Longitudinal Allometry of Sulcal Morphology in Health and Schizophrenia.

Scaling between subcomponents of folding and total brain volume (TBV) in healthy individuals (HIs) is allometric. It is unclear whether this is true in schizophrenia (SZ) or first-episode psychosis (FEP). This study confirmed normative allometric scaling norms in HIs using discovery and replication samples. Cross-sectional and longitudinal diagnostic differences in folding subcomponents were then assessed using an allometric framework. Structural imaging from a longitudinal (Sample 1: HI and SZ, nHI Baseline = 298, nSZ Baseline = 169, nHI Follow-up = 293, nSZ Follow-up = 168, totaling 1087 images, all individuals ≥ 2 images, age 16-69 years) and a cross-sectional sample (Sample 2: nHI = 61 and nFEP = 89, age 10-30 years), all human males and females, is leveraged to calculate global folding and its nested subcomponents: sulcation index (SI, total sulcal/cortical hull area) and determinants of sulcal area: sulcal length and sulcal depth. Scaling of SI, sulcal area, and sulcal length with TBV in SZ and FEP was allometric and did not differ from HIs. Longitudinal age trajectories demonstrated steeper loss of SI and sulcal area through adulthood in SZ. Longitudinal allometric analysis revealed that both annual change in SI and sulcal area was significantly stronger related to change in TBV in SZ compared with HIs. Our results detail the first evidence of the disproportionate contribution of changes in SI and sulcal area to TBV changes in SZ. Longitudinal allometric analysis of sulcal morphology provides deeper insight into lifespan trajectories of cortical folding in SZ.SIGNIFICANCE STATEMENT Psychotic disorders are associated with deficits in cortical folding and brain size, but we lack knowledge of how these two morphometric features are related. We leverage cross-sectional and longitudinal samples in which we decompose folding into a set of nested subcomponents: sulcal and hull area, and sulcal depth and length. We reveal that, in both schizophrenia and first-episode psychosis, (1) scaling of subcomponents with brain size is different from expected scaling laws and (2) caution is warranted when interpreting results from traditional methods for brain size correction. Longitudinal allometric scaling points to loss of sulcal area as a principal contributor to loss of brain size in schizophrenia. These findings advance the understanding of cortical folding atypicalities in psychotic disorders.

Obstetric complications and genetic risk for schizophrenia: Differential role of antenatal and perinatal events in first episode psychosis.

BACKGROUND: Obstetric complications (OCs) are key contributors to psychosis risk. However, it is unclear whether they increase psychosis vulnerability independently of genetic risk, in interaction with it, or are a manifestation of psychosis proneness. We examined the role of distinct types of OCs in terms of psychosis risk and tested whether they interact differently with genetic vulnerability, whilst accounting for other known environmental risk factors. STUDY DESIGN: 405 participants (219 first episode psychosis patients and 186 healthy volunteers) underwent a comprehensive assessment of OCs, measured using the Lewis-Murray scale and divided into complications of pregnancy, abnormalities of foetal growth and development, and complications of delivery. Participants were compared in terms of history of OCs, polygenic risk score for schizophrenia (PRS-SZ) and interactions between these. RESULTS: Both complications of pregnancy and abnormalities of foetal growth were significantly associated with case-control status (p = 0.02 and 0.03, respectively), whereas complications of delivery were not. PRS-SZ showed a significant association with psychosis (p = 0.04), but there were no significant interactions between genetic risk for schizophrenia and OCs, either when these were considered globally or separated based on their timeframe. CONCLUSIONS: We observed no significant interaction between genetic and obstetric vulnerability, yet distinct types of OCs may have a different impact on psychosis risk, based on their nature and timeframe. Examining their differential role might clarify their relative contributions to this risk.

Developmental pathways from preschool temper tantrums to later psychopathology.

