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Background: Proton radiotherapy treatment plans are currently restricted by the range uncertainties originating from the stopping power ratio (SPR) prediction based on single‐energy computed tomography (SECT). Various studies have shown that multi‐energy CT (MECT) can reduce the range uncertainties due to medical implant materials and age‐related variations in tissue composition. None of these has directly applied the basis material density (MD) images produced by projection‐based MECT systems for SPR prediction. Purpose: To present and evaluate a novel proton SPR prediction method based on MD images from dual‐energy CT (DECT), which could reduce the range uncertainties currently associated with proton radiotherapy. Methods: A theoretical basis material decomposition into water and iodine material densities was performed for various pediatric and adult human reference tissues, as well as other non‐tissue materials, by minimizing the root‐mean‐square relative attenuation error in the energy interval from 40 to 140 keV. A model (here called MD‐SPR) mapping predicted MDs to theoretically calculated reference SPRs was created with locally weighted scatterplot smoothing (LOWESS) data‐fitting. The goodness of fit of the MD‐SPR model was evaluated for the included reference tissues. MD images of two electron density phantoms, combined to form a head‐ and an abdomen‐sized phantom setup, were acquired with a clinical projection‐based fast‐kV switching DECT scanner. The MD images were compared to the theoretically predicted MDs of the tissue surrogates and other non‐tissue materials in the phantoms, as well as used for input to the MD‐SPR model for generation of SPR images. The SPR images were subsequently compared to theoretical reference SPRs of the materials in the phantoms, as well as to SPR images from a commercial algorithm (DirectSPR, Siemens Healthineers, Forchheim, Germany) using image‐based consecutive scan DECT for the same phantom setups. Results: The predicted SPRs of the tissue surrogates were similar for MD‐SPR and DirectSPR, where the adipose and bone tissue surrogates were within 1% difference to the reference SPRs, while other non‐adipose soft tissue surrogates (breast, brain, liver, muscle) were all underestimated by between −0.7% and −1.8%. The SPRs of the non‐tissue materials (polymethyl methacrylate (PMMA), polyether ether ketone (PEEK), graphite and Teflon) were within 2.8% for MD‐SPR images, compared to 6.8% for DirectSPR. Conclusions: The MD‐SPR model performed similar compared to other published methods for the human reference tissues. The SPR prediction for tissue surrogates was similar to DirectSPR and showed potential to improve SPR prediction for non‐tissue materials. [ABSTRACT FROM AUTHOR]

All psychiatric phenomena are positively associated, and several different models can account for this observation. These include the correlated factors, network, general psychopathology as outcome, and hierarchical models. Advantages of hierarchical models, which consist of one general and several (general factor‐residualized) specific factors, is that the general factor provides an opportunity to reliably measure global distress and impairment, while the specific factors might improve the ability to discriminate between individuals with different kinds of problems. Nevertheless, other models also have their respective advantages, and it remains challenging to empirically determine which model best accounts for the positive manifold in psychiatry. Instead, I present two non‐empirical arguments in favor of hierarchical models. First, by measuring the general factor in isolation, the specific factors tend to include both favorable and unfavorable correlates, which might reduce stigma compared to psychiatric diagnoses that by and large are associated with only unfavorable outcomes. Second, the general psychopathology factor displays an unusual psychometric property in that it includes symptoms of opposite meaning if they have similar valence (e.g., self‐reported symptoms such as gullible and paranoid, lazy and workaholic, and terrified and apathetic load in the same direction), which one might want to measure in isolation from variance capturing the content of symptoms. I conclude by speculating that tests designed based on hierarchical models might help clinical assessment. [ABSTRACT FROM AUTHOR]

