Multiplex accurate sensitive quantitation (MASQ) with application to minimal residual disease in acute myeloid leukemia

Measuring minimal residual disease in cancer has applications for prognosis, monitoring treatment and detection of recurrence. Simple sequence-based methods to detect nucleotide substitution variants have error rates (about 10-3) that limit sensitive detection. We developed and characterized the performance of MASQ (multiplex accurate sensitive quantitation), a method with an error rate below 10-6. MASQ counts variant templates accurately in the presence of millions of host genomes by using tags to identify each template and demanding consensus over multiple reads. Since the MASQ protocol multiplexes 50 target loci, we can both integrate signal from multiple variants and capture subclonal response to treatment. Compared to existing methods for variant detection, MASQ achieves an excellent combination of sensitivity, specificity and yield. We tested MASQ in a pilot study in acute myeloid leukemia (AML) patients who entered complete remission. We detect leukemic variants in the blood and bone marrow samples of all five patients, after induction therapy, at levels ranging from 10-2 to nearly 10-6. We observe evidence of sub-clonal structure and find higher target variant frequencies in patients who go on to relapse, demonstrating the potential for MASQ to quantify residual disease in AML

Correlations of Behavioral Deficits with Brain Pathology Assessed through Longitudinal MRI and Histopathology in the R6/2 Mouse Model of HD

Huntington's disease (HD) is caused by the expansion of a CAG repeat in the huntingtin (HTT) gene. The R6/2 mouse model of HD expresses a mutant version of exon 1 HTT and develops motor and cognitive impairments, a widespread huntingtin (HTT) aggregate pathology and brain atrophy. Despite the vast number of studies that have been performed on this model, the association between the molecular and cellular neuropathology with brain atrophy, and with the development of behavioral phenotypes remains poorly understood. In an attempt to link these factors, we have performed longitudinal assessments of behavior (rotarod, open field, passive avoidance) and of regional brain abnormalities determined through magnetic resonance imaging (MRI) (whole brain, striatum, cortex, hippocampus, corpus callosum), as well as an end-stage histological assessment. Detailed correlative analyses of these three measures were then performed. We found a gender-dependent emergence of motor impairments that was associated with an age-related loss of regional brain volumes. MRI measurements further indicated that there was no striatal atrophy, but rather a lack of striatal growth beyond 8 weeks of age. T2 relaxivity further indicated tissue-level changes within brain regions. Despite these dramatic motor and neuroanatomical abnormalities, R6/2 mice did not exhibit neuronal loss in the striatum or motor cortex, although there was a significant increase in neuronal density due to tissue atrophy. The deposition of the mutant HTT (mHTT) protein, the hallmark of HD molecular pathology, was widely distributed throughout the brain. End-stage histopathological assessments were not found to be as robustly correlated with the longitudinal measures of brain atrophy or motor impairments. In conclusion, modeling pre-manifest and early progression of the disease in more slowly progressing animal models will be key to establishing which changes are causally related. © 2013 Rattray et al

Interpersonal and affective dimensions of psychopathic traits in adolescents : development and validation of a self-report instrument

We report the development and psychometric evaluations of a self-report instrument designed to screen for psychopathic traits among mainstream community adolescents. Tests of item functioning were initially conducted with 26 adolescents. In a second study the new instrument was administered to 150 high school adolescents, 73 of who had school records of suspension for antisocial behavior. Exploratory factor analysis yielded a 4-factor structure (Impulsivity α = .73, Self-Centredness α = .70, Callous-Unemotional α = .69, and Manipulativeness α = .83). In a third study involving 328 high school adolescents, 130 with records of suspension for antisocial behaviour, competing measurement models were evaluated using confirmatory factor analysis. The superiority of a first-order model represented by four correlated factors that was invariant across gender and age was confirmed. The findings provide researchers and clinicians with a psychometrically strong, self-report instrument and a greater understanding of psychopathic traits in mainstream adolescents

Cold Hardiness and Supercooling Capacity in the Overwintering Larvae of the Codling Moth, Cydia pomonella

The codling moth, Cydia pomonella L. (Lepidoptera: Tortricidae), a worldwide apple pest, is classified as a freeze-intolerant organism and one of the most cold-tolerant pests. The objectives of this study were to examine the supercooling point of overwintering and non-diapausing larvae of C. pomonella as an index of its cold hardiness, and to assess larval mortality following 24 h exposure to extreme low temperatures ranging from -5 to -25°C. The mean (±SE) supercooling point for feeding larvae (third through fifth instars) was -12.4 ± 1.1°C. The mean supercooling point for cocooned, non-diapausing larvae (i.e., non-feeding stages) decreased as the days that the arvae were cocooned increased and changed between -15.1 ± 1.2°C for one to two day cocooned arvae and -19.2 ± 1.8°C for less than five day cocooned larvae. The mean (±SE) supercooling point for other non-feeding stages containing pupae and overwintering larvae were -19.9 ± 1.0°C and -20.2 ± 0.2°C, respectively. Mean supercooling points of C. pomonella larvae were significantly lower during the winter months than the summer months, and sex had no effect on the supercooling point of C. pomonella larvae. The mortality of larvae increased significantly after individuals were exposed to temperatures below the mean supercooling point of the population. The supercooling point was a good predictor of cold hardiness

Low temperature magneto-morphological characterisation of coronene and the resolution of previously observed unexplained phenomena

