Algebraic synchronization criterion and computing reset words

We refine a uniform algebraic approach for deriving upper bounds on reset thresholds of synchronizing automata. We express the condition that an automaton is synchronizing in terms of linear algebra, and obtain upper bounds for the reset thresholds of automata with a short word of a small rank. The results are applied to make several improvements in the area. We improve the best general upper bound for reset thresholds of finite prefix codes (Huffman codes): we show that an $n$-state synchronizing decoder has a reset word of length at most $O(n \log^3 n)$. In addition to that, we prove that the expected reset threshold of a uniformly random synchronizing binary $n$-state decoder is at most $O(n \log n)$. We also show that for any non-unary alphabet there exist decoders whose reset threshold is in $\varTheta(n)$. We prove the \v{C}ern\'{y} conjecture for $n$-state automata with a letter of rank at most $\sqrt[3]{6n-6}$. In another corollary, based on the recent results of Nicaud, we show that the probability that the \v{C}ern\'y conjecture does not hold for a random synchronizing binary automaton is exponentially small in terms of the number of states, and also that the expected value of the reset threshold of an $n$-state random synchronizing binary automaton is at most $n^{3/2+o(1)}$. Moreover, reset words of lengths within all of our bounds are computable in polynomial time. We present suitable algorithms for this task for various classes of automata, such as (quasi-)one-cluster and (quasi-)Eulerian automata, for which our results can be applied.Comment: 18 pages, 2 figure

Development of an international standard set of outcome measures for patients with atrial fibrillation: a report of the International Consortium for Health Outcomes Measurement (ICHOM) atrial fibrillation working group.

AIMS: As health systems around the world increasingly look to measure and improve the value of care that they provide to patients, being able to measure the outcomes that matter most to patients is vital. To support the shift towards value-based health care in atrial fibrillation (AF), the International Consortium for Health Outcomes Measurement (ICHOM) assembled an international Working Group (WG) of 30 volunteers, including health professionals and patient representatives to develop a standardized minimum set of outcomes for benchmarking care delivery in clinical settings. METHODS AND RESULTS: Using an online-modified Delphi process, outcomes important to patients and health professionals were selected and categorized into (i) long-term consequences of disease outcomes, (ii) complications of treatment outcomes, and (iii) patient-reported outcomes. The WG identified demographic and clinical variables for use as case-mix risk adjusters. These included baseline demographics, comorbidities, cognitive function, date of diagnosis, disease duration, medications prescribed and AF procedures, as well as smoking, body mass index (BMI), alcohol intake, and physical activity. Where appropriate, and for ease of implementation, standardization of outcomes and case-mix variables was achieved using ICD codes. The standard set underwent an open review process in which over 80% of patients surveyed agreed with the outcomes captured by the standard set. CONCLUSION: Implementation of these consensus recommendations could help institutions to monitor, compare and improve the quality and delivery of chronic AF care. Their consistent definition and collection, using ICD codes where applicable, could also broaden the implementation of more patient-centric clinical outcomes research in AF

ApoB siRNA-induced Liver Steatosis is Resistant to Clearance by the Loss of Fatty Acid Transport Protein 5 (Fatp5)

The association between hypercholesterolemia and elevated serum apolipoprotein B (APOB) has generated interest in APOB as a therapeutic target for patients at risk of developing cardiovascular disease. In the clinic, mipomersen, an antisense oligonucleotide (ASO) APOB inhibitor, was associated with a trend toward increased hepatic triglycerides, and liver steatosis remains a concern. We found that siRNA-mediated knockdown of ApoB led to elevated hepatic triglycerides and liver steatosis in mice engineered to exhibit a human-like lipid profile. Many genes required for fatty acid synthesis were reduced, suggesting that the observed elevation in hepatic triglycerides is maintained by the cell through fatty acid uptake as opposed to fatty acid synthesis. Fatty acid transport protein 5 (Fatp5/Slc27a5) is required for long chain fatty acid (LCFA) uptake and bile acid reconjugation by the liver. Fatp5 knockout mice exhibited lower levels of hepatic triglycerides due to decreased fatty acid uptake, and shRNA-mediated knockdown of Fatp5 protected mice from diet-induced liver steatosis. Here, we evaluated if siRNA-mediated knockdown of Fatp5 was sufficient to alleviate ApoB knockdown-induced steatosis. We determined that, although Fatp5 siRNA treatment was sufficient to increase the proportion of unconjugated bile acids 100-fold, consistent with FATP5's role in bile acid reconjugation, Fatp5 knockdown failed to influence the degree, zonal distribution, or composition of the hepatic triglycerides that accumulated following ApoB siRNA treatment

