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El 4-metil anisol se oxida en una primera etapa para formar un catión radical, el cual sufre una deprotonación. Aunque la literatura reporta un pico de oxidación correspondiente a la pérdida de dos electrones, se han encontrado, en este trabajo, condiciones bajo las cuales ese pico se desdobla en dos de un electrón cada uno. El catión radical es deprotonado para formar un radical neutro, el cual sufre una oxidación posterior a una especie catiónica. Hay dos tipos de reacción que pueden ocurrir, dependiendo de las condiciones: ataque nucleofílico a la especie intermediaria por el acetonitrilo, con posterior hidrólisis para formar una acetamida o polimerización del 4-metil anisol.4-methyl anisole is oxidized, in a first stage to produce a cation radical that undergoes deprotonation. Although a single oxidation peak is reported in literature corresponding to the loss of two electrons, we have been able to split it into a couple of peaks for one electron each. The cation radical is deprotonated to form a neutral radical which oxidizes to a cationic species. Two kind of reactions can occur, depending upon the reaction conditions: Whether a nucleophylic attack of the acetonitrile on the intermediate species, or polymerization of 4-methyl anisole.

El 4-metil anisol se oxida en una primera etapa para formar un catión radical, el cual sufre una deprotonación. Aunque la literatura reporta un pico de oxidación correspondiente a la pérdida de dos electrones, se han encontrado, en este trabajo, condiciones bajo las cuales ese pico se desdobla en dos de un electrón cada uno. El catión radical es deprotonado para formar un radical neutro, el cual sufre una oxidación posterior a una especie catiónica. Hay dos tipos de reacción que pueden ocurrir, dependiendo de las condiciones: ataque nucleofílico a la especie intermediaria por el acetonitrilo, con posterior hidrólisis para formar una acetamida o polimerización del 4-metil anisol.

Fibromyalgia (FM) is often accompanied by chronic fatigue syndrome (CFS). It is a poorly understood disorder that mainly affects women and leads to chronic pain, fatigue, and insomnia, among other symptoms, which decrease quality of life. Due to the inefficiency of current pharmacological treatments, increasing interest is being directed towards non-pharmacological multicomponent therapies. However, nutrition and chronobiology are often overlooked when developing multicomponent therapies. This narrative and critical review explore the relevance of nutritional and chronobiological strategies in the therapeutic management of FM and the often-associated CFS. Reviewed literature offers scientific evidence for the association of dietary habits, nutrient levels, body composition, gut microbiota imbalance, chronobiological alterations, and their interrelation with the development and severity of symptoms. This review highlights the key role of nutrition and chronobiology as relevant and indispensable components in a multidisciplinary approach to FM and CFS.

Trimethylamine-N-oxide (TMAO) is the main diet-induced metabolite produced by the gut microbiota, and it is mainly eliminated through renal excretion. TMAO has been correlated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) and related complications, such as cardiovascular mortality or major adverse cardiovascular events (MACE). Meta-analyses have postulated that high circulating TMAO levels are associated with an increased risk of cardiovascular events and all-cause mortality, but the link between TMAO and CVD remains not fully consistent. The results of prospective studies vary depending on the target population and the outcome studied, and the adjustment for renal function tends to decrease or reverse the significant association between TMAO and the outcome studied, strongly suggesting that the association is substantially mediated by renal function. Importantly, one Mendelian randomization study did not find a significant association between genetically predicted higher TMAO levels and cardiometabolic disease, but another found a positive causal relationship between TMAO levels and systolic blood pressure, which-at least in part-could explain the link with renal function. The mechanisms by which TMAO can increase this risk are not clearly elucidated, but current evidence indicates that TMAO induces cholesterol metabolism alterations, inflammation, endothelial dysfunction, and platelet activation. Overall, there is no fully conclusive evidence that TMAO is a causal factor of ASCVD, and, especially, whether TMAO induces or just is a marker of hypertension and renal dysfunction requires further study.