Temper tantrums are sudden, overt negative emotional displays that are disproportionate to the eliciting event. Research supports that severe temper tantrums during the preschool period are associated with preschool psychopathology, but few studies have identified which characteristics of preschool tantrums are predictive of distal psychopathological outcomes in later childhood and adolescence. To examine this question, we used a prospective, longitudinal dataset enriched for early psychopathology. Participants (N = 299) included 3-to 6-year-old children (47.8% female) assessed for tantrums and early childhood psychopathology using diagnostic interviews and then continually assessed using diagnostic interviews over 10 subsequent time points throughout childhood and adolescence. We identified two unique groupings of tantrum behaviors: aggression towards others/objects (e.g., hitting others) and aggression towards self (e.g., hitting self). While both types of tantrum behaviors were associated with early childhood psychopathology severity, tantrum behaviors characterized by aggression towards self were more predictive of later psychopathology. Children displaying high levels of both types of tantrum behaviors had more severe externalizing problems during early childhood and more severe depression and oppositional defiant disorder across childhood and adolescence. Findings suggest that tantrum behaviors characterized by aggression towards self are particularly predictive of later psychopathology.

Obstetric complications and clinical presentation in first episode of psychosis.

OBJECTIVE: Psychotic disorders exhibit a complex aetiology that combines genetic and environmental factors. Among the latter, obstetric complications (OCs) have been widely studied as risk factors, but it is not yet well understood how OCs relate to the heterogeneous presentations of psychotic disorders. We assessed the clinical phenotypes of individuals with a first episode of psychosis (FEP) in relation to the presence of OCs. METHODS: Two-hundred seventy-seven patients with an FEP were assessed for OCs using the Lewis-Murray scale, with data stratified into three subscales depending on the timing and the characteristics of the obstetric event, namely: complications of pregnancy, abnormal foetal growth and development and difficulties in delivery. We also considered other two groups: any complications during the pregnancy period and all OCs taken altogether. Patients were clinically evaluated with the Positive and Negative Syndrome Scale for schizophrenia. RESULTS: Total OCs and difficulties in delivery were related to more severe psychopathology, and this remained significant after co-varying for age, sex, traumatic experiences, antipsychotic dosage and cannabis use. CONCLUSIONS: Our results highlight the relevance of OCs for the clinical presentation of psychosis. Describing the timing of the OCs is essential in understanding the heterogeneity of the clinical presentation.

The reward positivity shows increased amplitude and decreased latency with increasing age in early childhood.

The reward positivity (RewP) is a widely studied measure of neural response to rewards, yet little is known about normative developmental characteristics of the RewP during early childhood. The present study utilized a pooled community sample of 309 4- to 6-year-old children who participated in the Doors guessing game to examine the latency and amplitude of the RewP. Peak detection of the gain-loss difference waveform was conducted for electrodes Fz, Cz, Pz, Oz and the mean activity in a 100 ms window centered around this peak was analyzed. There was a significant decrease in RewP latency (RewP was earlier) and increase in RewP amplitude (RewP magnitude was larger) with advancing age in this cross-sectional analysis. Further, these were independent effects, as both RewP latency and RewP amplitude were uniquely associated with children's age. Moreover, our results indicate that the RewP latency in 4- to 6-year-olds falls outside the 250-350 ms window typically used to quantify the RewP (RewP latency in our sample = 381 ms; SD = 60.15). The internal consistency for latency (.64) and amplitude (.27) of the RewP were characterized by moderate to low reliability, consistent with previous work on the reliability of difference scores. Overall, results demonstrate RewP differences in both timing and amplitude across age in early childhood, and suggest that both amplitude and latency of the RewP might function as individual difference measures of reward processing. These findings are discussed in the context of methodological considerations and the development of reward processing across early childhood.

Early signs of autism in infants whose mothers suffered from a threatened preterm labour: a 30-month prospective follow-up study.

Infants born after a threatened preterm labour (TPL infants) are at high risk of autism spectrum disorder (ASD). Studying this population may provide insight on the pathophysiological underpinnings of this condition. This study aimed to (i) ascertain the presence and autistic symptom load in TPL infants aged age 30 months relative to non-TPL infants, regardless of preterm birth; (ii) explore the association between early (at 6 months) psychomotor development and temperament features with the autistic symptom load of TPL infants at age 30 months and (iii) examine the association among perinatal risk factors for ASD development with the autistic symptom load of TPL infants at age 30 months. A group of 111 mother-infant pairs recruited at TPL diagnosis and a group of 47 healthy mother-infant controls completed the follow-up. Irrespective of preterm birth, TPL infants showed higher autistic symptom load at age 30 months than non-TPL infants. TPL infants presented poorer communication and problem-solving skills, reduced smiling and laughter, and greater vocal reactivity at age 6 months, predicting higher autistic symptom load at age 30 months. Higher levels of anxiety symptoms in TPL mothers after a TPL diagnosis also predicted higher autistic symptom load for the infants at age 30 months. These results suggest that TPL infants may be an undescribed cluster, with features that differentiate them from other "at-risk" populations. These findings support the need for routine assessment of TPL infants and screening of anxiety symptoms in mothers.

