Neuroanatomical spread of amyloid β and tau in Alzheimer's disease: implications for primary prevention.

With recent advances in our understanding of the continuous pathophysiological changes that begin many years prior to symptom onset, it is now apparent that Alzheimer's disease cannot be adequately described by discrete clinical stages, but should also incorporate the continuum of biological changes that precede and underlie the clinical representation of the disease. By jointly considering longitudinal changes of all available biomarkers and clinical assessments, variation within individuals can be integrated into a single continuous measure of disease progression and used to identify the earliest pathophysiological changes. Disease time, a measure of disease severity, was estimated using a Bayesian latent time joint mixed-effects model applied to an array of imaging, biomarker and neuropsychological data. Trajectories of regional amyloid β and tau PET uptake were estimated as a function of disease time. Regions with early signs of elevated amyloid β uptake were used to form an early, focal composite and compared to a commonly used global composite, in a separate validation sample. Disease time was estimated in 279 participants (183 cognitively unimpaired individuals, 61 mild cognitive impairment and 35 Alzheimer's disease dementia patients) with available amyloid β and tau PET data. Amyloid β PET uptake levels in the posterior cingulate and precuneus start high and immediately increase with small increases of disease time. Early elevation in tau PET uptake was found in the inferior temporal lobe, amygdala, banks of the superior temporal sulcus, entorhinal cortex, middle temporal lobe, inferior parietal lobe and the fusiform gyrus. In a separate validation sample of 188 cognitively unimpaired individuals, the early, focal amyloid β PET composite showed a 120% increase in the accumulation rate of amyloid β compared to the global composite (P < 0.001), resulting in a 60% increase in the power to detect a treatment effect in a primary prevention trial design. Ordering participants on a continuous disease time scale facilitates the inspection of the earliest signs of amyloid β and tau pathology. To detect early changes in amyloid β pathology, focusing on the earliest sites of amyloid β accumulation results in more powerful and efficient study designs in early Alzheimer's disease. Targeted composites could be used to re-examine the thresholds for amyloid β-related study inclusion, especially as the field shifts to focus on primary and secondary prevention. Clinical trials of anti-amyloid β treatments may benefit from the use of focal composites when estimating drug effects on amyloid β and tau changes in populations with minimal amyloid β and tau pathology and limited expected short-term accumulation

Bee happy:Bumblebees show decision-making that reflects emotion-like states

Bumblebees show decision-making that reflects emotion-like states</jats:p

Psychosocial Characteristics and Obstetric Health of Women Attending a Specialist Substance Use Antenatal Clinic in a Large Metropolitan Hospital

Objective. This paper reports the findings comparing the obstetrical health, antenatal care, and psychosocial characteristics of pregnant women with a known history of substance dependence (n = 41) and a comparison group of pregnant women attending a general antenatal clinic (n = 47). Method. Face-to-face interviews were used to assess obstetrical health, antenatal care, physical and mental functioning, substance use, and exposure to violence. Results. The substance-dependent group had more difficulty accessing antenatal care and reported more obstetrical health complications during pregnancy. Women in the substance-dependent group were more likely to report not wanting to become pregnant and were less likely to report using birth control at the time of conception. Conclusions. The profile of pregnant women (in specialised antenatal care for substance dependence) is one of severe disadvantage and poor health. The challenge is to develop and resource innovative and effective multisectoral systems to educate women and provide effective care for both women and infants

Becoming a written word: eye movements reveal order of acquisition effects following incidental exposure to new words during silent reading

We know that from mid-childhood onwards most new words are learned implicitly via reading; however, most word learning studies have taught novel items explicitly. We examined incidental word learning during reading by focusing on the well-documented finding that words which are acquired early in life are processed more quickly than those acquired later. Novel words were embedded in meaningful sentences and were presented to adult readers early (day 1) or later (day 2) during a five-day exposure phase. At test adults read the novel words in semantically neutral sentences. Participants’ eye movements were monitored throughout exposure and test. Adults also completed a surprise memory test in which they had to match each novel word with its definition. Results showed a decrease in reading times for all novel words over exposure, and significantly longer total reading times at test for early than late novel words. Early-presented novel words were also remembered better in the offline test. Our results show that order of presentation influences processing time early in the course of acquiring a new word, consistent with partial and incremental growth in knowledge occurring as a function of an individual’s experience with each word

