Simvastatin is among the most commonly used prescription medications for cholesterol reduction. A single coding single‐nucleotide polymorphism, rs4149056T>C, in SLCO1B1 increases systemic exposure to ...simvastatin and the risk of muscle toxicity. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for simvastatin based on SLCO1B1 genotype. This article is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium guideline for SLCO1B1 and simvastatin‐induced myopathy.
Clinical Pharmacology & Therapeutics (2014); 96 4, 423–428. doi:10.1038/clpt.2014.125
Recent theoretical work in developmental psychology suggests that humans are predisposed to align their mental states with those of other individuals. One way this manifests is in
; that is, ...intentional communication aimed at aligning individuals' mental states with respect to events in their shared environment. This idea has received strong empirical support. The purpose of this paper is to extend this account by proposing an integrative model of the biobehavioral dynamics of cooperative communication. Our formulation is based on
. Active inference suggests that action-perception cycles operate to minimize uncertainty and optimize an individual's internal model of the world. We propose that humans are characterized by an evolved
that their mental states are aligned with, or similar to, those of conspecifics (i.e., that 'we are the same sort of creature, inhabiting the same sort of niche'). The use of cooperative communication emerges as the principal means to gather evidence for this belief, allowing for the development of a shared narrative that is used to disambiguate interactants' (hidden and inferred) mental states. Thus, by using cooperative communication, individuals effectively attune to a hermeneutic niche composed, in part, of others' mental states; and, reciprocally, attune the niche to their own ends via epistemic niche construction. This means that niche construction enables features of the niche to encode precise, reliable cues about the
or
of certain action policies (e.g., the utility of using communicative constructions to disambiguate mental states, given expectations about shared prior beliefs). In turn, the alignment of mental states (prior beliefs) enables the emergence of a novel, contextualizing scale of
dynamics that encompasses the actions and mental states of the ensemble of interactants and their shared environment. The dynamics of this contextualizing layer of cultural organization feedback, across scales, to constrain the variability of the prior expectations of the individuals who constitute it. Our theory additionally builds upon the active inference literature by introducing a new set of neurobiologically plausible computational hypotheses for cooperative communication. We conclude with directions for future research.
Aim
To evaluate the progressively lowered stress threshold (PLST) conceptual model as an explanation for behavioural symptoms of dementia and test several of its hypothesized propositions. The PLST ...model suggests that due to impairments in coping, persons living with dementia have a reduced threshold for stress and respond with more behavioural symptoms of dementia as stress accumulates throughout the day.
Design
Intensive longitudinal design.
Methods
A sample of N = 165 family caregivers completed brief daily diary surveys for 21 days between the dates of 7/2019 and 8/2020, reporting on a total of 2841 days. Dynamic structural equation modelling was used as the analytic technique to examine the impact of caregiver and care recipient environmental stressors on the diversity of behavioural symptoms of dementia to account for the nested data structure and autoregressive relationships.
Findings
Results show direct relationships between environmental stressors and diversity of behavioural symptoms of dementia that same day and the following day.
Conclusion
Findings provide support for the PLST model propositions. Further, findings suggest an extension to the conceptual model is warranted given evidence of an exposure/recovery trajectory and the lagged effects of stress exposure on behavioural symptoms of dementia presentation.
Impact
This study tested whether a commonly used nursing model does in fact explain the occurrence of behavioural symptoms of dementia. The main findings support using the model as an intervention framework and suggest the model should be adapted to consider recovery trajectories. Since behavioural symptoms of dementia represent complex and dynamic temporal phenomena, traditional longitudinal assessments and analyses are an insufficient measurement modality for testing models. Findings inform the design of environmental‐modification type interventions for behavioural symptoms of dementia management and the methods to evaluate such interventions.
How do humans come to acquire shared expectations about how they ought to behave in distinct normalized social settings? This paper offers a normative framework to answer this question. We introduce ...the computational construct of 'deontic value' - based on active inference and Markov decision processes - to formalize conceptions of social conformity and human decision-making. Deontic value is an attribute of choices, behaviors, or action sequences that inherit directly from deontic cues in our econiche (e.g., red traffic lights); namely, cues that denote an obligatory social rule. Crucially, the prosocial aspect of deontic value rests upon a particular form of circular causality: deontic cues exist in the environment in virtue of the environment being modified by repeated actions, while action itself is contingent upon the deontic value of environmental cues. We argue that this construction of deontic cues enables the epistemic (i.e., information-seeking) and pragmatic (i.e., goal- seeking) values of any behavior to be 'cached' or 'outsourced' to the environment, where the environment effectively 'learns' about the behavior of its denizens. We describe the process whereby this particular aspect of value enables learning of habitual behavior over neurodevelopmental and transgenerational timescales.
Computational prediction of the phenotypic propensities of noncoding single nucleotide variants typically combines annotation of genomic, functional and evolutionary attributes into a single score. ...Here, we evaluate if the claimed excellent accuracies of these predictions translate into high rates of success in addressing questions important in biological research, such as fine mapping causal variants, distinguishing pathogenic allele(s) at a given position, and prioritizing variants for genetic risk assessment. A significant disconnect is found to exist between the statistical modelling and biological performance of predictive approaches. We discuss fundamental reasons underlying these deficiencies and suggest that future improvements of computational predictions need to address confounding of allelic, positional and regional effects as well as imbalance of the proportion of true positive variants in candidate lists.