Background: regular physical exercise is essential to maintain or improve functional capacity in older adults. Multimorbidity, functional limitation, social barriers and currently, coronavirus disease of 2019, among others, have increased the need for home-based exercise (HBE) programmes and digital health interventions (DHI). Our objective was to evaluate the effectiveness of HBE programs delivered by DHI on physical function, health-related quality of life (HRQoL) improvement and falls reduction in older adults., Design: systematic review and meta-analysis., Participants: community-dwelling older adults over 65 years., Intervention: exercises at home through DHI., Outcomes Measures: physical function, HRQoL and falls., Results: twenty-six studies have met the inclusion criteria, including 5,133 participants (range age 69.5 ± 4.0-83.0 ± 6.7). The HBE programmes delivered with DHI improve muscular strength (five times sit-to-stand test, -0.56 s, 95% confidence interval, CI -1.00 to -0.11; P = 0.01), functional capacity (Barthel index, 5.01 points, 95% CI 0.24-9.79; P = 0.04) and HRQoL (SMD 0.18; 95% CI 0.05-0.30; P = 0.004); and reduce events of falls (odds ratio, OR 0.77, 95% CI 0.64-0.93; P = 0.008). In addition, in the subgroup analysis, older adults with diseases improve mobility (SMD -0.23; 95% CI -0.45 to -0.01; P = 0.04), and balance (SMD 0.28; 95% CI 0.09-0.48; P = 0.004)., Conclusion: the HBE programmes carried out by DHI improve physical function in terms of lower extremity strength and functional capacity. It also significantly reduces the number of falls and improves the HRQoL. In addition, in analysis of only older adults with diseases, it also improves the balance and mobility., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The main aim of this work is to review the mechanisms via which high-density lipoprotein (HDL)-mediated cholesterol trafficking through the central nervous system (CNS) occurs in the context of Alzheimer's disease (AD). Alzheimer's disease is characterized by the accumulation of extracellular amyloid beta (Aβ) and abnormally hyperphosphorylated intracellular tau filaments in neurons. Cholesterol metabolism has been extensively implicated in the pathogenesis of AD through biological, epidemiological, and genetic studies, with the APOE gene being the most reproducible genetic risk factor for the development of AD. This manuscript explores how HDL-mediated cholesterol is transported in the CNS, with a special emphasis on its relationship to Aβ peptide accumulation and apolipoprotein E (ApoE)-mediated cholesterol transport. Indeed, we reviewed all existing works exploring HDL-like-mediated cholesterol efflux and cholesterol uptake in the context of AD pathogenesis. Existing data seem to point in the direction of decreased cholesterol efflux and the impaired entry of cholesterol into neurons among patients with AD, which could be related to impaired Aβ clearance and tau protein accumulation. However, most of the reviewed studies have been performed in cells that are not physiologically relevant for CNS pathology, representing a major flaw in this field. The ApoE4 genotype seems to be a disruptive element in HDL-like-mediated cholesterol transport through the brain. Overall, further investigations are needed to clarify the role of cholesterol trafficking in AD pathogenesis.

Human movement behaviours such as physical activity (PA) and sedentary behaviour (SB) during waking time have a significant impact on health-related quality of life (HRQoL) in older adults. In this study, we aimed to analyse the association between self-reported and device-measured SB and PA with HRQoL in a cohort of community-dwelling older adults from four European countries. A subsample of 1193 participants from the SITLESS trial (61% women and 75.1 ± 6.2 years old) were included in the analysis. The association between self-reported and objective measures of SB and PA with HRQoL were quantified using Spearman's Rho coefficients. The strength of the associations between self-reported and device-measured PA and SB with self-rated HRQoL (mental composite score, MCS; physical composite score, PCS) were assessed through multivariate multiple regression analysis. Self-reported and device-measured PA and SB levels showed significant but poor associations with PCS ( p < 0.05). The association with MCS was only significant but poor with self-reported light PA (LPA) and moderate-to-vigorous PA (MVPA). In conclusion, the findings of this study suggest that both self-reported and device-measured PA of all intensities were positively and significantly associated, while SB was negatively and significantly associated with the PCS of the SF-12.