Emotional Self-Control, Interpersonal Shame, and Racism as Predictors of Help-Seeking Attitudes among Asian Americans: An Application of the Intrapersonal-Interpersonal-Sociocultural Framework

The present study is a cross-sectional investigation of emotional self-control, interpersonal shame, and subtle racism as predictors of Asian American attitudes toward professional help-seeking in a sample of Asian American college students (N = 153). The authors applied and extended P. Y. Kim and Lee’s (2014) intrapersonal-interpersonal framework of Asian American help-seeking to include racism as a sociocultural correlate. It was hypothesized that emotional self-control (intrapersonal correlate), interpersonal shame variables of external shame and family shame (interpersonal correlates), and racism (sociocultural correlate) would incrementally predict professional help-seeking attitudes, controlling for previous counseling experience. Participants completed an online survey containing the demographic and study variables. Hierarchical regression analyses (Step 1: counseling experience; Step 2: emotional self-control; Step 3: interpersonal shame [external and family]; Step 4: racism) indicated that emotional self-control and racism were negative predictors of favorable attitudes, whereas external shame was a positive predictor of favorable help-seeking attitudes. The findings have implications for advancing the Asian American literature pertaining to professional help-seeking correlates and for practitioners working with Asian American students to favorably impact mental health service utilization

E-prints and Journal Articles in Astronomy: a Productive Co-existence

Are the e-prints (electronic preprints) from the arXiv repository being used instead of the journal articles? In this paper we show that the e-prints have not undermined the usage of journal papers in the astrophysics community. As soon as the journal article is published, the astronomical community prefers to read the journal article and the use of e-prints through the NASA Astrophysics Data System drops to zero. This suggests that the majority of astronomers have access to institutional subscriptions and that they choose to read the journal article when given the choice. Within the NASA Astrophysics Data System they are given this choice, because the e-print and the journal article are treated equally, since both are just one click away. In other words, the e-prints have not undermined journal use in the astrophysics community and thus currently do not pose a financial threat to the publishers. We present readership data for the arXiv category "astro-ph" and the 4 core journals in astronomy (Astrophysical Journal, Astronomical Journal, Monthly Notices of the Royal Astronomical Society and Astronomy & Astrophysics). Furthermore, we show that the half-life (the point where the use of an article drops to half the use of a newly published article) for an e-print is shorter than for a journal paper. The ADS is funded by NASA Grant NNG06GG68G. arXiv receives funding from NSF award #0404553Comment: 8 pages, 4 figures, submitted to Learned Publishin

What do different beliefs tell us? An examination of factual, opinion-based, and religious beliefs

Children and adults differentiate statements of religious belief from statements of fact and opinion, but the basis of that differentiation remains unclear. Across three experiments, adults and 8–10-year-old children heard statements of factual, opinion-based, and religious belief. Adults and children judged that statements of factual belief revealed more about the world, statements of opinion revealed more about individuals, and statements of religious belief provided information about both. Children—unlike adults—judged that statements of religious belief revealed more about the world than the believer. These results led to three conclusions. First, judgments concerning the relative amount of information statements of religious belief provide about individuals change across development, perhaps because adults have more experience with diversity. Second, recognizing that statements of religious belief provide information about both the world and the believer does not require protracted learning. Third, statements of religious belief are interpreted as amalgams of factual and opinion-based statements.Psycholog