The polyaromatic hydrocarbon coronene has been the molecule of choice for understanding the physical properties of graphene for over a decade. The modelling of the latter by the former was considered to be valid, as since it was first synthesised in 1932, the physical behaviour of coronene has been determined extremely accurately. We recently discovered however, an unforeseen polymorph of coronene, which exists as an enantiotrope with the previously observed crystal structure. Using low-temperature magnetisation and crystallographic measurements, we show here for the first time that the electronic and magnetic properties of coronene depend directly on the temperature at which it is observed, with hysteretic behaviour exhibited between 300 K and 100 K. Furthermore we determine that this behaviour is a direct result of the appearance and disappearance of the newly-discovered polymorph during thermal cycling. Our results not only highlight the need for theoretical models of graphene to take into account this anomalous behaviour at low temperatures, but also explain puzzling experimental observations of coronene dating back over 40 years

The Influence of Victim Vulnerability and Gender on Police Officers’ Assessment of Intimate Partner Violence Risk

This study investigated the influence of victim vulnerability factors and gender on risk assessment for intimate partner violence (IPV). 867 cases of male and female perpetrated IPV investigated by Swedish police officers using the Brief Spousal Assault Form for the Evaluation of Risk (BSAFER) were examined. For male-to-female IPV, victim vulnerability factors were associated with summary risk judgments and risk management recommendations. For femaleto-male IPV, vulnerability factors were more often omitted, and consistent associations were not found between vulnerability factors, summary risk judgments, and risk management. Results indicate that B-SAFER victim vulnerability factors can assist in assessing male-to-female IPV risk. Further research is necessary to examine the use of B-SAFER victim vulnerability factors for female-to-male IPV, as results showed victim vulnerability factors to be less relevant to officers’ decision making, particularly their management recommendations. However, several variables external to the B-SAFER, such as the availability of management strategies may account for these findings

Constructing meaning about the delinquency of young girls in public-housing neighbourhoods

UID/SOC/04647/2013 SFRH/BPD/116119/2016Rooted in the theoretical approaches of social ecology and in childhood studies, the Ph.D. research project on which this paper is based aimed to achieve a better understanding of children’s socialization processes in multi-problematic spaces, particularly concerning their involvement in violence and delinquency. A case study based on ethnographic research and child-centred methods was carried out in six public-housing neighbourhoods in Portugal, which were chosen because they had relatively high levels of social deprivation, violence and crime. The specificity of the social group under study—children aged from 6 to 12 years old—and their living conditions, led us to extend the data collected by trying to learn, from the girls, the reasoning and the meanings they assign to their own actions in daily social practices. The intention was to study the features of girls’ socialization in the field through their own accounts of their lives and to examine their perspectives on offending behaviours. The genderized process of social learning in delinquency identified in the girls’ conversation is an important variable, as familial and social experiences tend to facilitate their entry into delinquency. The transmission of delinquent values takes place essentially within the female family circle or via female peers, rather than from the influence of male individuals.authorsversionpublishe

Correlates of self-reported offending in children with a first police contact from distinct socio-demographic and ethnic groups

<p>Abstract</p> <p>Background</p> <p>This study aims to identify risk factors for level of offending among childhood offenders from different socio-economic status (SES) neighborhoods and ethnic origins.</p> <p>Method</p> <p>Three groups of childhood first time police arrestees were studied using standardized instruments for individual and parental characteristics: native Dutch offenders from moderate to high SES neighborhoods, native Dutch offenders from low SES neighborhoods, and offenders of non-Western origin from low SES neighborhoods.</p> <p>Results</p> <p>All subgroups showed high rates of externalizing disorders (27.2% to 41.8%) and familial difficulties (25.7% to 50.5%). Few differences between neighborhoods were found in the prevalence and impact of risk factors. However, the impact of some family risk factors on offending seemed stronger in the low SES groups. Regarding ethnical differences, family risk factors were more prevalent among non-Western childhood offenders. However, the association of these factors with level of offending seemed lower in the non-Western low SES group, while the association of some individual risk factors were stronger in the non-Western low SES group. Turning to the independent correlation of risk factors within each of the groups, in the Dutch moderate to high SES group, 23.1% of the variance in level of offending was explained by ADHD and behavioral problems; in the Dutch low SES group, 29.0% of the variance was explained by behavioral problems and proactive aggression; and in the non-Western low SES group, 41.2% of the variance was explained by substance use, sensation seeking, behavioral peer problems, and parental mental health problems.</p> <p>Conclusions</p> <p>Thereby, the study indicates few neighborhood differences in the impact of individual and parental risk factors on offending, while individual and parental risk factors may differ between ethnic groups.</p

Modifiable predictors of depression following childhood maltreatment: a systematic review and meta-analysis

Although maltreatment experiences in childhood increase the risk for depression, not all maltreated children become depressed. This review aims to systematically examine the existing literature to identify modifiable factors that increase vulnerability to, or act as a buffer against, depression, and could therefore inform the development of targeted interventions. Thirteen databases (including Medline, PsychINFO, SCOPUS) were searched (between 1984 and 2014) for prospective, longitudinal studies published in English that included at least 300 participants and assessed associations between childhood maltreatment and later depression. The study quality was assessed using an adapted Newcastle-Ottawa Scale checklist. Meta-analyses (random effects models) were performed on combined data to estimate the effect size of the association between maltreatment and depression. Meta-regressions were used to explore effects of study size and quality. We identified 22 eligible articles (N=12 210 participants), of which 6 examined potential modifiable predictors of depression following maltreatment. No more than two studies examined the same modifiable predictor; therefore, it was not possible to examine combined effects of modifiable predictors with meta-regression. It is thus difficult to draw firm conclusions from this study, but initial findings indicate that interpersonal relationships, cognitive vulnerabilities and behavioral difficulties may be modifiable predictors of depression following maltreatment. There is a lack of well-designed, prospective studies on modifiable predictors of depression following maltreatment. A small amount of initial research suggests that modifiable predictors of depression may be specific to maltreatment subtypes and gender. Corroboration and further investigation of causal mechanisms is required to identify novel targets for intervention, and to inform guidelines for the effective treatment of maltreated children