Associations between lifestyle factors and multidimensional frailty:A cross-sectional study among community-dwelling older people

BACKGROUND: Multidimensional frailty, including physical, psychological, and social components, is associated to disability, lower quality of life, increased healthcare utilization, and mortality. In order to prevent or delay frailty, more knowledge of its determinants is necessary; one of these determinants is lifestyle. The aim of this study is to determine the association between lifestyle factors smoking, alcohol use, nutrition, physical activity, and multidimensional frailty. METHODS: This cross-sectional study was conducted in two samples comprising in total 45,336 Dutch community-dwelling individuals aged 65 years or older. These samples completed a questionnaire including questions about smoking, alcohol use, physical activity, sociodemographic factors (both samples), and nutrition (one sample). Multidimensional frailty was assessed with the Tilburg Frailty Indicator (TFI). RESULTS: Higher alcohol consumption, physical activity, healthy nutrition, and less smoking were associated with less total, physical, psychological and social frailty after controlling for effects of other lifestyle factors and sociodemographic characteristics of the participants (age, gender, marital status, education, income). Effects of physical activity on total and physical frailty were up to considerable, whereas the effects of other lifestyle factors on frailty were small. CONCLUSIONS: The four lifestyle factors were not only associated with physical frailty but also with psychological and social frailty. The different associations of frailty domains with lifestyle factors emphasize the importance of assessing frailty broadly and thus to pay attention to the multidimensional nature of this concept. The findings offer healthcare professionals starting points for interventions with the purpose to prevent or delay the onset of frailty, so community-dwelling older people have the possibility to aging in place accompanied by a good quality of life

Functional outcomes across development in offspring of parents with bipolar disorder

Objective: Whereas the risk and course of psychopathology in offspring of parents with bipolar disorder (BD) have been the primary focus of high-risk offspring studies to date, functional outcomes have not been given much attention. We present a systematic review of functional outcomes and quality of life (QoL) across development in offspring of parents with BD and aim to explore the role of offspring psychopathology in these outcomes. Method: We searched Embase, MEDLINE, PsycINFO, Web of Science, Cochrane Central, and Google Scholar from inception to June 24, 2022, for studies referring to functional outcomes (global, social, academic or occupational) or QoL in offspring of parents with BD. Results: From the 6470 records identified, 39 studies were retained (global = 17; social = 17; school = 16; occupational = 3; QoL = 5), including 13 studies that examined multiple domains. For all domains, high heterogeneity was found in study methods and quality. Only 56 % of studies adjusted for offspring psychopathology, impeding interpretation. Global and social functioning generally seemed to be impaired among older offspring (&gt;16 years). Academic performance appeared to be unaffected. School behavior, occupational functioning, and QoL showed mixed results. Offspring psychopathology is associated with social functioning, but the relationship of offspring psychopathology with other domains is less clear. Conclusion: Studies on functional outcome in offspring of parents with BD show predominantly mixed results. Inconsistent adjustment of psychopathology and age limits conclusive interpretation. Functional outcomes should be prioritized as research topics in high-risk studies and the potential associations between familial risk status, offspring psychopathology, and age may inform prevention strategies.</p

DNA damage activates a complex transcriptional response in murine lymphocytes that includes both physiological and cancer-predisposition programs

BACKGROUND: Double strand (ds) DNA breaks are a form of DNA damage that can be generated from both genotoxic exposures and physiologic processes, can disrupt cellular functions and can be lethal if not repaired properly. Physiologic dsDNA breaks are generated in a variety of normal cellular functions, including the RAG endonuclease-mediated rearrangement of antigen receptor genes during the normal development of lymphocytes. We previously showed that physiologic breaks initiate lymphocyte development-specific transcriptional programs. Here we compare transcriptional responses to physiological DNA breaks with responses to genotoxic DNA damage induced by ionizing radiation. RESULTS: We identified a central lymphocyte-specific transcriptional response common to both physiologic and genotoxic breaks, which includes many lymphocyte developmental processes. Genotoxic damage causes robust alterations to pathways associated with B cell activation and increased proliferation, suggesting that genotoxic damage initiates not only the normal B cell maturation processes but also mimics activated B cell response to antigenic agents. Notably, changes including elevated levels of expression of Kras and mmu-miR-155 and the repression of Socs1 were observed following genotoxic damage, reflecting induction of a cancer-prone phenotype. CONCLUSIONS: Comparing these transcriptional responses provides a greater understanding of the mechanisms cells use in the differentiation between types of DNA damage and the potential consequences of different sources of damage. These results suggest genotoxic damage may induce a unique cancer-prone phenotype and processes mimicking activated B cell response to antigenic agents, as well as the normal B cell maturation processes

A theory of normed simulations

In existing simulation proof techniques, a single step in a lower-level specification may be simulated by an extended execution fragment in a higher-level one. As a result, it is cumbersome to mechanize these techniques using general purpose theorem provers. Moreover, it is undecidable whether a given relation is a simulation, even if tautology checking is decidable for the underlying specification logic. This paper introduces various types of normed simulations. In a normed simulation, each step in a lower-level specification can be simulated by at most one step in the higher-level one, for any related pair of states. In earlier work we demonstrated that normed simulations are quite useful as a vehicle for the formalization of refinement proofs via theorem provers. Here we show that normed simulations also have pleasant theoretical properties: (1) under some reasonable assumptions, it is decidable whether a given relation is a normed forward simulation, provided tautology checking is decidable for the underlying logic; (2) at the semantic level, normed forward and backward simulations together form a complete proof method for establishing behavior inclusion, provided that the higher-level specification has finite invisible nondeterminism.Comment: 31 pages, 10figure