Nestedness is a property of interaction networks widely observed in natural mutualistic communities, among other systems. A perfectly nested network is characterized by the peculiarity that the interactions of any node form a subset of the interactions of all nodes with higher degree. Despite a widespread interest on this pattern, no general consensus exists on how to measure it. Instead, several nestedness metrics, based on different but not necessarily independent properties of the networks, coexist in the literature, blurring the comparison between ecosystems. In this work, we present a detailed critical study of the behavior of six nestedness metrics and the variants of two of them. In order to evaluate their performance, we compare the obtained values of the nestedness of a large set of real networks among them and against a maximum-entropy and maximum-likelihood null model. We also analyze the dependencies of each metrics on different network parameters, as size, fill, and eccentricity. Our results point out, first, that the metrics do not rank networks universally in terms of their degree of nestedness. Furthermore, several metrics show significant dependencies on the network properties considered. The study of these dependencies allows us to understand some of the observed systematic shifts against the null model. Altogether, this paper intends to provide readers with a critical guide on how to measure nestedness patterns, by explaining the functioning of several metrics and disclosing their qualities and flaws. Besides, we also aim to extend the application of null models based on maximum entropy to the scarcely explored area of ecological networks. Finally, we provide a fully documented repository that allows constructing the null model and calculating the studied nestedness indexes. In addition, it provides the probability matrices to build the null model for a large dataset of more than 200 bipartite networks., Competing Interests: The authors declare no competing interests., (© 2020 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Exercise is a form of physical activity (PA). PA is an important marker of health and quality of life in older adults. The purpose of this study was to conduct a systematic review of the literature to assess the effect of exercise-based interventions on an at least six-month follow up PA measure, and to describe the specific strategies implemented during the intervention to strengthen the sustainability of PA in community-dwelling 65+ year-old adults. We registered and conducted a systematic review and meta-analysis (PROSPERO: CRD42017070892) of randomized clinical trials (RCT). We searched three electronic databases during January 2018 to identify RCT assessing any type of exercise-based intervention. Studies had to report a pre-, post-, and at least 6-month post-intervention follow-up. To be included, at least one PA outcome had to be assessed. The effect of exercise-based interventions was assessed compared to active (e.g., a low-intensity type of exercise, such as stretching or toning activities) and non-active (e.g., usual care) control interventions at several time points. Secondary analyses were conducted, restricted to studies that reported specific strategies to enhance the sustainability of PA. The intervention effect was measured on self-reported and objective measures of time spent in PA, by means of standardized mean differences. Standardized mean differences of PA level were pooled. Pooled estimates of effect were computed with the DerSimonian-Laird method, applying a random effects model. The risk of bias was also assessed. We included 12 studies, comparing 18 exercise intervention groups to four active and nine non-active control groups. Nine studies reported specific strategies to enhance the long-term sustainability of PA. The strategies were mostly related to the self-efficacy, self-control, and behavior capability principles based on the social cognitive theory. Exercise interventions compared to active control showed inconclusive and heterogeneous results. When compared to non-active control, exercise interventions improved PA time at the six-months follow up (standardized mean difference (SMD) 0.30; 95%CI 0.15 to 0.44; four studies; 724 participants; I 2 0%), but not at the one- or two-years follow-ups. No data were available on the mid- and long-term effect of adding strategies to enhance the sustainability of PA. Exercise interventions have small clinical benefits on PA levels in community-dwelling older adults, with a decline in the observed improvement after six months of the intervention cessation., Competing Interests: The authors declare no conflict of interest.

