New supporting data to guide the use of evident toxicity in acute oral toxicity studies (OECD TG 420).

Currently there are three test guidelines (TG) for acute oral toxicity studies of substances or mixtures from the Organisation for Economic Co-operation and Development (OECD). TG 423 and TG 425 use lethality as an endpoint, while TG 420 replaces death with 'evident toxicity', defined as clear signs that exposure to a higher dose would result in death. However, the perceived subjectivity of 'evident toxicity' may be preventing wider use of TG 420. To address this, the UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) and the European Partnership for Alternative Approaches to Animal Testing (EPAA) collaborated to provide recommendations on the recognition of 'evident toxicity'. Historical data from acute oral toxicity studies were analysed for clinical signs at the lower dose that could have predicted death at the higher dose. Several signs including ataxia, laboured respiration, and eyes partially closed, alone or in combination, are highly predictive. Others such as lethargy, decreased respiration, and loose faeces have lower but still appreciable positive predictive value (PPV). The data has been used to develop recommendations to promote use of TG 420 and thus reduce the suffering and numbers of animals used in acute oral toxicity studies.

Beyond purified dietary fibre supplements: Compositional variation between cell wall fibre from different plants influences human faecal microbiota activity and growth in vitro.

Dietary fibre is a major energy source for the human gut microbiota, but it is unclear to what extent the fibre source and complexity affect microbial growth and metabolite production. Cell wall material and pectin were extracted from five different dicotyledon plant sources, apples, beet leaves, beetroots, carrots and kale, and compositional analysis revealed differences in the monosaccharide composition. Human faecal batch incubations were conducted with 14 different substrates, including the plant extracts, wheat bran and commercially available carbohydrates. Microbial activity was determined for up to 72 h by measuring gas and fermentation acid production, total bacteria (by qPCR) and microbial community composition by 16S rRNA amplicon sequencing. The more complex substrates gave rise to more microbiota variation compared with the pectins. The comparison of different plant organs showed that the leaves (beet leaf and kale) and roots (carrot and beetroot) did not give rise to similar bacterial communities. Rather, the compositional features of the plants, such as high arabinan levels in beet and high galactan levels in carrot, appear to be major predictors of bacterial enrichment on the substrates. Thus, in-depth knowledge on dietary fibre composition should aid the design of diets focused on optimizing the microbiota.

Are motivational and self-regulation factors associated with 12 months' weight regain prevention in the NoHoW study? An analysis of European adults.

PURPOSE: Preventing weight regain can only be achieved by sustained changes in energy balance-related behaviors that are associated with weight, such as diet and physical activity. Changes in motivation and self-regulatory skills can support long-term behavioral changes in the context of weight loss maintenance. We propose that experiencing a supportive climate care is associated with enhanced satisfaction of basic psychological needs, intrinsic goals, and autonomous motivation. These factors are expected to be associate with the utilization of self-regulation skills, leading to more sustained behavior changes and ultimately preventing weight regain. This hypothesis was tested in this ancillary analysis of the NoHoW trial, where the study arms were pooled and followed for 12 months. METHODS: The NoHoW was a three-center, large-scale weight regain prevention full factorial trial. In this longitudinal study, data were collected in adults who lost > 5% weight in the past year (N = 870, complete data only, 68.7% female, 44.10 ± 11.86 years, 84.47 ± 17.03 kg) during their participation in a 12-month digital behavior change intervention. Weight and validated measures of motivational- and self-regulatory skills-related variables were collected at baseline, six- and 12 months. Change variables were used in Mplus' path analytical models informed by NoHoW's logic model. RESULTS: The bivariate correlations confirmed key mediators' potential effect on weight outcomes in the expected causal direction. The primary analysis showed that a quarter of the variance (r2 = 23.5%) of weight regain prevention was achieved via the mechanisms of action predicted in the logic model. Specifically, our results show that supportive climate care is associated with needs satisfaction and intrinsic goal content leading to better weight regain prevention via improvements in self-regulatory skills and exercise-controlled motivation. The secondary analysis showed that more mechanisms of action are significant in participants who regained or maintained their weight. CONCLUSIONS: These results contribute to a better understanding of the mechanisms of action leading to behavior change in weight regain prevention. The most successful participants used only a few intrinsic motivation-related mechanisms of action, suggesting that habits may have been learned. While developing a digital behavior change intervention, researchers and practitioners should consider creating supportive climate care to improve needs satisfaction and intrinsic goal contents. TRIAL REGISTRATION: ISRCTN, ISRCTN88405328 , registered 12/22/2016.

