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Archives of Endocrinology and Metabolism Nov 2022It is now well recognized that over the lifetime of a patient with osteoporosis, more than one medication will be needed to treat the disease and to decrease fracture... (Review)
Review
It is now well recognized that over the lifetime of a patient with osteoporosis, more than one medication will be needed to treat the disease and to decrease fracture risk. Though current gaps in osteoporosis therapy can be potentially mitigated with sequential and combination regimens, how to move seamlessly amongst the multiple treatments currently available for osteoporosis for sustained efficacy is still unclear. Data from recent studies show that an anabolic agent such as teriparatide or romosozumab followed by an antiresorptive affords maximal gain in BMD and possibly better and earlier fracture risk reduction compared to a regimen which follows the opposite sequence. Sequentially moving to a bisphosphonate such as alendronate from an anabolic agent such as abaloparatide has also been shown to preserve the fracture reduction benefits seen with the latter. This sequence of an anabolic agent followed by an antiresorptive should especially be considered in the high-risk patient with imminent fracture risk to rapidly reduce the risk of subsequent fractures. The data surrounding optimum timing of initiation of bisphosphonate therapy following denosumab discontinuation is still unclear. Though data suggests that combining a bisphosphonate with teriparatide does not provide substantial BMD gains compared to monotherapy, the concomitant administration of denosumab with teriparatide has been shown to significantly increase areal BMD as well as to increase volumetric BMD and estimated bone strength. This narrative review explores the available evidence regarding the various sequential and combination therapy approaches and the potential role they could play in better managing osteoporosis.
Topics: Humans; Female; Teriparatide; Denosumab; Bone Density Conservation Agents; Bone Density; Osteoporosis; Diphosphonates; Fractures, Bone; Osteoporosis, Postmenopausal
PubMed: 36382762
DOI: 10.20945/2359-3997000000564 -
Formal Methods in System Design 2019Hyperproperties, such as non-interference and observational determinism, relate multiple system executions to each other. They are not expressible in standard temporal...
Hyperproperties, such as non-interference and observational determinism, relate multiple system executions to each other. They are not expressible in standard temporal logics, like LTL, CTL, and CTL*, and thus cannot be monitored with standard runtime verification techniques. extends linear-time temporal logic (LTL) with explicit quantification over traces in order to express hyperproperties. We investigate the runtime verification problem of formulas for three different input models: (1) The model, where a number of system executions is processed in parallel. (2) The model, where system executions are processed sequentially, one execution at a time. In this model, the number of incoming executions is a-priori unbounded and may in fact grow forever. (3) The where the traces are processed sequentially and the number of incoming executions is . We show that the existence of a bound in the parallel and bounded sequential models leads to a different notion of monitorability than in the unbounded sequential model. We show that deciding the monitoriability problem for alternation-free HyperLTL is -complete while the problem is undecidable in general. For every input model, we provide monitoring algorithms along with run-time and storage optimizations. By recognizing properties of specifications such as reflexivity, symmetry, and transitivity, we reduce the number of comparisons between traces. For the sequential models, we present a technique that minimizes the number of traces that need to be stored. We evaluate our optimizations, showing that this leads to a more scalable monitoring and, in particular, a significantly lower memory consumption.
PubMed: 31806925
DOI: 10.1007/s10703-019-00334-z -
Microsystems & Nanoengineering 2021Droplet microfluidic methods have opened up the possibility of studying a plethora of phenomena ranging from biological to physical or chemical processes at ultra low...
Droplet microfluidic methods have opened up the possibility of studying a plethora of phenomena ranging from biological to physical or chemical processes at ultra low volumes and high throughput. A key component of such approaches is the ability to trap droplets for observation, and many device architectures for achieving this objective have been developed. A challenge with such approaches is, however, recovering the droplets following their confinement for applications involving further analysis. Here, we present a device capable of generating, confining and releasing microdroplets in a sequential manner. Through a combination of experimental and computational simulations, we shed light on the key features required for successful droplet storage and retrieval. Moreover, we explore the effect of the flow rate of the continuous phase on droplet release, determining that a critical rate is needed to ensure complete droplet deformation through constrictions holding the droplets in place prior to release. Finally, we find that once released, droplets can be retrieved and collected off chip. The ability to generate, store and sequentially release droplets renders such a device particularly promising for future applications where reactions may not only be monitored on-chip, but droplets can also be retrieved for further analysis, facilitating new exploratory avenues in the fields of analytical chemistry and biology.