Adherence improvement in patients with ulcerative colitis: a multidisciplinary consensus document.

OBJECTIVES: a) to analyze the evidence available about poor adherence/non-adherence, including prevalences, associated factors, and interventions in ulcerative colitis (UC) patients; b) to provide a framework to improve poor adherence/non-adherence. METHODS: a qualitative approach was used. A literature review was performed using Medline. Primary searches were performed with Mesh and free texts to identify articles that analyzed prevalence, causes, associated factors, and interventions designed to improve poor adherence/non-adherence in UC patients. Study quality was evaluated using the Oxford scale. The results were presented and discussed in a nominal group meeting comprising a multidisciplinary committee of six gastroenterologists, one psychologist, one nurse, and one patient. Several overarching principles and recommendations were generated. A consensus procedure was implemented via a Delphi process, during which each committee member produced a score ranging from 0 = totally disagree to 10 = totally agree. Agreement was considered when at least 70 % of participants had voted ≥ 7. RESULTS: the literature review included 75 articles. Non-adherence rates ranged from 7 % to 72 %. We found a great variability in the methods employed to assess adherence, associated factors, and interventions designed to improve adherence. Overall, eight overarching principles and six recommendations were generated, all of them achieving the pre-established agreement level, including, among others, the identification, classification, and management of non-adherence. CONCLUSIONS: Poor adherence/non-adherence are common in UC patients, this being a relevant clinical concern. Health professionals should address this issue and actively involve their patients in implementing effective, individualized interventions to improve adherence.

Circulating cell-free DNA improves the molecular characterisation of Ph-negative myeloproliferative neoplasms.

Genetic studies in patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) are essential to establish the correct diagnosis and to optimise their management. Recently, it has been demonstrated that it is possible to detect molecular alterations analysing cell-free DNA (cfDNA) in plasma samples, which is known as liquid biopsy. We have assessed the molecular profile of a cohort of 107 MPN patients [33 polycythaemia vera (PV), 56 essential thrombocythaemia (ET), 14 primary myelofibrosis (PMF) and 4 unclassifiable MPN] by next-generation sequencing (NGS) using cfDNA and paired granulocyte DNA. A high concentration of cfDNA in plasma was observed in patients with high molecular complexity, in MPL-mutated cases, and in PMF patients. Targeted sequencing of cfDNA showed a comparable mutational profile (100% accuracy) to the one obtained in granulocytic DNA and a strong correlation was observed between the variant allele frequency (VAF) of gene mutations in both DNA sources. The median VAF detected in cfDNA (29·0%; range: 0·95-91·73%) was significantly higher than the VAF detected in granulocytes (median 25·2%; range: 0·10-95·5%), especially for MPL mutations (44·3% vs. 22·5%). In conclusion, our data support the use of cfDNA as a fast, sensitive and accurate strategy for performing molecular characterisation of MPN patients.

Metformin and an insulin/IGF-1 receptor inhibitor are synergistic in blocking growth of triple-negative breast cancer.