Introduction: SITLESS is a randomised controlled trial determining whether exercise referral schemes can be enhanced by self-management strategies to reduce sedentary behaviour and increase physical activity in the long term, in community-dwelling older citizens. The intervention is complex and requires a process evaluation to understand how implementation, causal mechanisms and context shape outcomes. The specific aims are to assess fidelity and reach of the implementation, understand the contextual aspects of each intervention site, evaluate the mechanisms of impact, and explore perceived effects., Methods and Analysis: Following the Medical Research Council guidance on complex interventions, a combination of qualitative and quantitative procedures is applied, including observational checklists and attendance registries, standardised scales (ie, Marcus's Self-Efficacy Questionnaire, Physical Activity Self-Regulation Scale and the Lubben Social Network Scale) at baseline, postintervention and follow-up assessments, semistructured questionnaires gathering contextual characteristics, and participant observations of the sessions. Semistructured interviews and focus groups with the participants and trainers are conducted at postintervention and during the follow-up to explore their experiences. Outcomes from the standardised scales are analysed as moderators within the impact evaluation. Descriptive results on context and perceived effects complement results on impact. The qualitative and quantitative findings will help to refine the logic model to finally support the interpretation of the results on the effectiveness of the intervention., Ethics and Dissemination: The study design was approved by the respective Ethical Committee of Ramon Llull University, Southern Denmark, Northern Ireland and Ulm University. Participation is voluntary, and all participants are asked to sign informed consent before starting the study. A dissemination plan operationalises how to achieve a social impact by reaching academic and non-academic stakeholders. A data management plan describes the specific data sets and regulates its deposition and curation. All publications will be open access., Trial Registration Number: NCT02629666; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

It has been highlighted the original article (1) contained a typesetting mistake in the authorship, and that author Caterine Vicens was omitted.

[This corrects the article DOI: 10.1371/journal.pone.0190750.].

Introduction: Studies had not yet overcome the most relevant barriers to physical activity (PA) adherence. An exercise referral scheme (ERS) with mechanisms to promote social support might enhance adherence to PA in the long term., Setting: A randomised controlled trial in 10 primary care centres in Spain., Objective: To assess the effectiveness of a primary care-based ERS linked to municipal resources and enhancing social support and social participation in establishing adherence to PA among adults over a 15-month period., Participants: 422 insufficiently active participants suffering from at least one chronic condition were included. 220 patients (69.5 (8.4) years; 136 women) were randomly allocated to the intervention group (IG) and 202 (68.2 (8.9) years; 121 women) to the control group (CG)., Interventions: The IG went through a 12-week standardised ERS linked to community resources and with inclusion of mechanisms to enhance social support. The CG received usual care from their primary care practice., Outcomes: The main outcome measure was self-report PA with the International Physical Activity Questionnaire and secondary outcomes included stages of change and social support to PA practice., Data Collection: Participant-level data were collected via questionnaires at baseline, and at months 3, 9 and 15., Blinding: The study statistician and research assessors were blinded to group allocation., Results: Compared with usual care, follow-up data at month 15 for the ERS group showed a significant increase of self-reported PA (IG: 1373±1845 metabolic equivalents (MET) min/week, n=195; CG: 919±1454 MET min/week, n=144; P=0.009). Higher adherence (in terms of a more active stage of change) was associated with higher PA level at baseline and with social support., Conclusions: Prescription from ordinary primary care centres staff yielded adherence to PA practice in the long term. An innovative ERS linked to community resources and enhancing social support had shown to be sustainable in the long term., Trial Registration Number: NCT00714831; Results., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background and Objectives: Prolonged sitting time (ST) has negative consequences on health. Changing this behavior is paramount in overweight/obese individuals because they are more sedentary than those with normal weight. The aim of the study was to establish the pattern of sedentary behavior and its relationship to health, socio-demographics, occupation, and education level in Catalan overweight/obese individuals., Methods: A descriptive study was performed at 25 healthcare centers in Catalonia (Spain) with 464 overweight/moderately obese patients, aged25 to 65 years. Exclusion criteria were chronic diseases which contraindicated physical activity and language barriers. Face-to-face interviews were conducted to collect data on age, gender, educational level, social class, and marital status. Main outcome was 'sitting time' (collected by the Marshall questionnaire); chronic diseases and anthropometric measurements were registered., Results: 464 patients, 58.4% women, mean age 51.9 years (SD 10.1), 76.1% married, 60% manual workers, and 48.7% had finished secondary education. Daily sitting time was 6.2 hours on working days (374 minutes/day, SD: 190), and about 6 hours on non-working ones (357 minutes/day, SD: 170). 50% of participants were sedentary ≥6 hours. The most frequent sedentary activities were: working/academic activities around 2 hours (128 minutes, SD: 183), followed by watching television, computer use, and commuting. Men sat longer than women (64 minutes more on working days and 54 minutes on non-working days), and individuals with office jobs (91 minutes),those with higher levels of education (42 minutes), and younger subjects (25 to 35 years) spent more time sitting., Conclusions: In our study performed in overweight/moderately obese patients the mean sitting time was around 6 hours which was mainly spent doing work/academic activities and watching television. Men, office workers, individuals with higher education, and younger subjects had longer sitting time. Our results may help design interventions targeted at these sedentary patients to decrease sitting time.

