Comparing proxy rated quality of life of people living with dementia in care homes.

BACKGROUND: Improving quality of life (QOL) for people with dementia is a priority. In care homes, we often rely on proxy ratings from staff and family but we do not know if, or how, they differ in care homes. METHODS: We compared 1056 pairs of staff and family DEMQOL-Proxy ratings from 86 care homes across England. We explored factors associated with ratings quantitatively using multilevel modelling and, qualitatively, through thematic analysis of 12 staff and 12 relative interviews. RESULTS: Staff and family ratings were weakly correlated (ρs = 0.35). Median staff scores were higher than family's (104 v. 101; p < 0.001). Family were more likely than staff to rate resident QOL as 'Poor' (χ2 = 55.91, p < 0.001). Staff and family rated QOL higher when residents had fewer neuropsychiatric symptoms and severe dementia. Staff rated QOL higher in homes with lower staff:resident ratios and when staff were native English speakers. Family rated QOL higher when the resident had spent longer living in the care home and was a native English. Spouses rated residents' QOL higher than other relatives. Qualitative results suggest differences arise because staff felt good care provided high QOL but families compared the present to the past. Family judgements centre on loss and are complicated by decisions about care home placement and their understandings of dementia. CONCLUSION: Proxy reports differ systematically between staff and family. Reports are influenced by the rater:staff and family may conceptualise QOL differently.

The ACCEPT-study: design of an RCT with an active treatment control condition to study the effectiveness of the Dutch version of PEERS® for adolescents with autism spectrum disorder.

BACKGROUND: Social skills interventions are commonly deployed for adolescents with autism spectrum disorder (ASD). Because effective and appropriate social skills are determined by cultural factors that differ throughout the world, the effectiveness of these interventions relies on a good cultural fit. Therefore, the ACCEPT study examines the effectiveness of the Dutch Program for the Education and Enrichment of Relational Skills (PEERS®) social skills intervention. METHODS/DESIGN: This study is a two-arm parallel group randomized controlled trial (RCT) in which adolescents are randomly assigned (after baseline assessment) to one of two group interventions (PEERS® vs. active control condition). In total, 150 adolescents are to be included, with multi-informant involvement of their parents and teachers. The ACCEPT study uses an active control condition (puberty psychoeducation group training, focussing on social-emotional development) and explores possible moderators and mediators in improving social skills. The primary outcome measure is the Contextual Assessment of Social Skills (CASS). The CASS assesses social skills performance in a face to face social interaction with an unfamiliar, typically developing peer, making this a valuable instrument to assess the social conversational skills targeted in PEERS®. In addition, to obtain a complete picture of social skills, self-, parent- and teacher-reported social skills are assessed using the Social Skills improvement System (SSiS-RS) and Social Responsiveness Scale (SRS-2). Secondary outcome measures (i.e. explorative mediators) include social knowledge, social cognition, social anxiety, social contacts and feelings of parenting competency of caregivers. Moreover, demographic and diagnostic measures are assessed as potential moderators of treatment effectiveness. Assessments of adolescents, parents, and teachers take place at baseline (week 0), intermediate (week 7), post intervention (week 14), and at follow-up (week 28). CONCLUSION: This is the first RCT on the effectiveness of the PEERS® parent-assisted curriculum which includes an active control condition. The outcome of social skills is assessed using observational assessments and multi-informant questionnaires. Additionally, factors related to social learning are assessed at several time points, which will enable us to explore potential mediators and moderators of treatment effect. TRAIL REGISTRATION: Dutch trail register NTR6255 (NL6117). Registered February 8th, 2017 - retrospectively registered.

Neonatal levels of neurotrophic factors and risk of autism spectrum disorders.