Habitual consumption of high-fibre bread fortified with bean hulls increased plasma indole-3-propionic concentration and decreased putrescine and deoxycholic acid faecal concentrations in healthy volunteers.

Only 6 to 8 % of the UK adults meet the daily recommendation for dietary fibre. Fava bean processing lead to vast amounts of high-fibre by-products such as hulls. Bean hull fortified bread was formulated to increase and diversify dietary fibre while reducing waste. This study assessed the bean hull: suitability as a source of dietary fibre; the systemic and microbial metabolism of its components and postprandial events following bean hull bread rolls. Nine healthy participants (53·9 ± 16·7 years) were recruited for a randomised controlled crossover study attending two 3 days intervention sessions, involving the consumption of two bread rolls per day (control or bean hull rolls). Blood and faecal samples were collected before and after each session and analysed for systemic and microbial metabolites of bread roll components using targeted LC-MS/MS and GC analysis. Satiety, gut hormones, glucose, insulin and gastric emptying biomarkers were also measured. Two bean hull rolls provided over 85 % of the daily recommendation for dietary fibre; but despite being a rich source of plant metabolites (P = 0·04 v. control bread), these had poor systemic bioavailability. Consumption of bean hull rolls for 3 days significantly increased plasma concentration of indole-3-propionic acid (P = 0·009) and decreased faecal concentration of putrescine (P = 0·035) and deoxycholic acid (P = 0·046). However, it had no effect on postprandial plasma gut hormones, bacterial composition and faecal short chain fatty acids amount. Therefore, bean hulls require further processing to improve their bioactives systemic availability and fibre fermentation.

Consumption of foods with the highest nutritional quality, and the lowest greenhouse gas emissions and price, differs between socio-economic groups in the UK population.

OBJECTIVE: To establish a baseline understanding of whether consuming food with the highest nutritional quality, lowest greenhouse gas emissions (GHGE) and cost differs between different UK demographic and socio-economic population groups. DESIGN: Multiple linear regression models were fitted to evaluate the relationship between predictor socio-demographic variables in this study (i.e. sex, ethnic group, age, BMI and level of deprivation) and the response variables (i.e. consumption of items considered most nutritious, with a low GHGE and price, as a proportion of total items consumed). SETTING: The UK. PARTICIPANTS: 1374 adult (18-65 years) participants from the National Diet and Nutrition Survey latest waves 9-11 (2016-2017 and 2018-2019). RESULTS: Based on the total energy consumption in a day, the average diet-based GHGE was significantly higher for participants with a higher BMI. Non-white and most deprived participants spent significantly (P < 0·001) less money per total energy consumption. Participants with a BMI between 18·6 and 39·9 kg/m2 and those living in the least deprived areas consumed a significantly (P < 0·001) higher amount of those items considered the most nutritious, with the lowest GHGE and cost per 100 kcal. CONCLUSIONS: Consumption of food with the highest nutritional quality, lowest GHGE and cost in the UK varies among those with different socio-demographic characteristics, especially the deprivation level of participants. Our analysis endorses the consideration of environmental sustainability and affordability, in addition to the consideration of nutritional quality from a health perspective, to make current dietary guidelines more encompassing and equitable.

Exploratory analysis of reflective, reactive, and homeostatic eating behaviour traits on weight change during the 18-month NoHoW weight maintenance trial.

Behaviour change interventions for weight management have found varied effect sizes and frequent weight re-gain after weight loss. There is interest in exploring whether differences in eating behaviour can be used to develop tailored weight management programs. This secondary analysis of an 18-month weight maintenance randomised controlled trial (RCT) aimed to investigate the association between individual variability in weight maintenance success and change in eating behaviour traits (EBT). Data was analysed from the NoHoW trial (Scott et al., 2019), which was designed to measure processes of change after weight loss of ≥5% body weight in the previous year. The sample included 1627 participants (mean age = 44.0 years, SD = 11.9, mean body mass index (BMI) = 29.7 kg/m2, SD = 5.4, gender = 68.7% women/31.3% men). Measurements of weight (kg) and 7 EBTs belonging to domains of reflective, reactive, or homeostatic eating were taken at 4 time points up to 18-months. Increases in measures of 'reactive eating' (binge eating, p < .001), decreases in 'reflective eating' (restraint, p < .001) and changes in 'homeostatic eating' (unlimited permission to eat, p < .001 and reliance on hunger and satiety cues, p < .05) were significantly and independently associated with concomitant weight change. Differences in EBT change were observed between participants who lost, maintained, or re-gained weight for all EBTs (p < .001) except for one subscale of intuitive eating (eating for physical reasons, p = .715). Participants who lost weight (n = 322) exhibited lower levels of reactive eating and higher levels of reflective eating than participants who re-gained weight (n = 668). EBT domains can identify individuals who need greater support to progress in weight management interventions. Increasing reflective eating and reducing reactive eating may enhance weight management success.