PURPOSE: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor survival outcomes. Metformin has been shown to have antitumor effects by lowering serum levels of the mitogen insulin and having pleiotropic effects on cancer cell signaling pathways. BMS-754807 is a potent and reversible inhibitor of both insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR). Both drugs have been reported to have some efficacy in TNBC. However, it is unclear whether the combination of the two drugs is more effective than single drug treatment in TNBC. METHODS: We treated a panel of TNBC cell lines with metformin and BMS-754807 alone and in combination and tested cell viability using MTS assays. We used the CompuSyn software to analyze for additivity, synergism, or antagonism. We also examined the molecular mechanism by performing reverse phase protein assay (RPPA) to detect the candidate pathways altered by single drugs and the drug combination and used Western blotting to verify and expand the findings. RESULTS: The combination of metformin and BMS-754807 showed synergy in 11 out of 13 TNBC cell lines tested (85%). RPPA analysis detected significant alterations by the drug combination of multiple proteins known to regulate cell cycle and tumor growth. In particular, the drug combination significantly increased levels of total and phosphorylated forms of the cell cycle inhibitor p27Kip1 and decreased the level of the p27Kip1 E3 ligase SCFSkp2. CONCLUSIONS: We conclude that the combination of metformin and BMS-754807 is more effective than either drug alone in inhibiting cell proliferation in the majority of TNBC cell lines, and that one important mechanism may be suppression of SCFSkp2 and subsequent stabilization of the cell cycle inhibitor p27Kip1. This combination treatment may represent an effective targeted therapy for a significant subset of TNBC cases and should be further evaluated.

The longitudinal effect of antipsychotic burden on psychosocial functioning in first-episode psychosis patients: the role of verbal memory.

BACKGROUND: Previous literature supports antipsychotics' (AP) efficacy in acute first-episode psychosis (FEP) in terms of symptomatology and functioning but also a cognitive detrimental effect. However, regarding functional recovery in stabilised patients, these effects are not clear. Therefore, the main aim of this study is to investigate dopaminergic/anticholinergic burden of (AP) on psychosocial functioning in FEP. We also examined whether cognitive impairment may mediate these effects on functioning. METHODS: A total of 157 FEP participants were assessed at study entry, and at 2 months and 2 years after remission of the acute episode. The primary outcomes were social functioning as measured by the functioning assessment short test (FAST). Cognitive domains were assessed as potential mediators. Dopaminergic and anticholinergic AP burden on 2-year psychosocial functioning [measured with chlorpromazine (CPZ) and drug burden index] were independent variables. Secondary outcomes were clinical and socio-demographic variables. RESULTS: Mediation analysis found a statistical but not meaningful contribution of dopaminergic receptor blockade burden to worse functioning mediated by cognition (for every 600 CPZ equivalent points, 2-year FAST score increased 1.38 points). Regarding verbal memory and attention, there was an indirect effect of CPZ burden on FAST (b = 0.0045, 95% CI 0.0011-0.0091) and (b = 0.0026, 95% CI 0.0001-0.0006) respectively. However, only verbal memory post hoc analyses showed a significant indirect effect (b = 0.009, 95% CI 0.033-0.0151) adding premorbid IQ as covariate. We did not find significant results for anticholinergic burden. CONCLUSION: CPZ dose effect over functioning is mediated by verbal memory but this association appears barely relevant.

Molecular characterisation of oncogenic urothelial mosaic mutations in patients with extensive keratinocytic epidermal naevi.

Background: Keratinocytic epidermal naevi (KENs) are congenital benign skin mosaic lesions that share common mutations with some subsets of urothelial carcinomas. Moreover, several patients with extensive KEN who also developed urothelial carcinomas at young ages have been reported. Thus, patients with extensive KEN may harbour mosaic urothelial oncogenic mutations that would favour the early development of urothelial carcinomas. Methods: We selected five patients with extensive KEN involving the lower part of the back and performed a molecular characterisation of urothelial and cutaneous samples using a next-generation sequencing (NGS) custom panel targeting candidate oncogenic genes. Results: Mosaic pathogenic mutations were detected in KEN in all patients. In four out of five patients, mosaic pathogenic mutations in FGFR2 or HRAS were also detected in samples from the urothelial tract. Moreover, we report a patient who developed urothelial carcinomas at age 29 and harboured an HRAS G12S mutation both in skin and urothelial tumour samples. Conclusions: We conclude that patients with extensive KEN involving the lower part of the back frequently harbour oncogenic mutations in the urothelium that may induce the development of carcinomas. NGS panels can be considered as highly sensitive tools to identify this subgroup of patients, which might permit adoption of screening measures to detect malignant transformation at early stages.

Getting in synch: Unpacking the role of parent-child synchrony in the development of internalizing and externalizing behaviors.