OBJECTIVE: To examine levels of 3 neurotrophic factors (NTFs): Brain derived neurotrophic factor (BDNF), Neurotrophin-4 (NT-4), and transforming growth factor-ß (TGF-ß) in dried blood spot samples of neonates diagnosed with autism spectrum disorders (ASD) later in life and frequency-matched controls. METHOD: Biologic samples were retrieved from the Danish Newborn Screening Biobank. NTFs for 414 ASD cases and 820 controls were measured using Luminex technology. Associations were analyzed with continuous measures (Tobit regression) as well as dichotomized at the lower and upper 10th percentiles cutoff points derived from the controls' distributions (logistic regression). RESULTS: ASD cases were more likely to have BDNF levels falling in the lower 10th percentile (odds ratios [OR], 1.53 [95% confidence intervals (CI), 1.04-2.24], P-value = 0.03). Similar pattern was seen for TGF-ß in females with ASD (OR, 2.36 [95% CI, 1.05-5.33], P-value = 0.04). For NT-4, however, ASD cases diagnosed with ICD-10 only were less likely to have levels in upper 10th percentile compared with controls (OR, 0.22 [95% CI, 0.05-0.98], P-value = 0.05). CONCLUSION: Results cautiously indicate decreased NTFs levels during neonatal period in ASD. This may contribute to the pathophysiology of ASD through impairments of neuroplasticity. Further research is required to confirm our results and to examine the potential therapeutic effects of NTFs in ASD.

How Well Can we Diagnose Autism in Adults? Evaluating an Informant-based Interview: The Dutch Developmental, Dimensional and Diagnostic Interview - Adult Version (3Di-Adult).

The current study evaluated a brief, informant-based autism interview: the Developmental, Dimensional and Diagnostic Interview - Adult Version (3Di-Adult). Feasibility, reliability and validity of the Dutch 3Di-Adult was tested amongst autistic participants (n = 62) and a non-autistic comparison group (n = 30) in the Netherlands. The 3Di-Adult consists of two scales based on DSM-5 criteria: A scale 'Social communication and social interaction' and B scale 'Restricted, repetitive patterns of behavior, interests or activities'. ROC curves were used to determine cut-off scores for the A and the B scale, using an ASD diagnosis made by an independent clinician as the criterion. Mean administration time was 42 min. Internal consistency of the A scale (α = 0.92) and the B scale (α = 0.85) were good. Inter-rater reliability (ICCs = 0.99) and inter-rater agreement (ICCs ≥ 0.90) were promising. The 3Di-Adult showed good sensitivity (80.6%) and specificity (93.3%). Positive and negative predictive value were 96.2% and 70.0% respectively. Comparisons with the Autism-Spectrum Quotient-Short to investigate the convergent validity showed moderate, significant correlations with the 3Di-Adult in the total sample. Males, as compared to females, displayed significantly more autistic features on the 3Di-Adult. No relationship was found of the 3Di-Adult with education level, intelligence and age of the participants or informants. The feasibility and psychometric properties of the Dutch 3Di-Adult are promising, indicating that it can be a time-efficient, valid and reliable tool to use in diagnosing autism in adults according to DSM-5 criteria.

Recruitment of ethnic minorities into cancer clinical trials: experience from the front lines.

Throughout the world there are problems recruiting ethnic minority patients into cancer clinical trials. A major barrier to trial entry may be distrust of research and the medical system. This may be compounded by the regulatory framework governing research with an emphasis on written consent, closed questions and consent documentation, as well as fiscal issues. The Leicester UK experience is that trial accrual is better if British South Asian patients are approached by a senior doctor rather than someone of perceived lesser hierarchical status and a greater partnership between the hospital and General Practitioner may increase trial participation of this particular ethnic minority. In Los Angeles, USA, trial recruitment was improved by a greater utilisation of Hispanic staff and a Spanish language-based education programme. Involvement of community leaders is essential. While adhering to national, legal and ethnical standards, information sheets and consent, it helps if forms can be tailored towards the local ethnic minority population. Written translations are often of limited value in the recruitment of patients with no or limited knowledge of English. In some cultural settings, tape-recorded verbal consent (following approval presentations) may be an acceptable substitute for written consent, and appropriate legislative changes should be considered to facilitate this option. Approaches should be tailored to specific minority populations, taking consideration of their unique characteristics and with input from their community leadership.

Risk indicators of anxiety throughout adolescence: the TRAILS study.