Background: Older adults are the fastest growing segment of the world's population. Recent evidence indicates that excessive sitting time is harmful to health, independent of meeting the recommended moderate to vigorous physical activity (PA) guidelines. The SITLESS project aims to determine whether exercise referral schemes (ERS) can be enhanced by self-management strategies (SMSs) to reduce sedentary behaviour (SB), increase PA and improve health, quality of life and function in the long term, as well as psychosocial outcomes in community-dwelling older European citizens from four countries, within a three-armed pragmatic randomised controlled trial, compared with ERS alone and also with general recommendations about PA., Methods: A total of 1338 older adults will be included in this study, recruited from four European countries through different existing primary prevention pathways. Participants will be randomly allocated into an ERS of 16 weeks (32 sessions, 45-60 min per session), ERS enhanced by seven sessions of SMSs and four telephone prompts, or a control group. Outcomes will be assessed at baseline, month 4 (end of ERS intervention), month 16 (12 months post intervention) and month 22 (18 months post intervention). Primary outcomes will include measures of SB (time spent sedentary) and PA (counts per minute). Secondary outcomes will include muscle and physical function, health economics' related outcomes, anthropometry, quality of life, social networks, anxiety and depressive symptoms, disability, fear of falling, executive function and fatigue. A process evaluation will be conducted throughout the trial. The full analysis set will follow an intention-to-treat principle and will include all randomised participants for whom a baseline assessment is conducted. The study hypothesis will be tested with mixed linear models with repeated measures, to assess changes in the main outcomes (SB and PA) over time (baseline to month 22) and between study arms., Discussion: The findings of this study may help inform the design and implementation of more effective interventions to reduce SB and increase PA levels, and hence improve long-term health outcomes in the older adult population. SITLESS aims to support policy-makers in deciding how or whether ERS should be further implemented or restructured in order to increase its adherence, impact and cost-effectiveness., Trial Registration: ClinicalTrials.gov, NCT02629666 . Registered 19 November 2015.

Background and Objectives: Prolonged sitting time has negative consequences on health, although the population is not well aware of these harmful effects. We explored opinions expressed by primary care patients diagnosed as overweight or moderately obese concerning their time spent sitting, willingness to change, and barriers, facilitators, goals and expectations related to limiting this behaviour., Methods: A descriptive-interpretive qualitative study was carried out at three healthcare centres in Barcelona, Spain, and included 23 patients with overweight or moderate obesity, aged 25 to 65 years, who reported sitting for at least 6 hours a day. Exclusion criteria were inability to sit down or stand up from a chair without help and language barriers that precluded interview participation. Ten in-depth, semi-structured interviews (5 group, 5 individual) were audio recorded from January to July 2012 and transcribed. The interview script included questions about time spent sitting, willingness to change, barriers and facilitators, and the prospect of assistance from primary healthcare professionals. An analysis of thematic content was made using ATLAS.Ti and triangulation of analysts., Results: The most frequent sedentary activities were computer use, watching television, and motorized journeys. There was a lack of awareness of the amount of time spent sitting and its negative consequences on health. Barriers to reducing sedentary time included work and family routines, lack of time and willpower, age and sociocultural limitations. Facilitators identified were sociocultural change, free time and active work, and family surroundings. Participants recognized the abilities of health professionals to provide help and advice, and reported a preference for patient-centred or group interventions., Conclusions: Findings from this study have implications for reducing sedentary behaviour. Patient insights were used to design an intervention to reduce sitting time within the frame of the SEDESTACTIV clinical trial.