Caesarean scar pregnancy Ash, A; Smith, A; Maxwell, D
BJOG : an international journal of obstetrics and gynaecology,
March 2007, Letnik:
114, Številka:
3
Journal Article
Recenzirano
Caesarean scar pregnancy is one of the rarest forms of ectopic pregnancy. Little is known about its incidence and natural history. With increasing incidence of caesarean section worldwide, more and ...more cases are diagnosed and reported. Transvaginal ultrasound and colour flow Doppler provides a high diagnostic accuracy with very few false positives. A delay in diagnosis and/or treatment can lead to uterine rupture, major haemorrhage, hysterectomy and serious maternal morbidity. Early diagnosis can offer treatment options of avoiding uterine rupture and haemorrhage, thus preserving the uterus and future fertility. Management plan should be individually tailored. Available data suggest that termination of pregnancy is the treatment of choice in the first trimester soon after the diagnosis. Expectant treatment has a poor prognosis because of risk of rupture. There are no reliable scientific data on the risk of recurrence of the condition in future pregnancy, role of the interval between the previous caesarean delivery and occurrence of caesarean scar pregnancy, and effect of caesarean wound closure technique on caesarean scar pregnancy. In this article, we aim to find the demography, pathophysiology, clinical presentation, most appropriate methods of diagnosis and management, with their implications in clinical practice for this condition.
While substantial task-related neural activity has been observed during motor tasks in rodent primary motor cortex and premotor cortex, the long-term stability of these responses in healthy rats is ...uncertain, limiting the interpretability of longitudinal changes in the specific patterns of neural activity associated with learning or motor recovery following injury. This study examined the stability of task-related neural activity associated with execution of two distinct reaching tasks in healthy rodents. A novel automated rodent behavioral apparatus was constructed and rats were trained to perform a reaching task combining a 'gross' lever press and a 'fine' pellet retrieval. In each animal, two chronic microelectrode arrays were implanted in motor cortex spanning the caudal forelimb area (rodent primary motor cortex) and the rostral forelimb area (rodent premotor cortex). We recorded multiunit spiking and local field potential activity from 10 days to 7-10 weeks post-implantation to characterize the patterns of neural activity observed during each task component and analyzed the consistency of channel-specific task-related neural activity. Task-related changes in neural activity were observed on the majority of channels. While the task-related changes in multi-unit spiking and local field potential spectral power were consistent over several weeks, spectral power changes were more stable, despite the trade-off of decreased spatial and temporal resolution. These results show that neural activity in rodent primary and premotor cortex is associated with specific phases of reaching movements with stable patterns of task-related activity across time, establishing the relevance of the rodent for future studies designed to examine changes in task-related neural activity during recovery from focal cortical lesions.
Hepatitis C virus is a blood-borne infection and the leading cause of chronic liver disease (including cirrhosis and cancer) and liver transplantation. Since the identification of HCV in 1989, there ...has been an extensive effort to identify and improve treatment options. An important milestone was reached in 2011 with the approval of the first-generation HCV NS3/4A protease inhibitors. However, new therapies are needed to improve cure rates, shorten treatment duration, and improve tolerability. Here we summarize the extensive medicinal chemistry effort to develop novel P2 cyclopentane macrocyclic inhibitors guided by HCV NS3 protease assays, the cellular replicon system, structure-based design, and a panel of DMPK assays. The selection of compound 29 (simeprevir, TMC435) as clinical candidate was based on its excellent biological, PK, and safety pharmacology profile. Compound 29 has recently been approved for treatment of chronic HCV infection in combination with pegylated interferon-α and ribavirin in Japan, Canada, and USA.
Cancer stage at diagnosis is important information for management and treatment of individual patients as well as in epidemiological studies to evaluate effectiveness of health care system in ...managing cancer patients. Population‐based studies to examine international disparities on cancer survival by stage, however, has been challenging due to the lack of international standardization on recording stage information and variation in stage completeness across regions and countries. The International Cancer Benchmarking Partnership (ICBP) previously assessed the availability and comparability of staging information for colorectal, lung, female breast and ovarian cancers. Stage conversion algorithms were developed to aggregate and map all stage information into a single staging system to allow international comparison by stage at diagnosis. In this article, we developed stage conversion algorithms for three additional cancers, namely oesophageal, gastric and pancreatic cancers. We examined all stage information available, evaluated stage completeness, applied each stage conversion algorithm, and assessed the magnitude of misclassification using data from six Canadian cancer registries (Alberta, Manitoba, Newfoundland, Nova Scotia, Prince Edward Island and Saskatchewan). In addition, we discussed five recommendations for registries to improve international cancer survival comparison by stage: (a) improve collection and completeness of staging data; (b) promote a comparable definition for stage at diagnosis; (c) promote the use of a common stage classification system; (d) record versions of staging classifications and (e) use multiple data sources for valid staging data.
When someone masters a skill, their performance looks to us like second nature: it looks as if their actions are smoothly performed without explicit, knowledge-driven, online monitoring of their ...performance. Contemporary computational models in motor control theory, however, are
instructionist
: that is, they cast skillful performance as a knowledge-driven process. Optimal motor control theory (OMCT), as representative
par excellence
of such approaches, casts skillful performance as an instruction, instantiated in the brain, that needs to be executed—a motor command. This paper aims to show the limitations of such instructionist approaches to skillful performance. We specifically address the question of whether the assumption of control-theoretic models is warranted. The first section of this paper examines the instructionist assumption, according to which skillful performance consists of the execution of theoretical instructions harnessed in motor representations. The second and third sections characterize the implementation of motor representations as motor commands, with a special focus on formulations from OMCT. The final sections of this paper examine predictive coding and active inference—behavioral modeling frameworks that descend, but are distinct, from OMCT—and argue that the instructionist, control-theoretic assumptions are ill-motivated in light of new developments in active inference.
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