BACKGROUND: The aim was to identify risk indicators from preadolescence (age period 10-12) that significantly predict unfavorable deviations from normal anxiety development throughout adolescence (age period 10-17 years). METHODS: Anxiety symptoms were assessed in a community sample of 2,220 boys and girls at three time-points across a 5-year interval. Risk indicators were measured at baseline and include indicators from the child, family, and peer domain. Associations with anxiety were measured with multilevel growth curve analyses. RESULTS: A stable difference in anxiety over adolescence was found between high and low levels of a range of child factors (frustration, effortful control), family factors (emotional warmth received from parents, lifetime parental internalizing problems), and peer factor (victims of bullying) (P <.001). In contrast, the difference in anxiety between high and low levels of factors, such as self-competence, unfavorable parenting styles, and bully victims, decreased over adolescence (P <.001). For other family factors, associations were weaker (.05

Use of the ketogenic diet and dietary practices in the UK.

BACKGROUND: In 2000, a survey showed that use of the ketogenic diet as a treatment for intractable epilepsy in the UK was low. Subsequently, the number of medical publications supporting its efficacy has increased and demand from parents for this treatment has also increased. This survey was undertaken to determine whether there had been an increase in the use of the ketogenic diet and the necessary resources to provide it. METHODS: A survey of paediatric dietitians in the UK was undertaken. Data were collected on their experience of implementing a ketogenic diet, the type of diet used, patient caseloads, other members of the care team, the process for initiation of the diet and funding. RESULTS: Twenty-eight hospitals offered the ketogenic diet treatment with a total of 152 patients. The caseload per dietitian ranged from 1-36 patients. The classical diet was prescribed for 74% cases. The majority of patients began the diet as outpatients. Six dietitians were specifically funded to provide the treatment. Fifty more dietitians had experience of implementing the diet but currently had no patients. The reasons given for this were no referrals, no funding or not working with patients with epilepsy. CONCLUSIONS: The number of patients on the ketogenic diet had increased since 2000. However, numbers remained low and the main reasons given were the lack of referrals and a lack of funding. Recommendations are made to improve the dietetic and funding resources available so that an efficacious treatment for intractable epilepsy of childhood can be made more widely available.

Urbanicity, hypothalamic-pituitary-adrenal axis functioning, and behavioral and emotional problems in children: a path analysis.

BACKGROUND: Urbanization is steadily increasing worldwide. Previous research indicated a higher incidence of mental health problems in more urban areas, however, very little is known regarding potential mechanisms underlying this association. We examined whether urbanicity was associated with mental health problems in children directly, and indirectly via hypothalamic-pituitary-adrenal (HPA)-axis functioning. METHODS: Utilizing data from two independent samples of children we examined the effects of current urbanicity (n = 306, ages seven to 12 years) and early childhood urbanicity (n = 141, followed from birth through age 7 years). Children's mothers reported on their mental health problems and their family's socioeconomic status. Salivary cortisol samples were collected during a psychosocial stress procedure to assess HPA axis reactivity to stress, and at home to assess basal HPA axis functioning. Neighborhood-level urbanicity and socioeconomic conditions were extracted from Statistics Netherlands. Path models were estimated using a bootstrapping procedure to detect indirect effects. RESULTS: We found no evidence for a direct effect of urbanicity on mental health problems, nor were there indirect effects of urbanicity through HPA axis functioning. Furthermore, we did not find evidence for an effect of urbanicity on HPA axis functioning or effects of HPA axis functioning on mental health problems. CONCLUSIONS: Possibly, the effects of urbanicity on HPA axis functioning and mental health do not manifest until adolescence. An alternative explanation is a buffering effect of high family socioeconomic status as the majority of children were from families with an average or high socioeconomic status. Further studies remain necessary to conclude that urbanicity does not affect children's mental health via HPA axis functioning.

Adult Manifestation of Milder Forms of Autism Spectrum Disorder; Autistic and Non-autistic Psychopathology.

We compared the presence of autistic and comorbid psychopathology and functional impairments in young adults who received a clinical diagnosis of Pervasive Developmental Disorders Not Otherwise Specified or Asperger's Disorder during childhood to that of a referred comparison group. While the Autism Spectrum Disorder group on average scored higher on a dimensional ASD self- and other-report measure than clinical controls, the majority did not exceed the ASD cutoff according to the Autism Diagnostic Observation Schedule. Part of the individuals with an ASD diagnosis in their youth no longer show behaviors that underscribe a clinical ASD diagnosis in adulthood, but have subtle difficulties in social functioning and a vulnerability for a range of other psychiatric disorders.