Background: There is growing evidence suggesting that prolonged sitting has negative effects on people's weight, chronic diseases and mortality. Interventions to reduce sedentary time can be an effective strategy to increase daily energy expenditure. The purpose of this study is to evaluate the effectiveness of a six-month primary care intervention to reduce daily of sitting time in overweight and mild obese sedentary patients., Method/design: The study is a randomized controlled trial (RCT). Professionals from thirteen primary health care centers (PHC) will randomly invite to participate mild obese or overweight patients of both gender, aged between 25 and 65 years old, who spend 6 hours at least daily sitting. A total of 232 subjects will be randomly allocated to an intervention (IG) and control group (CG) (116 individuals each group). In addition, 50 subjects with fibromyalgia will be included.Primary outcome is: (1) sitting time using the activPAL device and the Marshall questionnaire. The following parameters will be also assessed: (2) sitting time in work place (Occupational Sitting and Physical Activity Questionnaire), (3) health-related quality of life (EQ-5D), (4) evolution of stage of change (Prochaska and DiClemente's Stages of Change Model), (5) physical inactivity (catalan version of Brief Physical Activity Assessment Tool), (6) number of steps walked (pedometer and activPAL), (7) control based on analysis (triglycerides, total cholesterol, HDL, LDL, glycemia and, glycated haemoglobin in diabetic patients) and (8) blood pressure and anthropometric variables. All parameters will be assessed pre and post intervention and there will be a follow up three, six and twelve months after the intervention. A descriptive analysis of all variables and a multivariate analysis to assess differences among groups will be undertaken. Multivariate analysis will be carried out to assess time changes of dependent variables. All the analysis will be done under the intention to treat principle., Discussion: If the SEDESTACTIV intervention shows its effectiveness in reducing sitting time, health professionals would have a low-cost intervention tool for sedentary overweight and obese patients management., Trial Registration: A service of the U.S. National Institutes of Health. Developed by the National Library of Medicine. ClinicalTrials.gov NCT01729936.

Background: Effective promotion of exercise could result in substantial savings in healthcare cost expenses in terms of direct medical costs, such as the number of medical appointments. However, this is hampered by our limited knowledge of how to achieve sustained increases in physical activity., Objectives: To assess the effectiveness of a Primary Health Care (PHC) based physical activity program in reducing the total number of visits to the healthcare center among inactive patients, over a 15-month period., Research Design: Randomized controlled trial., Subjects: Three hundred and sixty-two (n = 362) inactive patients suffering from at least one chronic condition were included. One hundred and eighty-three patients (n = 183; mean (SD); 68.3 (8.8) years; 118 women) were randomly allocated to the physical activity program (IG). One hundred and seventy-nine patients (n = 179; 67.2 (9.1) years; 106 women) were allocated to the control group (CG). The IG went through a three-month standardized physical activity program led by physical activity specialists and linked to community resources., Measures: The total number of medical appointments to the PHC, during twelve months before and after the program, was registered. Self-reported health status (SF-12 version 2) was assessed at baseline (month 0), at the end of the intervention (month 3), and at 12 months follow-up after the end of the intervention (month 15)., Results: The IG had a significantly reduced number of visits during the 12 months after the intervention: 14.8 (8.5). The CG remained about the same: 18.2 (11.1) (P = .002)., Conclusions: Our findings indicate that a 3-month physical activity program linked to community resources is a short-duration, effective and sustainable intervention in inactive patients to decrease rates of PHC visits., Trial Registration: ClinicalTrials.gov NCT00714831.