Effect of different food groups on energy intake within and between individuals.

PURPOSE: Energy intake varies day-to-day because we select different foods, and different amounts of these foods. Energy balance is not tightly regulated over the short-term, and the variability in diet results in an energy surplus or deficit. The aim of this study was to explore how consuming more, or less, than usual amounts of foods contributed towards balancing of total energy intake (TEI) within a day. METHODS: Four-day food records came from 6155 adult participants of the National Diet and Nutrition Survey to study these effects. Within-individual regression models of the energy from 60 food groups on TEI were calculated. Energy intake variation within-individuals was regressed separately on the variation in amounts of each food group. Regression models were also fitted to individual four day means. RESULTS: Within-individual coefficients ranged from about 0 for high-fibre breakfast cereals to 1.7 for sugar preserves and spreads. Three food groups (e.g. low-calorie soft drinks) tended to reduce TEI, and 13 food groups (e.g. margarine and other spreads, and alcoholic drinks) tended to elevate TEI above the energy content of the food group when more than usual amounts were consumed. Foods groups of higher energy densities, or lower fibre content (e.g. typical "snack" foods, low-fibre bread, and processed meat) tended to promote greater TEI more so than did food groups of lower energy densities (e.g. meat, fish, high-fibre foods, and potatoes). CONCLUSION: Different food groups vary considerably in the extent to which they affect TEI in free-living adults. The associations between consuming more, or less, than usual amounts of foods and the effects on TEI are consistent with those found in laboratory studies. Importantly, the present study found similar associations, but using a different methodology and in observational data, providing novel information on energy intake compensation.

Hemp and buckwheat are valuable sources of dietary amino acids, beneficially modulating gastrointestinal hormones and promoting satiety in healthy volunteers.

PURPOSE: This study evaluated the postprandial effects following consumption of buckwheat, fava bean, pea, hemp and lupin compared to meat (beef); focussing on biomarkers of satiety, gut hormones, aminoacids and plant metabolites bioavailability and metabolism. METHODS: Ten subjects (n = 3 men; n = 7 women; 42 ± 11.8 years of age; BMI 26 ± 5.8 kg/m2) participated in six 1-day independent acute interventions, each meal containing 30 g of protein from buckwheat, fava bean, pea, hemp, lupin and meat (beef). Blood samples were collected during 24-h and VAS questionnaires over 5-h. RESULTS: Volunteers consumed significantly higher amounts of most amino acids from the meat meal, and with few exceptions, postprandial composition of plasma amino acids was not significantly different after consuming the plant-based meals. Buckwheat meal was the most satious (300 min hunger scores, p < 0.05).Significant increase in GLP-1 plasma (AUC, iAUC p = 0.01) found after hemp compared with the other plant-based meals. Decreased plasma ghrelin concentrations (iAUC p < 0.05) found on plant (hemp) vs. meat meal. Several plasma metabolites after hemp meal consumption were associated with hormone trends (partial least squares-discriminant analysis (PLS-DA): 4-hydroxyphenylpyruvic acid, indole 3-pyruvic acid, 5-hydoxytryptophan, genistein and biochanin A with GLP-1, PYY and insulin; 3-hydroxymandelic acid and luteolidin with GLP-1 and ghrelin and 4-hydroxymandelic acid, benzoic acid and secoisolariciresinol with insulin and ghrelin. Plasma branched-chain amino acids (BCAAs), (iAUC, p < 0.001); and phenylalanine and tyrosine (iAUC, p < 0.05) were lower after buckwheat comparison with meat meal. CONCLUSION: Plants are valuable sources of amino acids which are promoting satiety. The impact of hemp and buckwheat on GLP-1 and, respectively, BCAAs should be explored further as could be relevant for aid and prevention of chronic diseases such as type 2 diabetes. Study registered with clinicaltrial.gov on 12th July 2013, study ID number: NCT01898351.