While substantial research supports the role of parent-child interactions on the emergence of psychiatric symptoms, few studies have explored biological mechanisms for this association. The current study explored behavioral and neural parent-child synchronization during frustration and play as predictors of internalizing and externalizing behaviors across a span of 1.5 years. Parent-child dyads first came to the laboratory when the child was 4-5 years old and completed the Disruptive Behavior Diagnostic Observation Schedule: Biological Synchrony (DB-DOS: BioSync) task while functional near-infrared spectroscopy (fNIRS) data were recorded. Parents reported on their child's internalizing and externalizing behaviors using the Child Behavior Checklist (CBCL) four times over 1.5 years. Latent growth curve (LGC) modeling was conducted to assess neural and behavioral synchrony as predictors of internalizing and externalizing trajectories. Consistent with previous investigations in this age range, on average, internalizing and externalizing behaviors decreased over the four time points. Parent-child neural synchrony during a period of play predicted rate of change in internalizing but not externalizing behaviors such that higher parent-child neural synchrony was associated with a more rapid decrease in internalizing behaviors. Our results suggest that a parent-child dyad's ability to coordinate neural activation during positive interactions might serve as a protective mechanism in the context of internalizing behaviors.

Does the child brain rest?: An examination and interpretation of resting cognition in developmental cognitive neuroscience.

In cognitive neuroscience, measurements of "resting baseline" are often considered stable across age and used as a reference point against which to judge cognitive state. The task-based approach-comparing resting baseline to task conditions-implies that resting baseline is an equalizer across participants and-in the case of studies of developmental changes in cognition-across age groups. In contrast, network neuroscience explicitly examines the development of "resting state" networks across age, at odds with the idea of a consistent resting baseline. Little attention has been paid to how cognition during rest may shift across development, particularly in children under the age of eight. Childhood is marked by striking maturation of neural systems, including a protracted developmental period for cognitive control systems. To grow and shape these cognitive systems, children have a developmental imperative to engage their neural circuitry at every possible opportunity. Thus, periods of "rest" without specific instructions may require additional control for children as they fight against developmental expectation to move, speak, or otherwise engage. We therefore theorize that the child brain does not rest in a manner consistent with the adult brain as longer rest periods may represent increased cognitive control. To shape this theory, we first review the extant literature on neurodevelopment across early childhood within the context of cognitive development. Next, we present nascent evidence for a destabilized baseline for comparisons across age. Finally, we present recommendations for designing, analyzing, and interpreting tasks conducted with young children as well as for resting state. Future work must aim to tease apart the cognitive context under which we examine functional brain development in young children and take considerations into account unique to each age.

Parent-child neural synchrony: a novel approach to elucidating dyadic correlates of preschool irritability.

BACKGROUND: Research to date has largely conceptualized irritability in terms of intraindividual differences. However, the role of interpersonal dyadic processes has received little consideration. Nevertheless, difficulties in how parent-child dyads synchronize during interactions may be an important correlate of irritably in early childhood. Innovations in developmentally sensitive neuroimaging methods now enable the use of measures of neural synchrony to quantify synchronous responses in parent-child dyads and can help clarify the neural underpinnings of these difficulties. We introduce the Disruptive Behavior Diagnostic Observation Schedule: Biological Synchrony (DB-DOS:BioSync) as a paradigm for exploring parent-child neural synchrony as a potential biological mechanism for interpersonal difficulties in preschool psychopathology. METHODS: Using functional near-infrared spectroscopy (fNIRS) 4- to 5-year-olds (N = 116) and their mothers completed the DB-DOS:BioSync while assessing neural synchrony during mild frustration and recovery. Child irritability was measured using a latent irritability factor that was calculated from four developmentally sensitive indicators. RESULTS: Both the mild frustration and the recovery contexts resulted in neural synchrony. However, less neural synchrony during the recovery context only was associated with more child irritability. CONCLUSIONS: Our results suggest that recovering after a frustrating period might be particularly challenging for children high in irritability and offer support for the use of the DB-DOS:BioSync task to elucidate interpersonal neural mechanisms of developmental psychopathology.

Children's awareness of the context-appropriate nature of emotion regulation strategies across emotions.