Should We Learn Probabilistic Models for Model Checking? A New Approach and An Empirical Study

Many automated system analysis techniques (e.g., model checking, model-based testing) rely on first obtaining a model of the system under analysis. System modeling is often done manually, which is often considered as a hindrance to adopt model-based system analysis and development techniques. To overcome this problem, researchers have proposed to automatically "learn" models based on sample system executions and shown that the learned models can be useful sometimes. There are however many questions to be answered. For instance, how much shall we generalize from the observed samples and how fast would learning converge? Or, would the analysis result based on the learned model be more accurate than the estimation we could have obtained by sampling many system executions within the same amount of time? In this work, we investigate existing algorithms for learning probabilistic models for model checking, propose an evolution-based approach for better controlling the degree of generalization and conduct an empirical study in order to answer the questions. One of our findings is that the effectiveness of learning may sometimes be limited.Comment: 15 pages, plus 2 reference pages, accepted by FASE 2017 in ETAP

KAP-1 promotes resection of broken DNA ends not protected by γ-H2AX and 53BP1 in G1-phase lymphocytes

The resection of broken DNA ends is required for DNA double-strand break (DSB) repair by homologous recombination (HR) but can inhibit normal repair by nonhomologous end joining (NHEJ), the main DSB repair pathway in G(1)-phase cells. Antigen receptor gene assembly proceeds through DNA DSB intermediates generated in G(1)-phase lymphocytes by the RAG endonuclease. These DSBs activate ATM, which phosphorylates H2AX, forming γ-H2AX in flanking chromatin. γ-H2AX prevents CtIP from initiating resection of RAG DSBs. Whether there are additional proteins required to promote resection of these DNA ends is not known. KRAB-associated protein 1 (KAP-1) (TRIM28) is a transcriptional repressor that modulates chromatin structure and has been implicated in the repair of DNA DSBs in heterochromatin. Here, we show that in murine G(1)-phase lymphocytes, KAP-1 promotes resection of DSBs that are not protected by H2AX and its downstream effector 53BP1. In these murine cells, KAP-1 activity in DNA end resection is attenuated by a single-amino-acid change that reflects a KAP-1 polymorphism between primates and other mammalian species. These findings establish KAP-1 as a component of the machinery that can resect DNA ends in G(1)-phase cells and suggest that there may be species-specific features to this activity

Accelerated Model Checking of Parametric Markov Chains

Parametric Markov chains occur quite naturally in various applications: they can be used for a conservative analysis of probabilistic systems (no matter how the parameter is chosen, the system works to specification); they can be used to find optimal settings for a parameter; they can be used to visualise the influence of system parameters; and they can be used to make it easy to adjust the analysis for the case that parameters change. Unfortunately, these advancements come at a cost: parametric model checking is---or rather was---often slow. To make the analysis of parametric Markov models scale, we need three ingredients: clever algorithms, the right data structure, and good engineering. Clever algorithms are often the main (or sole) selling point; and we face the trouble that this paper focuses on -- the latter ingredients to efficient model checking. Consequently, our easiest claim to fame is in the speed-up we have often realised when comparing to the state of the art

Verification of a distributed summation algorithm

A correctness proof of a variant of Segall's Propagation of Information with Feedback protocol is presented. The proof, which is carried out within the I/O automata model of Lynch and Tuttle, is standard except for the use of a prophecy variable. The aim of this paper is to show that, unlike what has been suggested in the literature, assertional methods based on invariant reasoning support an intuitive way to think about and understand this algorithm

Variability in benefit from intensive insulin therapy on cardiovascular events in individuals with type 1 diabetes: A post hoc analysis of the DCCT/EDIC study

Aim: To evaluate presence of treatment effect heterogeneity of intensive insulin therapy (INT) on occurrence of major adverse cardiovascular events (MACE) in individuals with type 1 diabetes. Methods: In participants from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, individual treatment effect of INT (≥3 daily insulin injections/insulin pump therapy) versus conventional therapy (once/twice daily insulin) on the risk of MACE was estimated using a penalized Cox regression model including treatment-by-covariate interaction terms. Results: In 1441 participants, 120 first MACE events were observed and 1279 individuals (89%) were predicted to benefit from INT with regard to MACE risk reduction. The study population was divided into four groups based on predicted treatment effect: one group with no predicted benefit and three tertiles with predicted treatment benefit. The median absolute reduction in 30-year risk of MACE across groups of predicted treatment effect ranged from −0.2% (i.e. risk increase; interquartile range [IQR] −0.1% to −0.3%) in the group with no predicted benefit to 6.6% (i.e. risk reduction; IQR 3.8%–10.9%; number needed to treat 15) in the highest tertile of predicted benefit. The observed benefit of preventing microvascular complications was stable across all subgroups of predicted MACE benefit. Conclusions: Although INT reduces the risk of MACE in the majority of individuals with type 1 diabetes, benefit varies substantially. These individual differences in the effect of INT underline the necessity for a better understanding of the individual response to intensive treatment

Automatic Verification and Conformance Testing for Validating Safety Properties of Reactive Systems

International audienceThis paper presents a combination of verification and conformance testing techniques for the formal validation of reactive systems. A formal specification of a system, which may be infinite-state, and a set of safety properties are assumed. Each property is verified on the specification using automatic techniques based on abstract interpretation, which are sound, but, as a price to pay for automation, are not necessarily complete. Next, for each property, a test case is automatically generated from the specification and the property, and is executed on a black-box implementation of the system to detect violations of the property by the implementation and non-conformances between implementation and specification. If the verification step did not conclude, the test execution may also detect violations of the property by the specificatio