Background: Although polygenic risk scores (PRS) predict psychiatric problems, these associations might be attributable to indirect pathways including population stratification, assortative mating, or dynastic effects (mediation via parental environments). The goal of this study was to examine whether PRS‐psychiatric symptom associations were attributable to indirect versus direct pathways. Methods: The sample consisted of 3,907 dizygotic (DZ) twin pairs. In childhood, their parents rated them on 98 symptoms. In adolescence (n = 2,393 DZ pairs), both the parents and the twins rated themselves on 20 symptoms. We extracted one general and seven specific factors from the childhood data, and one general and three specific factors from the adolescent data. We then regressed each general factor model onto ten psychiatric PRS simultaneously. We first conducted the regressions between individuals (β) and then within DZ twin pairs (βw), which controls for indirect pathways. Results: In childhood, the PRS for ADHD predicted general psychopathology (β = 0.09, 95% CI: [0.06, 0.12]; βw = 0.07 [0.01, 0.12]). Furthermore, the PRS for ADHD predicted specific inattention (β = 0.04 [0.00, 0.08]; βw = 0.09 [0.01, 0.17]) and specific hyperactivity (β = 0.07 [0.04, 0.11]; βw = 0.09 [0.01, 0.16]); the PRS for schizophrenia predicted specific learning (β = 0.08 [0.03, 0.13]; βw = 0.19 [0.08, 0.30]) and specific inattention problems (β = 0.05 [0.01, 0.09]; βw = 0.10 [0.02, 0.19]); and the PRS for neuroticism predicted specific anxiety (β = 0.06 [0.02, 0.10]; βw = 0.06 [0.00, 0.12]). Overall, the PRS‐general factor associations were similar between individuals and within twin pairs, whereas the PRS‐specific factors associations amplified by 84% within pairs. Conclusions: This implies that PRS‐psychiatric symptom associations did not appear attributable to indirect pathways such as population stratification, assortative mating, or mediation via parental environments. Rather, genetics appeared to directly influence symptomatology. [ABSTRACT FROM AUTHOR]

Background: Research has demonstrated that individuals who identify as a sexual minority (e.g., gay/lesbian, bisexual) are at increased risk for suicidality‐related outcomes. However, previous research is primarily limited by the lack of adjustment for unmeasured (i.e., genetic and environmental) confounding factors and previous psychopathology. Methods: Using the Child and Adolescent Twin Study in Sweden, we employed a co‐twin control design to examine the extent to which the association between sexual orientation and adolescent suicide attempt and self‐harm (SA/SH) was independent of genetic and environmental factors shared by twins, as well as measured symptoms of childhood psychopathology. Results: Adolescents who identified as a sexual minority (i.e., gay/lesbian, bisexual, or other sexual orientation) were at two‐fold increased odds for SA/SH (OR, 2.01 [95% confidence interval, 1.63–2.49) compared to heterosexual adolescents. When adjusting for all genetic and shared environmental factors that make twins similar and for measured childhood psychopathology, the association remained positive but attenuated to OR, 1.55 (1.11–2.16). Conclusions: Identifying as a sexual minority was associated with approximately 50% increased odds of SA/SH in adolescence after adjusting for unmeasured genetic and environmental factors shared by twins and for childhood psychopathology. The results support that environmental factors specifically associated with identifying as a sexual minority likely increase risk for SA/SH. Our findings highlight the need to monitor suicidality risk among this group. [ABSTRACT FROM AUTHOR]

Background: Top‐down volitional command of eye movements may serve as a candidate endophenotype of ADHD, an important function underlying goal‐directed action in everyday life. In this twin study, we examined the relation between performance on a response inhibition eye‐tracking paradigm and parent‐rated ADHD traits in a population‐based twin sample. We hypothesized that altered eye movement control is associated with the severity of ADHD traits and that this association is attributable to genetic factors. Methods: A total of 640 twins (320 pairs, 50% monozygotic) aged 9–14 years) from the Child and Adolescent Twin Study in Sweden (CATSS) participated. Twins performed the antisaccade task indexing inhibitory alterations as either direction errors (following exogenous cues rather than instructions) or premature anticipatory eye movements (failure to wait for cues). We calculated the associations of eye movement control and ADHD traits using linear regression mixed‐effects models and genetic and environmental influences with multivariate twin models. Results: Premature anticipatory eye movements were positively associated with inattentive traits (β =.17; 95% CI: 0.04, 0.31), while controlling for hyperactive behaviors and other covariates. Both premature anticipatory eye movements and inattention were heritable (h2 = 0.40, 95% CI: 0.22, 0.56; h2 = 0.55; 95% CI: 0.42, 0.65; respectively), and their genetic correlation was small but statistically significant (r =.19, 95% CI: 0.02, 0.36). However, the genetic correlation did not remain significant after adjusting for covariates (age, sex, hyperactivity traits, IQ). No link was found between direction errors and ADHD traits. Conclusions: This study indicates that there is a specific, genetically influenced, relation between top‐down eye movement control and the inattentive traits typical of ADHD. [ABSTRACT FROM AUTHOR]