PubMed: 34631144
DOI: 10.1038/s41378-021-00303-9 -
Biometrika Sep 2018The seminal work of Morgan & Rubin (2012) considers rerandomization for all the units at one time.In practice, however, experimenters may have to rerandomize units...
The seminal work of Morgan & Rubin (2012) considers rerandomization for all the units at one time.In practice, however, experimenters may have to rerandomize units sequentially. For example, a clinician studying a rare disease may be unable to wait to perform an experiment until all the experimental units are recruited. Our work offers a mathematical framework for sequential rerandomization designs, where the experimental units are enrolled in groups. We formulate an adaptive rerandomization procedure for balancing treatment/control assignments over some continuous or binary covariates, using Mahalanobis distance as the imbalance measure. We prove in our key result that given the same number of rerandomizations, in expected value, under certain mild assumptions, sequential rerandomization achieves better covariate balance than rerandomization at one time.
PubMed: 30174335
DOI: 10.1093/biomet/asy031 -
Transcription 2022The processing of the proximal and distal poly(A) sites in alternative polyadenylation (APA) has long been thought to independently occur on pre-mRNAs during... (Review)
Review
The processing of the proximal and distal poly(A) sites in alternative polyadenylation (APA) has long been thought to independently occur on pre-mRNAs during transcription. However, a recent study by our groups demonstrated that the proximal sites for many genes could be activated sequentially following the distal ones, suggesting a multi-cleavage-same-transcript mode beyond the canonical one-cleavage-per-transcript view. Here, we review the established mechanisms for APA regulation and then discuss the additional insights into APA regulation from the perspective of sequential polyadenylation, resulting in a unified leverage model for understanding the mechanisms of regulated APA.
Topics: Polyadenylation; Gene Expression Regulation
PubMed: 36004392
DOI: 10.1080/21541264.2022.2114776 -
Oral Diseases Sep 2022The aim of this study is to investigate the underlying mechanism of the recovery of periodontal ligament cells (PDLCs) sequentially exposed to inflammation and...
OBJECTIVES
The aim of this study is to investigate the underlying mechanism of the recovery of periodontal ligament cells (PDLCs) sequentially exposed to inflammation and mechanical loading.
MATERIALS AND METHODS
We divided PDLCs into four groups: control; compressive force (CF) alone (2.0 g/cm ); lipopolysaccharides (LPS) pretreatment (0.1 μg/ml) followed by simultaneous LPS and CF stimulation, simulating uncontrolled periodontitis; and LPS pretreatment followed by CF exposure, simulating controlled periodontitis. The expression of EphB4-ephrinB2 and EphA2-ephrinA2, and the level of osteoclastogenesis and osteogenesis were evaluated.
RESULTS
Simultaneous stimulation by LPS and CF, compared with CF alone and sequential LPS and CF exposure, significantly suppressed EphB4 and enhanced ephrinA2 expression. Similarly, the most intense osteoclastic differentiation was observed under simultaneous LPS and CF stimulation, while sequential exposure to LPS and CF only slightly increased osteoclastic cell numbers. Both the activation of EphB4 signaling and ephrinA2 silencing lowered osteoclastic differentiation, which had previously been upregulated by simultaneous LPS and CF stimulation. These treatments also increased osteogenic differentiation.
CONCLUSIONS
Simultaneous LPS and CF stimulation critically enhances osteoclastogenesis in PDLCs through the suppression of EphB4 and the induction of ephrinA2 signaling. Sequential LPS and CF exposure partially abolishes the osteolytic effects of simultaneous stimulation.
Topics: Cell Differentiation; Cells, Cultured; Ephrins; Humans; Lipopolysaccharides; Osteogenesis; Periodontal Ligament; Periodontitis
PubMed: 33872438
DOI: 10.1111/odi.13875 -
Topics in Cognitive Science Jan 2021It is argued that event perception and routine sequential action production share a range of characteristics (e.g., similar levels of automaticity, the involvement of...
