The high burden of cognitive impairment in hemodialysis and chronic kidney disease (CKD) patients has only recently become recognized. Up to 70% of hemodialysis patients aged 55 years and older have ...moderate to severe chronic cognitive impairment, yet it is largely undiagnosed. Recent studies describe the strong graded relation between estimated glomerular filtration rate and cognitive function in CKD patients. The process of conventional hemodialysis may induce recurrent episodes of acute cerebral ischemia, which, in turn, may contribute to acute decline in cognitive function during dialysis. Thus, the worst time to communicate with dialysis patients may be during the hemodialysis session. Both symptomatic and occult, subclinical ischemic cerebrovascular disease appears to play a large role in a proposed model of accelerated vascular cognitive impairment in these populations. Severe cognitive impairment or dementia among hemodialysis patients is associated with an approximately 2-fold increased risk of both mortality and dialysis withdrawal. Predialysis cognitive screening and adding dementia to the list of comorbidities on Form 2728 would provide critical information regarding the benefit versus risks of receiving dialysis. It could also improve quality of care and outcomes by raising clinicians' awareness of the potential effects of cognitive impairment on medication, fluid, and dietary compliance and the ability to make advance directive decisions among dialysis patients. Although much remains to be learned regarding the pathophysiology of cognitive impairment in kidney disease, the public health implications of this substantial burden are immediate.
Receding Horizon Temporal Logic Planning Wongpiromsarn, T.; Topcu, U.; Murray, R. M.
IEEE transactions on automatic control,
11/2012, Volume:
57, Issue:
11
Journal Article
Peer reviewed
Open access
We present a methodology for automatic synthesis of embedded control software that incorporates a class of linear temporal logic (LTL) specifications sufficient to describe a wide range of properties ...including safety, stability, progress, obligation, response and guarantee. To alleviate the associated computational complexity of LTL synthesis, we propose a receding horizon framework that effectively reduces the synthesis problem into a set of smaller problems. The proposed control structure consists of a goal generator, a trajectory planner, and a continuous controller. The goal generator reduces the trajectory generation problem into a sequence of smaller problems of short horizon while preserving the desired system-level temporal properties. Subsequently, in each iteration, the trajectory planner solves the corresponding short-horizon problem with the currently observed state as the initial state and generates a feasible trajectory to be implemented by the continuous controller. Based on the simulation property, we show that the composition of the goal generator, trajectory planner and continuous controller and the corresponding receding horizon framework guarantee the correctness of the system with respect to its specification regardless of the environment in which the system operates. In addition, we present a response mechanism to handle failures that may occur due to a mismatch between the actual system and its model. The effectiveness of the proposed technique is demonstrated through an example of an autonomous vehicle navigating an urban environment. This example also illustrates that the system is not only robust with respect to exogenous disturbances but is also capable of properly handling violation of the environment assumption that is explicitly stated as part of the system specification.
Epidemiological evidence demonstrates that cannabis use is associated with an increased risk of psychotic outcomes, and confirms a dose‐response relationship between the level of use and the risk of ...later psychosis. High‐potency cannabis and synthetic cannabinoids carry the greatest risk. Experimental administration of tetrahydrocannabinol, the active ingredient of cannabis, induces transient psychosis in normal subjects, but this effect can be ameliorated by co‐administration of cannabidiol. This latter is a constituent of traditional hashish, but is largely absent from modern high‐potency forms of cannabis. Argument continues over the extent to which genetic predisposition is correlated to, or interacts with, cannabis use, and what proportion of psychosis could be prevented by minimizing heavy use. As yet, there is not convincing evidence that cannabis use increases risk of other psychiatric disorders, but there are no such doubts concerning its detrimental effect on cognitive function. All of the negative aspects are magnified if use starts in early adolescence. Irrespective of whether use of cannabis is decriminalized or legalized, the evidence that it is a component cause of psychosis is now sufficient for public health messages outlining the risk, especially of regular use of high‐potency cannabis and synthetic cannabinoids.
After a median follow-up of 4.7 years, there were 1.6 more deaths per 1000 person-years among healthy older adults who were randomly assigned to receive aspirin than among those who received placebo. ...Cancer-related death accounted for much of the excess mortality.