Background: We examined whether childhood conduct problems predicted a wide range of adverse outcomes in emerging adulthood and whether the association with internalizing problems remained after adjusting for general comorbidity and externalizing problems. Methods: Participants were 18,649 twins from the Child and Adolescent Twin Study in Sweden. At age 9/12, parents rated their children on eight conduct problems. Adverse outcomes were retrieved from national registers in emerging adulthood (median follow‐up time = 9.2 years), including diagnoses of six psychiatric disorders, prescriptions of antidepressants, suicide attempts, criminality, high school ineligibility, and social welfare recipiency. We estimated risk for the separate outcomes and examined if conduct problems predicted an internalizing factor above and beyond a general comorbidity and an externalizing factor. We used twin analyses to estimate genetic and environmental contributions to these associations. Results: On the average, each additional conduct symptom in childhood was associated with a 32% increased risk of the adverse outcomes in emerging adulthood (mean hazard ratio = 1.32; range = 1.16, 1.56). A latent childhood conduct problems factor predicted the internalizing factor in emerging adulthood (βboys =.24, standard error, SE = 0.03; βgirls =.17, SE = 0.03), above and beyond its association with the externalizing (βboys = 0.21, SE = 0.04; βgirls = 0.17, SE = 0.05) and general factors (βboys = 0.45, SE = 0.03; βgirls = 0.34, SE = 0.04). These associations were differentially influenced by genetic and environmental factors. Conclusions: It is important to monitor boys and girls with conduct problems not only for future externalizing problems, but also for future internalizing problems. Prevention of specific outcomes, however, might require interventions at different levels. [ABSTRACT FROM AUTHOR]

Background: Autism spectrum disorder (ASD), Attention‐deficit/Hyperactivity disorder (ADHD), and other related neurodevelopmental disorders (NDDs) have, in some previous studies, been shown to increase the risk of being sexually victimized. However, no studies have examined whether the association is driven by a general NDD phenotype versus specific diagnoses, nor the etiology of the association. Method: Using a genetically informative, prospective design, we examined the association between ASD and ADHD in childhood and coercive sexual victimization up to age 18. A total of 4,500 children participating in the Child and Adolescent Twin Study in Sweden (CATSS) were rated by their parents on NDDs at age 9 or 12 years, and self‐reported at age 18 on lifetime experiences of coercive sexual touching and/or coercive sex. First, we regressed sexual victimization on the NDDs. Second, we regressed sexual victimization on general and specific NDD symptoms identified via a bifactor model. Third, we decomposed the observed associations into genetic and environmental parts. Results: In females, ASD was associated with an almost threefolded increased risk of coercive sexual victimization, and ADHD with a doubled risk. In males, the risk associated with ASD and ADHD was of the same magnitude but not significant. When controlling for overall NDD symptom load ASD or ADHD, no longer uniquely predicted coercive sexual victimization. The association between the NDD general factor and coercive sexual victimization was due to shared genetics. Conclusions: General NDD symptom load, rather than specific ASD or ADHD symptoms, seems to be a moderate vulnerability factor for coercive sexual victimization. We speculate that an evocative gene–environment correlation might account for this observation, such that sexual perpetrators actively target NDD individuals. [ABSTRACT FROM AUTHOR]

Background Studies have found an association between low birth weight and ADHD, but the nature of this relation is unclear. First, it is uncertain whether birth weight is associated with both of the ADHD dimensions, inattentiveness and hyperactivity-impulsivity. Second, it remains uncertain whether the association between birth weight and ADHD symptom severity is confounded by familial factors. Method Parents of all Swedish 9- and 12-year-old twins born between 1992 and 2000 were interviewed for DSM- IV inattentive and hyperactive-impulsive ADHD symptoms by the Autism - Tics, AD/ HD and other Comorbidities (A- TAC) inventory ( N = 21,775 twins). Birth weight was collected prospectively through the Medical Birth Registry. We used a within-twin pair design to control for genetic and shared environmental factors. Results Reduced birth weight was significantly associated with a mean increase in total ADHD (β = −.42; 95% CI: −.53, −.30), inattentive (β = −.26; 95% CI: −.33, −.19), and hyperactive-impulsive (β = −.16; 95% CI: −.22, −.10) symptom severity. These results imply that a change of one kilogram of birth weight corresponded to parents rating their child nearly one unit higher (going from 'no' to 'yes, to some extent' on a given symptom) on the total ADHD scale. These associations remained within pairs of MZ and DZ twins, and were also present when restricting the analyses to full term births. Conclusions There is an independent association between low birth weight and all forms of ADHD symptoms, even after controlling for all environmental and genetic confounds shared within twin pairs. These results indicate that fetal growth restriction (as reflected in birth weight differences within twin pairs) and/or the environmental factors which influence it is in the casual pathway leading to ADHD. [ABSTRACT FROM AUTHOR]