Adaptation of a Mindfulness-Based Intervention for Incarcerated Young Men: a Feasibility Study

Objectives: Incarcerated young men commonly experience problems with impulsivity and emotional dysregulation. Mindfulness training could help but the evidence is limited. This study developed and piloted an adapted mindfulness-based intervention for this group (n = 48). Methods: Feasibility of recruitment, retention, and data collection were assessed, and the effectiveness of mindfulness training measured using validated questionnaires. Twenty-five qualitative interviews were conducted to explore experiences of the course, and barriers and facilitators to taking part. Results: The findings indicated that recruitment and retention to mindfulness training groups was a challenge despite trying various adaptive strategies to improve interest, relevance, and acceptability. Quantitative data collection was feasible at baseline and post-course. There were significant improvements following training in impulsivity (effect size [ES] 0.72, 95% CI 0.32–1.11, p = 0.001), mental wellbeing (ES 0.50; 95% CI 0.18–0.80; p = 0.003), inner resilience (comprehensibility ES 0.35; 95% CI − 0.02–0.68; p = 0.03), and mindfulness (ES 0.32; 95% CI 0.03–0.60; p = 0.03). The majority (70%) of participants reported finding the course uncomfortable or disconcerting at first but if they chose to remain, this changed as they began to experience benefit. The body scan and breathing techniques were reported as being most helpful. Positive experiences included better sleep, less stress, feeling more in control, and improved relationships. Conclusions: Developing and delivering mindfulness training for incarcerated young men is feasible and may be beneficial, but recruitment and retention may limit reach. Further studies are required that include a control group

Cognitive Control in Adolescence: Neural Underpinnings and Relation to Self-Report Behaviors

Adolescence is commonly characterized by impulsivity, poor decision-making, and lack of foresight. However, the developmental neural underpinnings of these characteristics are not well established.To test the hypothesis that these adolescent behaviors are linked to under-developed proactive control mechanisms, the present study employed a hybrid block/event-related functional Magnetic Resonance Imaging (fMRI) Stroop paradigm combined with self-report questionnaires in a large sample of adolescents and adults, ranging in age from 14 to 25. Compared to adults, adolescents under-activated a set of brain regions implicated in proactive top-down control across task blocks comprised of difficult and easy trials. Moreover, the magnitude of lateral prefrontal activity in adolescents predicted self-report measures of impulse control, foresight, and resistance to peer pressure. Consistent with reactive compensatory mechanisms to reduced proactive control, older adolescents exhibited elevated transient activity in regions implicated in response-related interference resolution.Collectively, these results suggest that maturation of cognitive control may be partly mediated by earlier development of neural systems supporting reactive control and delayed development of systems supporting proactive control. Importantly, the development of these mechanisms is associated with cognitive control in real-life behaviors

Niemann-Pick disease type C

Niemann-Pick C disease (NP-C) is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120 000 live births. The broad clinical spectrum ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. The neurological involvement defines the disease severity in most patients but is typically preceded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in infancy or childhood). The first neurological symptoms vary with age of onset: delay in developmental motor milestones (early infantile period), gait problems, falls, clumsiness, cataplexy, school problems (late infantile and juvenile period), and ataxia not unfrequently following initial psychiatric disturbances (adult form). The most characteristic sign is vertical supranuclear gaze palsy. The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Cataplexy, seizures and dystonia are other common features. NP-C is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families) or the NPC2 genes. The exact functions of the NPC1 and NPC2 proteins are still unclear. NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides. Clinical examination should include comprehensive neurological and ophthalmological evaluations. The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes) after staining with filipin. Pronounced abnormalities are observed in about 80% of the cases, mild to moderate alterations in the remainder ("variant" biochemical phenotype). Genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis. The differential diagnosis may include other lipidoses; idiopathic neonatal hepatitis and other causes of cholestatic icterus should be considered in neonates, and conditions with cerebellar ataxia, dystonia, cataplexy and supranuclear gaze palsy in older children and adults. Symptomatic management of patients is crucial. A first product, miglustat, has been granted marketing authorization in Europe and several other countries for specific treatment of the neurological manifestations. The prognosis largely correlates with the age at onset of the neurological manifestations