The developmental course of anxiety symptoms during adolescence: the TRAILS study.

BACKGROUND: Little is known about the development of anxiety symptoms from late childhood to late adolescence. The present study determined developmental trajectories of symptoms of separation anxiety disorder (SAD), social phobia (SoPh), generalized anxiety disorder (GAD), panic disorder (PD), and obsessive-compulsive disorder (OCD) in a large prospective community cohort. METHODS: Anxiety symptoms were assessed in a community sample of 2220 boys and girls at three time-points across a 5-year interval. The Revised Child Anxiety and Depression Scale (RCADS) was used to assess anxiety symptoms, and multilevel growth-curve analyses were performed. RESULTS: All subtypes of anxiety first showed a decrease in symptoms (beta for age ranged from -.05 to -.13, p < .0001), followed by a leveling off of the decrease, and a subsequent slight increase in symptoms (beta for age-squared ranged from .006 to .01, p < .0001) from middle adolescence (GAD, SoPh, SAD) or late adolescence (PD and OCD) onwards. This increase in anxiety symptoms could not be explained by a co-occurring increase in depression symptoms. Girls had more anxiety symptoms than boys, and this difference remained stable during adolescence (p < .0001). Gender differences were strongly attenuated by adjustment for symptoms of depression. CONCLUSIONS: The current study shows that, in the general population, anxiety symptoms first decrease during early adolescence, and subsequently increase from middle to late adolescence. These findings extend our knowledge on the developmental course of anxiety symptoms during adolescence. This is the first study to separate the development of anxiety symptoms from that of symptoms of depression.

Baseline cortisol measures and developmental pathways of anxiety in early adolescence.

OBJECTIVE: This study investigated whether baseline cortisol measures predicted future anxiety, and compared cortisol values of groups with different developmental pathways of anxiety. METHOD: Cortisol levels were assessed in 1768 individuals (10-12 years). Anxiety levels were assessed at the same age and 2 years later. RESULTS: Cortisol measures did not predict future anxiety levels. Individuals with persistent anxiety problems did not show higher morning cortisol levels than those with persistently low, decreasing, or increasing anxiety levels. Instead, individuals with persistently high anxiety levels showed significantly lower evening cortisol levels than all other individuals. Further, participants with increasing anxiety levels showed higher morning cortisol levels (area under the curve; AUC) than individuals with persistently low anxiety levels. CONCLUSION: The extent to which the HPA-axis - by itself - plays a role in the aetiology of anxiety is questionable. Interactions of the HPA-axis with other biological or environmental factors may be more important.

[Stress reactivity as an underlying mechanism of anxiety? Findings from the TRAILS study]. / Stressgevoeligheid als onderliggend mechanisme voor angstproblemen? Bevindingen uit de TRAILS-studie.

This short report provides an overview of the results of a recent Dutch study on the relation between anxiety and the reactivity of two important stress response systems: the autonomic nervous system and the hypothalamic-pituitary-adrenal axis. Future research will have to investigate the reactivity of both stress response systems in combination with several other important biological, psychological and social factors. In this way it should be possible to obtain more insight into the complex and interacting systems that underlie anxiety.

Proto-oncogenes of the fos/jun family of transcription factors are positive regulators of myeloid differentiation.