Background Although neurodevelopmental disorders are demarcated as discrete entities in the Diagnostic Statistical Manual of mental disorders, empirical evidence indicates that there is a high degree of overlap among them. The first aim of this investigation was to explore if a single general factor could account for the large degree of observed overlap among neurodevelopmental problems, and explore whether this potential factor was primarily genetic or environmental in origin. The second aim was to explore whether there was systematic covariation, either genetic or environmental, over and above that contributed by the potential general factor, unique to each syndrome. Method Parents of all Swedish 9- and 12-year-old twin pairs born between 1992 and 2002 were targeted for interview regarding problems typical of autism spectrum disorders, ADHD and other neurodevelopmental conditions (response rate: 80 percent). Structural equation modeling was conducted on 6,595 pairs to examine the genetic and environmental structure of 53 neurodevelopmental problems. Results One general genetic factor accounted for a large proportion of the phenotypic covariation among the 53 symptoms. Three specific genetic subfactors identified 'impulsivity,' 'learning problems,' and 'tics and autism,' respectively. Three unique environment factors identified 'autism,' 'hyperactivity and impulsivity,' and 'inattention and learning problems,' respectively. Conclusion One general genetic factor was responsible for the wide-spread phenotypic overlap among all neurodevelopmental symptoms, highlighting the importance of addressing broad patient needs rather than specific diagnoses. The unique genetic factors may help guide diagnostic nomenclature, whereas the unique environmental factors may highlight that neurodevelopmental symptoms are responsive to change at the individual level and may provide clues into different mechanisms and treatments. Future research would benefit from assessing the general factor separately from specific factors to better understand observed overlap among neurodevelopmental problems. [ABSTRACT FROM AUTHOR]

The neurotoxicity of amyloid-β protein (Aβ) is widely regarded as one of the fundamental causes of neurodegeneration in Alzheimer's disease (AD). This toxicity is related to Aβ aggregation into oligomers, protofibrils and fibrils. Recent studies suggest that intracellular Aβ, which causes profound toxicity, could be one of the primary therapeutic targets in AD. So far, no compounds targeting intracellular Aβ have been identified. We have investigated the toxicity induced by intracellular Aβ in a neuroblastoma MC65 line and found that it was closely related to intracellular accumulation of oligomeric complexes of Aβ (Aβ-OCs). We further identified a cell-permeable tricyclic pyrone named CP2 that ameliorates this toxicity and significantly reduces the levels of Aβ-OCs. In aqueous solution, CP2 attenuates Aβ oligomerization and prevents the oligomer-induced death of primary cortical neurons. CP2 analogs represent a new class of promising compounds for the amelioration of Aβ toxicities within both intracellular and extracellular sites. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Offspring of parents with bipolar disorder have increased risks of their own psychopathology. However, a large‐scale survey of psychiatric, somatic, and adverse social outcomes up to adulthood, which could aid in prioritizing and tailoring prevention, is lacking. It also remains to clarify how risks are modified by other parental factors.Swedish population registers were linked to compare offspring having (N = 24,788) and not having (N = 247,880) a parent with bipolar disorder with respect to psychiatric diagnoses and psychotropic medication, birth‐related and somatic conditions, social outcomes, accidents, suicide attempts, and mortality. Individuals were followed until age 18. We estimated the influence of lifetime parental psychiatric comorbidity, bipolar disorder subtype, and sex on outcomes.Children of parents with bipolar disorder had 2–3 times higher risks of all psychiatric diagnoses, except for bipolar disorder, for which the risk was 11‐fold. Significantly increased risks were also found for several somatic conditions, low school grades, criminal behavior, victimization, accidents, and suicidal behavior. Adjusting for lifetime parental psychiatric comorbidity attenuated most associations. Offspring of a parent with bipolar disorder type 2 had statistically significantly higher risks of attention deficit hyperactivity disorder, respiratory tract conditions, and accidents compared with offspring of a parent with bipolar disorder type 1. Offspring of mothers with bipolar disorder had higher risks of several psychiatric diagnoses, respiratory tract conditions, low school grades, and accidents compared with offspring of fathers with bipolar disorder. Having two parents with bipolar disorder entailed the highest risks of psychiatric outcomes in offspring.Early intervention and family support are particularly warranted for the offspring of a parent with bipolar disorder in the presence of lifetime parental psychiatric comorbidity, when the parent has bipolar disorder type 2, or when the mother or both parents have bipolar disorder. [ABSTRACT FROM AUTHOR]