E-education in pathology including certification of e-institutions

E–education or electronically transferred continuous education in pathology is one major application of virtual microscopy. The basic conditions and properties of acoustic and visual information transfer, of teaching and learning processes, as well as of knowledge and competence, influence its implementation to a high degree. Educational programs and structures can be judged by access to the basic conditions, by description of the teaching resources, methods, and its program, as well as by identification of competences, and development of an appropriate evaluation system. Classic teaching and learning methods present a constant, usually non-reversible information flow. They are subject to personal circumstances of both teacher and student. The methods of information presentation need to be distinguished between static and dynamic, between acoustic and visual ones. Electronic tools in education include local manually assisted tools (language assistants, computer-assisted design, etc.), local passive tools (slides, movies, sounds, music), open access tools (internet), and specific tools such as Webinars. From the medical point of view information content can be divided into constant (gross and microscopic anatomy) and variable (disease related) items. Most open access available medical courses teach constant information such as anatomy or physiology. Mandatory teaching resources are image archives with user–controlled navigation and labelling, student–oriented user manuals, discussion forums, and expert consultation. A classic undergraduate electronic educational system is WebMic which presents with histology lectures. An example designed for postgraduate teaching is the digital lung pathology system. It includes a description of diagnostic and therapeutic features of 60 rare and common lung diseases, partly in multimedia presentation. Combining multimedia features with the organization structures of a virtual pathology institution will result in a virtual pathology education institution (VPEI), which can develop to a partly automated distant learning faculty in medicine

Risk-taking, delay discounting, and time perspective in adolescent gamblers: an experimental study

Previous research has demonstrated that adult pathological gamblers (compared to controls) show risk-proneness, foreshortened time horizon, and preference for immediate rewards. No study has ever examined the interplay of these factors in adolescent gambling. A total of 104 adolescents took part in the research. Two equal-number groups of adolescent non-problem and problem gamblers, defined using the South Oaks Gambling Screen-Revised for Adolescents (SOGS-RA), were administered the Balloon Analogue Risk Task (BART), the Consideration of Future Consequences (CFC-14) Scale, and the Monetary Choice Questionnaire (MCQ). Adolescent problem gamblers were found to be more risk-prone, more oriented to the present, and to discount delay rewards more steeply than adolescent non-problem gamblers. Results of logistic regression analysis revealed that BART, MCQ, and CFC scores predicted gambling severity. These novel finding provides the first evidence of an association among problematic gambling, high risk-taking proneness, steep delay discounting, and foreshortened time horizon among adolescents. It may be that excessive gambling induces shortsighted behaviors that, in turn, facilitate gambling involvement

The influence of the accessory genome on bacterial pathogen evolution

Bacterial pathogens exhibit significant variation in their genomic content of virulence factors. This reflects the abundance of strategies pathogens evolved to infect host organisms by suppressing host immunity. Molecular arms-races have been a strong driving force for the evolution of pathogenicity, with pathogens often encoding overlapping or redundant functions, such as type III protein secretion effectors and hosts encoding ever more sophisticated immune systems. The pathogens’ frequent exposure to other microbes, either in their host or in the environment, provides opportunities for the acquisition or interchange of mobile genetic elements. These DNA elements accessorise the core genome and can play major roles in shaping genome structure and altering the complement of virulence factors. Here, we review the different mobile genetic elements focusing on the more recent discoveries and highlighting their role in shaping bacterial pathogen evolution