Case Definition and Design Sensitivity

In a case-referent study, cases of disease are compared to noncases with respect to their antecedent exposure to a treatment in an effort to determine whether exposure causes some cases of the disease. Because exposure is not randomly assigned in the population, as it would be if the population were a vast randomized trial, exposed and unexposed subjects may differ prior to exposure with respect to covariates that may or may not have been measured. After controlling for measured preexposure differences, for instance by matching, a sensitivity analysis asks about the magnitude of bias from unmeasured covariates that would need to be present to alter the conclusions of a study that presumed matching for observed covariates removes all bias. The definition of a case of disease affects sensitivity to unmeasured bias. We explore this issue using: (i) an asymptotic tool, the design sensitivity, (ii) a simulation for finite samples, and (iii) an example. Under favorable circumstances, a narrower case definition can yield an increase in the design sensitivity, and hence an increase in the power of a sensitivity analysis. Also, we discuss an adaptive method that seeks to discover the best case definition from the data at hand while controlling for multiple testing. An implementation in R is available as SensitivityCaseControl

Using Primary Reinforcement to Enhance Translatability of a Human Affect and Decision-Making Judgment Bias Task

Good translatability of behavioral measures of affect (emotion) between human and nonhuman animals is core to comparative studies. The judgment bias (JB) task, which measures "optimistic" and "pessimistic" decision-making under ambiguity as indicators of positive and negative affective valence, has been used in both human and nonhuman animals. However, one key disparity between human and nonhuman studies is that the former typically use secondary reinforcers (e.g., money) whereas the latter typically use primary reinforcers (e.g., food). To address this deficiency and shed further light on JB as a measure of affect, we developed a novel version of a JB task for humans using primary reinforcers. Data on decision-making and reported affective state during the JB task were analyzed using computational modeling. Overall, participants grasped the task well, and as anticipated, their reported affective valence correlated with trial-by-trial variation in offered volume of juice. In addition, previous findings from monetary versions of the task were replicated: More positive prediction errors were associated with more positive affective valence, a higher lapse rate was associated with lower affective arousal, and affective arousal decreased as a function of number of trials completed. There was no evidence that more positive valence was associated with greater "optimism," but instead, there was evidence that affective valence influenced the participants' decision stochasticity, whereas affective arousal tended to influence their propensity for errors. This novel version of the JB task provides a useful tool for investigation of the links between primary reward and punisher experience, affect, and decision-making, especially from a comparative perspective

Characterizing the immune microenvironment of malignant peripheral nerve sheath tumor by PD-L1 expression and presence of CD8+ tumor infiltrating lymphocytes.

BackgroundMalignant peripheral nerve sheath tumor (MPNST) is an aggressive sarcoma with few treatment options. Tumor immune state has not been characterized in MPNST, and is important in determining response to immune checkpoint blockade. Our aim was to evaluate the expression of programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), and presence of CD8+ tumor infiltrating lymphocytes (TILs) in MPNST, and correlate these findings with clinical behavior and outcome.ResultsPD-L1 staining of at least 1% was seen in 0/20 nerves, 2/68 benign lesions and 9/53 MPNST. Two of 68 benign lesions and 7/53 (13%) MPNST had at least 5% PD-L1 staining. CD8 staining of at least 5% was seen in 1/20 (5%) nerves, 45/68 (66%) benign lesions and 30/53 (57%) MPNST. PD-L1 was statistically more prevalent in MPNST than both nerves and benign lesions (p=0.049 and p=0.008, respectively). Expression of PD-1 was absent in all tissue specimens. There was no correlation of PD-L1 or CD8 expression with disease state (primary versus metastatic) or patient survival.MethodsA comprehensive PNST tissue microarray was created from 141 surgical specimens including primary, recurrent, and metastatic MPNST (n=53), neurofibromas (n=57), schwannoma (n=11), and normal nerve (n=20). Cores were stained in triplicate for PD-L1, PD-1, and CD8, and expression compared between tumor types. These data were then examined for survival correlates in 35 patients with primary MPNST.ConclusionsMPNST is characterized by low PD-L1 and absent PD-1 expression with significant CD8+ TIL presence. MPNST immune microenvironment does not correlate with patient outcome