Modelling population responses to workplace minimum dietary standards introduced as workers return after social lockdowns.

BACKGROUND: Diet norms are the shared social behaviours and beliefs about diets. In many societies, including the UK, these norms are typically linked to unhealthy diets and impede efforts to improve food choices. Social interactions that could influence one another's food choices, were highly disrupted during the lockdowns in response to the COVID-19 pandemic. A return to workplaces and re-establishment of eating networks may present an opportunity to influence dietary norms by introducing minimum dietary standards to in workplaces, which could then spread through wider home and workplace networks. METHODS: An agent-based model was constructed to simulate a society reflecting the structure of a city population (1000 households) to explore changes in personal and social diet-related norms. The model tracked individual meal choices as agents interact in home, work or school settings and recorded changes in diet quality (range 1 to 100). Scenarios were run to compare individuals' diet quality with the introduction of minimum dietary standards with degrees of working from home. RESULTS: The more people mixed at work the greater the impact of minimum standards on improving diet norms. Socially isolated households remained unaffected by minimum standards, whereas household members exposed directly, in workplaces or schools, or indirectly, influenced by others in the household, had a large and linear increase in diet quality in relation to minimum standards (0.48 [95% CI 0.34, 0.62] per unit increase in minimum standards). Since individuals regressed to the new population mean, a small proportion of diets decreased toward lower population norms. The degree of return to work influenced the rate and magnitude of change cross the population (-2.4 points [-2.40, -2.34] in mean diet quality per 20% of workers isolating). CONCLUSIONS: These model results illustrate the qualitative impact social connectivity could have on changing diets through interventions. Norms can be changed more in a more connected population, and social interactions spread norms between contexts and amplified the influence of, for example, workplace minimum standards beyond those directly exposed. However, implementation of minimum standards in a single type of setting would not reach the whole population and in some cases may decrease diet quality. Any non-zero standard could yield improvements beyond the immediate adult workforce and this could spill between social contexts, but would be contingent on population connectivity.

Evaluation of the Immediate Effects of Web-Based Intervention Modules for Goals, Planning, and Coping Planning on Physical Activity: Secondary Analysis of a Randomized Controlled Trial on Weight Loss Maintenance.

BACKGROUND: The use of digital interventions can be accurately monitored via log files. However, monitoring engagement with intervention goals or enactment of the actual behaviors targeted by the intervention is more difficult and is usually evaluated based on pre-post measurements in a controlled trial. OBJECTIVE: The objective of this paper is to evaluate if engaging with 2 digital intervention modules focusing on (1) physical activity goals and action plans and (2) coping with barriers has immediate effects on the actual physical activity behavior. METHODS: The NoHoW Toolkit (TK), a digital intervention developed to support long-term weight loss maintenance, was evaluated in a 2 x 2 factorial randomized controlled trial. The TK contained various modules based on behavioral self-regulation and motivation theories, as well as contextual emotion regulation approaches, and involved continuous tracking of weight and physical activity through connected commercial devices (Fitbit Aria and Charge 2). Of the 4 trial arms, 2 had access to 2 modules directly targeting physical activity: a module for goal setting and action planning (Goal) and a module for identifying barriers and coping planning (Barriers). Module visits and completion were determined based on TK log files and time spent in the module web page. Seven physical activity metrics (steps; activity; energy expenditure; fairly active, very active and total active minutes; and distance) were compared before and after visiting and completing the modules to examine whether the modules had immediate or sustained effects on physical activity. Immediate effect was determined based on 7-day windows before and after the visit, and sustained effects were evaluated for 1 to 8 weeks after module completion. RESULTS: Out of the 811 participants, 498 (61.4%) visited the Goal module and 406 (50.1%) visited the Barriers module. The Barriers module had an immediate effect on very active and total active minutes (very active minutes: before median 24.2, IQR 10.4-43.0 vs after median 24.9, IQR 10.0-46.3; P=.047; total active minutes: before median 45.1, IQR 22.9-74.9 vs after median 46.9, IQR 22.4-78.4; P=.03). The differences were larger when only completed Barriers modules were considered. The Barriers module completion was also associated with sustained effects in fairly active and total active minutes for most of the 8 weeks following module completion and for 3 weeks in very active minutes. CONCLUSIONS: The Barriers module had small, significant, immediate, and sustained effects on active minutes measured by a wrist-worn activity tracker. Future interventions should pay attention to assessing barriers and planning coping mechanisms to overcome them. TRIAL REGISTRATION: ISRCTN Registry ISRCTN88405328; https://www.isrctn.com/ISRCTN88405328.

