to olanzapine or risperidone receiving short-or middle-term treatment, AP were associated with weight gain in both sex subgroups and no significant differences were reported.

Intraverbal Training for Individuals with Autism: The Current Status of Multiple Control.

Teaching complex intraverbal responding to children with autism spectrum disorder (ASD) can be challenging and often requires careful programming. Divergent and convergent multiple control are particularly important elements to incorporate into intraverbal training programs, as well as procedures to ensure responding is under control of both discriminative and conditional vocal verbal stimuli. The current study systematically reviewed research articles on intraverbal training methods for individuals with ASD published and available from 2005 to 2016. The purpose of the review was to assess the extent to which divergent and convergent control was incorporated into training and to determine whether systematic instruction ensured correct verbal conditional discriminations. Thirty-six studies met inclusion criteria and were included in this reviewed. A total of 5 studies taught intraverbal responding under divergent control and 21 taught responding under convergent control. Two studies sufficiently described procedures to ensure accurate verbal conditional discriminations across trials. The results highlight the need for additional research on systematic teaching procedures for complex intraverbal repertoires.

Does breast screening offer a survival benefit? A retrospective comparative study of oncological outcomes of screen-detected and symptomatic early stage breast cancer cases.

INTRODUCTION: Mammography screening reduces breast cancer mortality by up to 32%. However, some recent studies have questioned the impact of non-palpable breast cancer detection on mortality reduction. The aim of this study was to analyse the clinicopathological and long-term follow-up data of early stage screened and symptomatic breast cancer patients. PATIENTS AND METHOD: The institutional prospectively led database was systematically analysed for breast cancer cases diagnosed via the mammography screening program from 2002 to 2009. As a control group, symptomatic early stage breast cancer patients were collected randomly from the same database and matched for age and follow-up period. All medical records were reviewed retrospectively. RESULTS: Data from 298 breast cancer patients were collected from 47,718 mammography screenings. In addition, 331 symptomatic breast cancer patients were randomly selected. The screened group presented a significantly lower median tumour size (P < 0.00001). The incidence of negative regional lymph nodes was significantly higher in the screened group (P < 0.0006). The incidence of chemotherapy was 17% higher in the symptomatic group (P = 4*10-5). At the median follow-up of 65 and 80 months, the screened group did not exhibit better overall (P = 0.717) or disease-free survival (P = 0.081) compared to the symptomatic group. CONCLUSION: Our results do not suggest that mammography screening does not reduce breast cancer mortality but the mammography screening did not bring any significant improvement in patient overall or disease-free survival for the early stage breast cancer patients compared to the symptomatic group. The drawback of symptomatic early stage tumours compared to non-palpable tumours could be equalized by modern multimodality oncology treatments.

The functional and clinical relevance of childhood trauma-related admixture of affective, anxious and psychosis symptoms.

OBJECTIVE: Previous work has shown that across different patient samples, patients with childhood trauma are more likely to have co-occurrence of affective, anxious and psychosis symptoms than non-traumatized patients. However, the clinical relevance of trauma-related admixture remains to be established. METHOD: We examined patients with mood disorder (NEMESIS-2; n = 1260), anxiety disorder (NEMESIS-2; n = 896) or psychotic disorder (GROUP; n = 532) in terms of symptom profiles, quality of life (QOL) and social functioning. RESULTS: Results showed that mood disorder patients with both trauma and co-occurrence of affective, anxious and psychosis symptoms had a lower QOL (B-12.6, 95% CI -17.7 to -7.5, P < 0.001), more help-seeking behaviour [odds ratio (OR) 2.5, 95% CI 1.1-5.7, P = 0.031] and higher prevalence of substance use disorders (OR 7.8, 95% CI 1.1-58.0, P = 0.044), compared with patients without trauma history and symptom admixture (Trauma-/CL-). Similar results were found in patients with an anxiety disorder. Traumatized patients with a psychotic disorder and admixture showed lower QOL (B-0.6, 95% CI -0.9 to -0.4, P < 0.001), higher prevalence of drug disorders (OR 2.2, 95% CI 1.2-3.9, P = 0.008) and lower global assessment of functioning (B-12.8, 95% CI -17.1 to -8.5, P < 0.001) than Trauma-/CL- patients. CONCLUSION: Stratification according to childhood trauma exposure thus identifies a phenotype characterized by admixture of affective, anxiety and psychotic symptoms that, when combined, has clinical relevance. Identification of functionally meaningful aetiological subgroups may aid clinical practice.

Involvement of microRNAs in the inflammatory pathways of pulmonary sarcoidosis.

Sarcoidosis is a multi-organ disease in which affected tissues are invaded with non-necrotizing granulomatous structures, mostly consisted of T helper 1 (Th1) cells and multinucleate giant cells. However, the etiology and pathogenesis of sarcoidosis is not known and the diagnosis is usually based on clinical examination involving radiography and histopathological analysis of biopsies of affected organs. Although the knowledge on the molecular background of sarcoidosis is limited, it seems that the important pathways involve transforming growth factor-ß (TGF-ß) and JAK/STAT, which may influence the interferon-γ (IFN-γ)-mediated signaling. Additionally, recently the role of microRNAs (miRNAs), the small non-coding RNA molecules, has been emphasized in different pathological conditions including autoimmune diseases. This review summarizes the current knowledge on the molecular pathways in the pathogenesis of sarcoidosis with a special emphasis on cytokines and miRNAs controlling immune cells proliferation and differentiation. Moreover, the possible role of T regulatory cells (CD4(+) CD25(+) FoxP3(+)) in this disease has been discussed.