The proto-oncogenes c-jun, junB, junD, and c-fos recently have been shown to encode for transcription factors with a leucine zipper that mediates dimerization to constitute active transcription factors; juns were shown to dimerize with each other and with c-fos, whereas fos was shown to dimerize only with juns. After birth, hematopoietic cells of the myeloid lineage, and some other terminally differentiated cell types, express high levels of c-fos. Still, the role of fos/jun transcription factors in normal myelopoiesis or in leukemogenesis has not been established. Recently, c-jun, junB, and junD were identified as myeloid differentiation primary response genes stably expressed following induction of terminal differentiation of myeloblastic leukemia M1 cells. Intriguingly, c-fos, though induced during normal myelopoiesis, was not induced upon M1 differentiation. To gain further insights into the role of fos/jun in normal myelopoiesis and leukemogenicity, M1fos and M1junB cell lines, which constitutively express c-fos and junB, respectively, were established. It was shown that enforced expression of c-fos, and to a lesser extent junB, in M1 cells results in both an increased propensity to differentiate and a reduction in the aggressiveness of the M1 leukemic phenotype. M1fos cells constitutively expressed immediate-early and late genetic markers of differentiated M1 cells. The in vitro differentiation of normal myeloblasts into mature macrophages and granulocytes, as well as the increased propensity of M1fos leukemic myeloblasts to be induced for terminal differentiation, was dramatically impaired with use of c-fos antisense oligomers in the culture media. Taken together, these observations show that the proto-oncogenes which encode for fos/jun transcription factors play important roles in promoting myeloid differentiation. The ability of the M1 leukemic myeloblasts to be induced for terminal differentiation in the absence of apparent fos expression indicates that there is some redundancy among the fos/jun family of transcription factors in promoting myeloid differentiation; however, juns alone cannot completely compensate for the lack of fos. Thus, genetic lesions affecting fos/jun expression may play a role in the development of "preleukemic" myelodysplastic syndromes and their further progression to leukemias.

Leukemia inhibitory factor and interleukin-6 trigger the same immediate early response, including tyrosine phosphorylation, upon induction of myeloid leukemia differentiation.

Leukemia inhibitory factor (LIF) and interleukin-6 (IL-6), two multifunctional cytokines lacking structural homology and binding to distinct receptors, share interesting functional similarities, which include induction of hematopoietic differentiation in normal and myeloid leukemia cells, induction of neuronal cell differentiation, and stimulation of acute-phase protein synthesis in hepatocytes. Structural information on the LIF receptor is not yet available, whereas recent cloning of the IL-6 receptor has shown it to be bipartite, with a signal-transducing subunit that lacks sequence homology to known protein kinases and produces second messengers of unknown nature. The molecular nature of the mechanisms which LIF and IL-6 use to induce cell differentiation is not known. To address this issue, we took advantage of a clone of M1 myeloblastic leukemia cells capable of being induced for terminal differentiation by both LIF and IL-6 directly activate the same set of immediate early response genes upon induction of M1 myeloid differentiation. At least two mechanisms of gene activation, one transcriptional and the other posttranscriptional, are shown to be involved. It is also shown that the LIF and IL-6 immediate early response, at suboptimal cytokine concentrations, is additive. Using a variety of protein kinase activators and inhibitors, we have shown that the intracellular signalling pathways for both LIF and IL-6 are distinct from those of known second messengers and involve protein phosphorylation, notably tyrosine phosphorylation of a 160-kDa protein, as an essential step(s) in the immediate early activation of MyD gene expression. These observations indicate that the functional similarities of LIF and IL-6 as inducers of cell differentiation prevail at the level of the complex differentiation immediate early response and implicate common mechanisms of signal transduction for LIF- and IL-6-induced differentiation.

The gadd and MyD genes define a novel set of mammalian genes encoding acidic proteins that synergistically suppress cell growth.

A remarkable overlap was observed between the gadd genes, a group of often coordinately expressed genes that are induced by genotoxic stress and certain other growth arrest signals, and the MyD genes, a set of myeloid differentiation primary response genes. The MyD116 gene was found to be the murine homolog of the hamster gadd34 gene, whereas MyD118 and gadd45 were found to represent two separate but closely related genes. Furthermore, gadd34/MyD116, gadd45, MyD118, and gadd153 encode acidic proteins with very similar and unusual charge characteristics; both this property and a similar pattern of induction are shared with mdm2, whic, like gadd45, has been shown previously to be regulated by the tumor suppressor p53. Expression analysis revealed that they are distinguished from other growth arrest genes in that they are DNA damage inducible and suggest a role for these genes in growth arrest and apoptosis either coupled with or uncoupled from terminal differentiation. Evidence is also presented for coordinate induction in vivo by stress. The use of a short-term transfection assay, in which expression vectors for one or a combination of these gadd/MyD genes were transfected with a selectable marker into several different human tumor cell lines, provided direct evidence for the growth-inhibitory functions of the products of these genes and their ability to synergistically suppress growth. Taken together, these observations indicate that these genes define a novel class of mammalian genes encoding acidic proteins involved in the control of cellular growth.