Emotion regulation (ER) substantially develops during the childhood years. This growth includes an increasing awareness that certain ER strategies are more appropriate in some contexts than others, but few studies have explored how children tailor ER strategies across contexts (i.e. context sensitivity). Understanding this could help clarify why some children have difficulties effectively regulating their emotions even when they have a broad strategy repertoire. The current study explored differences in Hispanic children's ER strategy context sensitivity across three emotions and explored attentional control as a possible moderator of this sensitivity. Children (N = 78; M = 9.91; SD = 1.14; 50% girls; household income M = 31-40k) completed an attentional control task and were interviewed about their ER strategy preferences for sadness, fear, and anger. Context sensitivity was measured as the proportion of endorsed ER strategies that theoretically "fit" the given emotion. Children showed more sensitivity for anger and fear compared to sadness. Attentional control predicted context sensitivity for sadness only, but this was qualified by age. Older children showed more context sensitivity with increasing attentional control. Findings provide insight into emotional development in late childhood by highlighting children's awareness of the context-appropriate nature of ER strategies across emotions.

Neuroanatomical deficits shared by youth with autism spectrum disorders and psychotic disorders.

Autism spectrum disorders (ASD) and early-onset psychosis (EOP) are neurodevelopmental disorders that share genetic, clinical and cognitive facets; it is unclear if these disorders also share spatially overlapping cortical thickness (CT) and surface area (SA) abnormalities. MRI scans of 30 ASD, 29 patients with early-onset first-episode psychosis (EO-FEP) and 26 typically developing controls (TD) (age range 10-18 years) were analyzed by the FreeSurfer suite to calculate vertex-wise estimates of CT, SA, and cortical volume. Two publicly available datasets of ASD and EOP (age range 7-18 years and 5-17 years, respectively) were used for replication analysis. ASD and EO-FEP had spatially overlapping areas of cortical thinning and reduced SA in the bilateral insula (all p's < .00002); 37% of all left insular vertices presenting with significant cortical thinning and 20% (left insula) and 61% (right insula) of insular vertices displaying decreased SA overlapped across both disorders. In both disorders, SA deficits contributed more to cortical volume decreases than reductions in CT did. This finding, as well as the novel finding of an absence of spatial overlap (for ASD) or marginal overlap (for EOP) of deficits in CT and SA, was replicated in the two nonoverlapping independent samples. The insula appears to be a region with transdiagnostic vulnerability for deficits in CT and SA. The finding of nonexistent or small spatial overlap between CT and SA deficits in young people with ASD and psychosis may point to the involvement of common aberrant early neurodevelopmental mechanisms in their pathophysiology.

Parasympathetic regulation in cognitive and emotional challenge contexts differentially predicts specific aspects of children's emotional functioning.

Parasympathetic regulation has been consistently linked with better emotional functioning in childhood, but it is still not clear if parasympathetic regulation serves as a transcontextual marker of adaptive emotional functioning or if this link is context-specific. This study tested this by examining the specificity of the relation between parasympathetic regulation in distinct types of challenge tasks and different aspects of children's emotional functioning. Emotional functioning included parent-reported emotional reactivity, parent-reported general emotion regulation ability, and child-reported emotion regulation strategy knowledge. One hundred and forty-four 4- to 9-year-olds (M = 6.88 years; SD = 1.80; 52% girls) participated in a cognitive (inhibitory control) and two discrete emotional (disappointing, fear-eliciting) challenges. Resting and reactive indices of respiratory sinus arrhythmia quantified parasympathetic regulation. Emotional reactivity was predicted by parasympathetic regulation during the cognitive challenge, general emotion regulation was predicted by regulation during the fear-eliciting task, and emotion regulation strategy knowledge was predicted by regulation during the disappointment task. Results highlight the importance of considering task context in investigations of how parasympathetic regulation relates to children's functioning.

Non-driver mutations in patients with JAK2V617F-mutated polycythemia vera or essential thrombocythemia with long-term molecular follow-up.