Note: Real time optical sensing of alpha-radiation emitting radioactive aerosols based on solid state nuclear track detector.

A sensitive radioactive aerosols sensor has been designed and developed. Its design guidance is based on the need for a low operational cost and reliable measurements to provide daily aerosol monitoring. The exposure of diethylene-glycol bis (allylcarbonate) to radiation causes modification of its physico-chemical properties like surface roughness and reflectance. In the present study, optical sensor based on the reflectance measurement has been developed with an aim to monitor real time presence of alpha radioactive aerosols emitted from thorium nitrate hydrate. The results shows that the fabricated sensor can detect 0.0157 kBq to 0.1572 kBq of radio activity by radioactive aerosols generated from (Th(NO3)4 ⋅ 5H2O) at 0.1 ml/min flow rate. The proposed instrument will be helpful to monitor radioactive aerosols in/around a nuclear facility, building construction sites, mines, and granite polishing factories.

Childhood trauma is associated with a specific admixture of affective, anxiety, and psychosis symptoms cutting across traditional diagnostic boundaries.

BACKGROUND: Meta-analyses link childhood trauma to depression, mania, anxiety disorders, and psychosis. It is unclear, however, whether these outcomes truly represent distinct disorders following childhood trauma, or that childhood trauma is associated with admixtures of affective, psychotic, anxiety and manic psychopathology throughout life. METHOD: We used data from a representative general population sample (NEMESIS-2, n = 6646), of whom respectively 1577 and 1120 had a lifetime diagnosis of mood or anxiety disorder, as well as from a sample of patients with a diagnosis of schizophrenia (GROUP, n = 825). Multinomial logistic regression was used to assess whether childhood trauma was more strongly associated with isolated affective/psychotic/anxiety/manic symptoms than with their admixture. RESULTS: In NEMESIS-2, largely comparable associations were found between childhood trauma and depression, mania, anxiety and psychosis. However, childhood trauma was considerably more strongly associated with their lifetime admixture. These results were confirmed in the patient samples, in which it was consistently found that patients with a history of childhood trauma were more likely to have a combination of multiple symptom domains compared to their non-traumatized counterparts. This pattern was also found in exposed individuals who did not meet criteria for a psychotic, affective or anxiety disorder and who did not seek help for subclinical psychopathology. CONCLUSIONS: Childhood trauma increases the likelihood of a specific admixture of affective, anxiety and psychotic symptoms cutting across traditional diagnostic boundaries, and this admixture may already be present in the earliest stages of psychopathology. These findings may have significant aetiological, pathophysiological, diagnostic and clinical repercussions.

A kinase inhibitor screen identifies Mcl-1 and Aurora kinase A as novel treatment targets in antiestrogen-resistant breast cancer cells.

Antiestrogen resistance is a major problem in breast cancer treatment. Therefore, the search for new therapeutic targets and biomarkers for antiestrogen resistance is crucial. In this study, we performed a kinase inhibitor screen on antiestrogen responsive MCF-7 cells and a panel of MCF-7-derived tamoxifen- and fulvestrant-resistant cell lines. Our focus was to identify common and distinct molecular mechanisms involved in tamoxifen- and fulvestrant-resistant cell growth. We identified 18 inhibitors, of which the majority was common for both tamoxifen- and fulvestrant-resistant cell lines. Two compounds, WP1130 and JNJ-7706621, exhibiting prominent preferential growth inhibition of antiestrogen-resistant cell lines, were selected for further studies. WP1130, a deubiquitinase inhibitor, induced caspase-mediated cell death in both tamoxifen- and fulvestrant-resistant cell lines by destabilization of the anti-apoptotic protein Mcl-1. Mcl-1 expression was found upregulated in the antiestrogen-resistant cell lines and depletion of Mcl-1 in resistant cells caused decreased viability. JNJ-7706621, a dual Aurora kinase and cyclin-dependent kinase inhibitor, specifically inhibited growth and caused G2 phase cell cycle arrest of the tamoxifen-resistant cell lines. Knockdown studies showed that Aurora kinase A is essential for growth of the tamoxifen-resistant cells and inhibition of Aurora kinase A resensitized tamoxifen-resistant cells to tamoxifen treatment. Preferential growth inhibition by WP1130 and JNJ-7706621 was also found in T47D-derived tamoxifen-resistant cell lines, pointing at Mcl-1 and Aurora kinase A as potential treatment targets. In addition, tumor samples from 244 estrogen receptor-positive breast cancer patients treated with adjuvant tamoxifen showed that higher expression level of Aurora kinase A was significantly associated with shorter disease-free and overall survival, demonstrating the potential of Aurora kinase A as a biomarker for tamoxifen resistance.