Growth of aligned ZnO nanorods.

Growth of high-density and aligned ZnO nanorods on ZnO film substrate has been demonstrated using vapor-transport of thermally evaporated Zn metal powders followed by condensation. Morphological studies show that the nanorods grow preferentially from a hexagonal ZnO base with a uniform hexagonal structure following three-dimensional island-like growth mechanism. Structural and spectroscopic properties clearly indicate that the nanorods are relatively good and defect-free in quality. These nanorods have potential for technological implications.

Nucleotide sequence and expression of a cDNA encoding MyD88, a novel myeloid differentiation primary response gene induced by IL6.

We report here the full length cDNA sequence and the deduced amino-acid sequence of MyD88, a novel myeloid differentiation primary response gene activated in M1D+ myeloid precursors, following induction of terminal differentiation and growth arrest by IL6. Detectable levels of MyD88 RNA were observed in myeloid precursor enriched murine bone-marrow, but not in several other non-myeloid murine tissues.

Complexity of the immediate early response of myeloid cells to terminal differentiation and growth arrest includes ICAM-1, Jun-B and histone variants.

Differentiation inducible leukemic as well as normal myeloid precursors treated with physiological myeloid differentiation inducer have been used to explore the immediate early genetic response of cells to terminal differentiation and growth arrest stimuli. cDNA clones of 12 distinct genes, referred to as MyD genes, which are activated in the absence of protein synthesis following induction of myeloid differentiation and growth arrest have been isolated. Sequence analysis of both ends of MyD cDNA clones, and analysis of MyD gene expression following induced differentiation of M1D+ and normal myeloid precursors, has shown that the immediate early genetic response of myeloid cells to the induction of terminal differentiation is complex. This complex response involves a variety of genes, some of which are known and others unknown, including: transient induction of ICAM-1, a gene encoding for a ligand to a cell surface adhesion receptor; stable induction of Jun-B, a gene encoding for a nuclear transcription factor; and increased expression of histone genes which encode for terminal differentiation histone variants. These findings demonstrate that terminal differentiation and growth arrest immediate early response genes encode for at least three distinct types of gene products, which may play a role to reprogram the transcriptional activity of proliferating and non-differentiated cells towards their conversion into terminally differentiated nonproliferating cells.

Sequence and expression of a cDNA encoding MyD118: a novel myeloid differentiation primary response gene induced by multiple cytokines.

We report here the full length cDNA sequence and the deduced amino acid sequence of MyD118, a novel myeloid differentiation primary response gene transiently expressed in M1D+ myeloid precursors following induction of terminal differentiation and growth arrest by IL6. MyD118 expression was observed to be induced also in the absence of protein synthesis, following stimulation of M1D+ cells by IL1, LPS and Leukemia Inhibitory Factor (LIF). Detectable levels of MyD118 RNA were observed in myeloid precursor enriched murine bone marrow, but not in several other nonmyeloid murine tissues.

Fibrin subunits in venous and arterial thromboembolism.

The subunit fibrin composition of thrombi of both venous and arterial origin was examined by sodium dodecyl sulphate gel electrophoresis. The thrombi were recovered by surgical intervention and all had the same fibrin subunit composition. The alpha chains were cross-linked as alpha-chain polymers alpha (p), the gamma chains as gamma-chain dimers (gamma-gamma) while the beta chains were not crosslinked; a further subunit of molecular weight 33 000 was shown to be present in all the fibrins examined and was a degradation fragment of the beta or gamma chains. This data suggests that the crosslinked alpha chains are rate limiting to the lysis of thrombi in vivo. The digestion of pulmonary emboli by plasmin yielded soluble degradation products which were identified as D dimer and E, the latter fragments being the major products obtained by the lysis of in-vitro made plasma clots. The similarity of the composition and lysis of thrombus fibrin to that formed in vitro augurs well for the justification of in-vitro research on mechanisms in thrombolysis.