JAK2V617F monitoring and NGS of non-driver genes was performed in 100 patients with polycythemia vera (PV) or essential thrombocythemia (ET) with long molecular follow-up. Patients who did not progress to myelofibrosis (MF) or acute myeloid leukemia (AML) after more than 10 years (n = 50) showed a low frequency of mutations at first sample (18%) and an incidence rate of 1.7 new mutations × 100 person-years. Mutations were detected at first sample in 83% of PV/ET patients who later progressed to AML (n = 12) with these patients having a rate of 25.6 mutations × 100 person-years. Presence of mutations at diagnosis was the unique risk factor for acquiring a new genetic event (HR 2.7, 95% CI 1.1-6.8, p = 0.03) after correction for age, PV diagnosis, and total duration of hydroxyurea (HU) exposure. Patients with additional mutation at first sample showed a higher probability of developing cytopenia under HU therapy and a higher risk of AML (HR 12.2, 95% CI 2.6-57.1, p = 0.001) with mutations in ASXL1 (p < 0.0001), TP53 (p = 0.01), SRSF2 (p < 0.0001), IDH1/2 (p < 0.0001), and RUNX1 (p < 0.0001) being associated with a higher probability of AML. Myelofibrotic transformation was more frequent in patients with additional mutations, especially in SF3B1 (p = 0.02) and IDH1/2 (p < 0.0001) although a persistently high or a progressive increase of the JAK2V617F allele burden while receiving cytoreduction was the strongest predictor of MF transformation (HR 10.8, 95% CI 2.4-49.1, p = 0.002). In conclusion, NGS may be useful to identify a minority of PV and ET patients with high genetic instability and increased risk of AML transformation.

Parent emotion regulation socializes children's adaptive physiological regulation.

Parenting practices play a major role in socializing children's developing regulatory abilities, but less is known about how parents' regulatory abilities relate to children's healthy functioning. This study examined whether parents' physiological and emotion regulation abilities corresponded to children's physiological and emotional responding to a structured laboratory-based disappointment task. Ninety-seven 3- to 7-year-olds (56 girls; M = 5.79 years) and one parent participated in a multi-method assessment of parents' and children's regulatory functioning. Direct (coaching children to use reappraisal) and indirect (resting physiology, dispositional use of reappraisal) aspects of parents' regulatory abilities were assessed. As expected, an adaptive pattern of parent regulatory abilities composed of higher resting respiratory sinus arrhythmia, use of reappraisal, and coaching reappraisal was associated with children's physiological reactivity after a disappointment indicative of more effective physiological calming in a recovery context (increased parasympathetic activation). In contrast, parents' regulatory abilities did not relate to changes in children's expressions of emotional distress.

Temperament in child and adolescent offspring of patients with schizophrenia and bipolar disorder.

Shared vulnerability in offspring of individuals with schizophrenia (SzO) and bipolar disorder (BpO) might manifest early during development through common temperament traits. Temperament dimensions in child and adolescent BpO (N = 80), SzO (N = 34) and the offspring of community controls (CcO) (N = 101) were assessed using the Revised Dimensions of Temperament Survey. The association between temperament dimensions and lifetime psychopathology (including threshold and subthreshold DSM-IV-TR diagnoses) and current socio-academic adjustment was assessed using logistic regression. Fully adjusted models showed that both BpO and SzO scored significantly lower in the positive mood dimension and in the adaptability factor than CcO, with small-medium effect sizes (Cohen's d ~ 0.3-0.5). BpO also scored lower in the activity factor and the activity dimensions than CcO (Cohen's d ~ 0.3). Lower scores in the positive mood dimension were associated with increased risk of impaired adjustment both in BpO [OR 2.30, 95% CI (1.18-4.46)] and in SzO [OR 2.87, 95% CI (1.07-7.66)]. In BpO, lower scores in positive mood were also associated with increased likelihood of internalizing [OR 1.84, 95% CI (1.28-2.64)] and externalizing disorders [OR 1.48, 95% CI (1.01-2.18)]; in SzO, higher scores in activity and flexibility were associated with increased likelihood of internalizing [OR 2.31, 95% CI (1.22-4.38)] and externalizing disorders [OR 3.28, 95% CI (1.2-9)], respectively. Early difficulties in emotion regulation might represent a shared vulnerability phenotype in BpO and SzO. The identification of extreme temperament traits could help to characterize subgroups at greater risk of psychopathology and impaired adjustment, in which targeted interventions are warranted.