It is argued that event perception and routine sequential action production share a range of characteristics (e.g., similar levels of automaticity, the involvement of sequentially and hierarchically organized schemata, and the coupled operation of predictive and monitoring processes). With this in mind, and in an effort to develop a mechanistic account of event perception, we consider how an existing model of routine sequential action production might be applied in the domain of event perception. We focus the discussion on the multiple roles of prediction in the two domains, and we consider the implications of the application of the model of action production to event perception and for sequential processing more generally.
Topics: Humans; Perception
PubMed: 31595694
DOI: 10.1111/tops.12462 -
Epidemics Jun 2022We introduce a Bayesian sequential data assimilation and forecasting method for non-autonomous dynamical systems. We applied this method to the current COVID-19...
We introduce a Bayesian sequential data assimilation and forecasting method for non-autonomous dynamical systems. We applied this method to the current COVID-19 pandemic. It is assumed that suitable transmission, epidemic and observation models are available and previously validated. The transmission and epidemic models are coded into a dynamical system. The observation model depends on the dynamical system state variables and parameters, and is cast as a likelihood function. The forecast is sequentially updated over a sliding window of epidemic records as new data becomes available. Prior distributions for the state variables at the new forecasting time are assembled using the dynamical system, calibrated for the previous forecast. Epidemic outbreaks are non-autonomous dynamical systems depending on human behavior, viral evolution and climate, among other factors, rendering it impossible to make reliable long-term epidemic forecasts. We show our forecasting method's performance using a SEIR type model and COVID-19 data from several Mexican localities. Moreover, we derive further insights into the COVID-19 pandemic from our model predictions. The rationale of our approach is that sequential data assimilation is an adequate compromise between data fitting and dynamical system prediction.
Topics: Bayes Theorem; COVID-19; Disease Outbreaks; Forecasting; Humans; Pandemics
PubMed: 35487155
DOI: 10.1016/j.epidem.2022.100564 -
Proceedings. Biological Sciences Jun 2022When we bring to mind something we have seen before, our eyes spontaneously unfold in a sequential pattern strikingly similar to that made during the original encounter,...
When we bring to mind something we have seen before, our eyes spontaneously unfold in a sequential pattern strikingly similar to that made during the original encounter, even in the absence of supporting visual input. Oculomotor movements of the eye may then serve the opposite purpose of acquiring new visual information; they may serve as self-generated cues, pointing to stored memories. Over 50 years ago Donald Hebb, the forefather of cognitive neuroscience, posited that such a sequential of eye movements supports our ability to mentally recreate visuospatial relations during episodic remembering. However, direct evidence for this influential claim is lacking. Here we isolate the sequential properties of spontaneous eye movements during encoding and retrieval in a pure recall memory task and capture their encoding-retrieval overlap. Critically, we show that the fidelity with which a series of consecutive eye movements from initial encoding is sequentially retained during subsequent retrieval predicts the quality of the recalled memory. Our findings provide direct evidence that such are replayed to assemble and reconstruct spatio-temporal relations as we remember and further suggest that distinct scanpath properties differentially contribute depending on the nature of the goal-relevant memory.
Topics: Cues; Eye Movements; Memory, Episodic; Mental Recall
PubMed: 35703049
DOI: 10.1098/rspb.2022.0964 -
Behavioral Sciences (Basel, Switzerland) Aug 2022This research investigated the link between ethical leadership and innovative work behavior by examining the role of self-efficacy as a mediating factor and the...
This research investigated the link between ethical leadership and innovative work behavior by examining the role of self-efficacy as a mediating factor and the sequential mediation of self-efficacy and work engagement. Using a survey approach, data were collected from 441 bank employees in the southern region of Thailand. The findings of the structural equation modeling (SEM) analysis revealed an association between ethical leadership and innovative work behavior and self-efficacy, respectively. Work engagement and innovative work behavior were both linked to self-efficacy. Work engagement was associated with innovative work behavior. According to the mediation analysis results, self-efficacy appeared to mediate the relationship between ethical leadership and innovative work behavior. Ultimately, it was shown that self-efficacy and work engagement were sequentially mediated by ethical leadership and innovative work behavior. This research provides insight into the understanding of the connection between ethical leadership and innovative work behavior. The key contributions of this research are the exploration-mediating function of self-efficacy and the sequential mediation roles of self-efficacy and work engagement.
PubMed: 36004837
DOI: 10.3390/bs12080266