We consider the control of interacting subsystems whose dynamics and constraints are decoupled, but whose state vectors are coupled non-separably in a single cost function of a finite horizon optimal ...control problem. For a given cost structure, we generate distributed optimal control problems for each subsystem and establish that a distributed receding horizon control implementation is stabilizing to a neighborhood of the objective state. The implementation requires synchronous updates and the exchange of the most recent optimal control trajectory between coupled subsystems prior to each update. The key requirements for stability are that each subsystem not deviate too far from the previous open-loop state trajectory, and that the receding horizon updates happen sufficiently fast. The venue of multi-vehicle formation stabilization is used to demonstrate the distributed implementation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
DnaA is a conserved key regulator of replication initiation in bacteria, and is homologous to ORC proteins in archaea and in eukaryotic cells. The ATPase binds to several high affinity binding sites ...at the origin region and upon an unknown molecular trigger, spreads to several adjacent sites, inducing the formation of a helical super structure leading to initiation of replication. Using FRAP analysis of a functional YFP-DnaA allele in Bacillus subtilis, we show that DnaA is bound to oriC with a half-time of 2.5 seconds. DnaA shows similarly high turnover at the replication machinery, where DnaA is bound to DNA polymerase via YabA. The absence of YabA increases the half time binding of DnaA at oriC, showing that YabA plays a dual role in the regulation of DnaA, as a tether at the replication forks, and as a chaser at origin regions. Likewise, a deletion of soj (encoding a ParA protein) leads to an increase in residence time and to overinitiation, while a mutation in DnaA that leads to lowered initiation frequency, due to a reduced ATPase activity, shows a decreased residence time on binding sites. Finally, our single molecule tracking experiments show that DnaA rapidly moves between chromosomal binding sites, and does not arrest for more than few hundreds of milliseconds. In Escherichia coli, DnaA also shows low residence times in the range of 200 ms and oscillates between spatially opposite chromosome regions in a time frame of one to two seconds, independently of ongoing transcription. Thus, DnaA shows extremely rapid binding turnover on the chromosome including oriC regions in two bacterial species, which is influenced by Soj and YabA proteins in B. subtilis, and is crucial for balanced initiation control, likely preventing fatal premature multimerization and strand opening of DnaA at oriC.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We examined longitudinally the course and predictors of treatment resistance in a large cohort of first-episode psychosis (FEP) patients from initiation of antipsychotic treatment. We hypothesized ...that antipsychotic treatment resistance is: (a) present at illness onset; and (b) differentially associated with clinical and demographic factors.
The study sample comprised 323 FEP patients who were studied at first contact and at 10-year follow-up. We collated clinical information on severity of symptoms, antipsychotic medication and treatment adherence during the follow-up period to determine the presence, course and predictors of treatment resistance.
From the 23% of the patients, who were treatment resistant, 84% were treatment resistant from illness onset. Multivariable regression analysis revealed that diagnosis of schizophrenia, negative symptoms, younger age at onset, and longer duration of untreated psychosis predicted treatment resistance from illness onset.
The striking majority of treatment-resistant patients do not respond to first-line antipsychotic treatment even at time of FEP. Clinicians must be alert to this subgroup of patients and consider clozapine treatment as early as possible during the first presentation of psychosis.
There is consistent and strong evidence that the incidence of all psychoses is higher in many migrant and minority ethnic populations in a number of countries. The reasons for this are, however, ...unclear and a wide range of explanations have been proposed, from genetic to neurodevelopmental to psychosocial. In this article, we describe and evaluate the available evidence for and against each of these. What this shows is that: (1) there are few studies that have directly investigated specific risk factors in migrant and minority ethnic populations, with often only 1 or 2 studies of any relevance to specific explanations and (2) what limited research there has been tends to implicate a diverse range of social factors (including childhood separation from parents, discrimination and, at an area level, ethnic density) as being of potential importance. In an attempt to synthesize these disparate findings and provide a basis for future research, we go on to propose an integrated model--of a sociodevelopmental pathway to psychosis--to account for the reported high rates in migrant and minority ethnic populations. Aspects of this model will be directly tested in a new Europe-wide incidence and case-control study that we will conduct over the next 3 years, as part of the European Network of National Schizophrenia Networks studying Gene-Environment Interactions programme.
Fluorescent microscopy is the primary method to study DNA organization within cells. However, the variability and low signal/noise commonly associated with live-cell time-lapse imaging challenges ...quantitative measurements. In particular, obtaining quantitative or mechanistic insight often depends on the accurate tracking of fluorescent particles. Here, we present ★Track, an inference method that determines the most likely temporal tracking of replicating intracellular particles such DNA loci while accounting for missing, merged, and spurious detections. It allows the accurate prediction of particle copy numbers as well as the timing of replication events. We demonstrate ★Track’s abilities and gain new insight into plasmid copy number control and the volume dependence of bacterial chromosome replication initiation. By enabling the accurate tracking of DNA loci, ★Track can help to uncover the mechanistic principles of chromosome organization and dynamics across a range of systems.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The therapeutic utility of siRNAs is limited by the requirement for complex formulations to deliver them to tissues. If potent single-stranded RNAs could be identified, they would provide a simpler ...path to pharmacological agents. Here, we describe single-stranded siRNAs (ss-siRNAs) that silence gene expression in animals absent lipid formulation. Effective ss-siRNAs were identified by iterative design by determining structure-activity relationships correlating chemically modified single strands and Argonaute 2 (AGO2) activities, potency in cells, nuclease stability, and pharmacokinetics. We find that the passenger strand is not necessary for potent gene silencing. The guide-strand activity requires AGO2, demonstrating action through the RNAi pathway. ss-siRNA action requires a 5′ phosphate to achieve activity in vivo, and we developed a metabolically stable 5′-(E)-vinylphosphonate (5′-VP) with conformation and sterioelectronic properties similar to the natural phosphate. Identification of potent ss-siRNAs offers an additional option for RNAi therapeutics and an alternate perspective on RNAi mechanism.
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► Chemically modified single-stranded siRNAs silence gene expression in animals ► ss-siRNAs require 5′ phosphate and association with AGO2 for gene silencing ► Passenger strand is dispensable for potent RNAi-mediated gene silencing ► Single-stranded siRNAs provide an alternate option for RNAi therapeutics
Chemically modified RNA oligonucleotides load into Ago2-containing RISC complexes to effect RNA silencing without the need for a passenger strand. These single-stranded siRNAs can be applied directly in animals and thus offer new alternatives for developing therapeutics and diagnostics.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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