Users' Experiences With the NoHoW Web-Based Toolkit With Weight and Activity Tracking in Weight Loss Maintenance: Long-term Randomized Controlled Trial.

BACKGROUND: Digital behavior change interventions (DBCIs) offer a promising channel for providing health promotion services. However, user experience largely determines whether they are used, which is a precondition for effectiveness. OBJECTIVE: The primary aim of this study is to evaluate user experiences with the NoHoW Toolkit (TK)-a DBCI that targets weight loss maintenance-over a 12-month period by using a mixed methods approach and to identify the main strengths and weaknesses of the TK and the external factors affecting its adoption. The secondary aim is to objectively describe the measured use of the TK and its association with user experience. METHODS: An 18-month, 2×2 factorial randomized controlled trial was conducted. The trial included 3 intervention arms receiving an 18-week active intervention and a control arm. The user experience of the TK was assessed quantitatively through electronic questionnaires after 1, 3, 6, and 12 months of use. The questionnaires also included open-ended items that were thematically analyzed. Focus group interviews were conducted after 6 months of use and thematically analyzed to gain deeper insight into the user experience. Log files of the TK were used to evaluate the number of visits to the TK, the total duration of time spent in the TK, and information on intervention completion. RESULTS: The usability level of the TK was rated as satisfactory. User acceptance was rated as modest; this declined during the trial in all the arms, as did the objectively measured use of the TK. The most appreciated features were weekly emails, graphs, goal setting, and interactive exercises. The following 4 themes were identified in the qualitative data: engagement with features, decline in use, external factors affecting user experience, and suggestions for improvements. CONCLUSIONS: The long-term user experience of the TK highlighted the need to optimize the technical functioning, appearance, and content of the DBCI before and during the trial, similar to how a commercial app would be optimized. In a trial setting, the users should be made aware of how to use the intervention and what its requirements are, especially when there is more intensive intervention content. TRIAL REGISTRATION: ISRCTN Registry ISRCTN88405328; https://www.isrctn.com/ISRCTN88405328. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1136/bmjopen-2019-029425.

Identification of psychological correlates of dietary misreporting under laboratory and free-living environments.

Errors inherent in self-reported measures of energy intake (EI) are substantial and well documented, but correlates of misreporting remain unclear. Therefore, potential predictors of misreporting were examined. In Study One, fifty-nine individuals (BMI = 26·1 (sd 3·8) kg/m2, age = 42·7 (sd 13·6) years, females = 29) completed a 14-d stay in a residential feeding behaviour suite where eating behaviour was continuously monitored. In Study Two, 182 individuals (BMI = 25·7 (sd 3·9) kg/m2, age = 42·4 (sd 12·2) years, females = 96) completed two consecutive days in a residential feeding suite and five consecutive days at home. Misreporting was directly quantified by comparing covertly measured laboratory weighed intakes (LWI) with self-reported EI (weighed dietary record (WDR), 24-h recall, 7-d diet history, FFQ). Personal (age, sex and %body fat) and psychological traits (personality, social desirability, body image, intelligence quotient and eating behaviour) were used as predictors of misreporting. In Study One, those with lower psychoticism (P = 0·009), openness to experience (P = 0·006) and higher agreeableness (P = 0·038) reduced EI on days participants knew EI was being measured to a greater extent than on covert days. Isolated associations existed between personality traits (psychoticism and openness to experience), eating behaviour (emotional eating) and differences between the LWI and self-reported EI, but these were inconsistent between dietary assessment techniques and typically became non-significant after accounting for multiplicity of comparisons. In Study Two, sex was associated with differences between LWI and the WDR (P = 0·009), 24-h recall (P = 0·002) and diet history (P = 0·050) in the laboratory, but not home environment. Personal and psychological correlates of misreporting identified displayed no clear pattern across studies or dietary assessment techniques and had little utility in predicting misreporting.

p value variability and subgroup testing.

This article discusses the variability and randomness of p values, the most widely used currency of evidence in nutritional and health studies. One implication of this, the importance of always testing interaction terms when subgroups are examined and presented separately is also discussed.

The nutritional and cardiovascular health benefits of rapeseed oil-fed farmed salmon in humans are not decreased compared with those of traditionally farmed salmon: a randomized controlled trial.

PURPOSE: Farmed fish are increasingly raised on feeds containing vegetable oils, which affects their composition and possibly health properties. We investigated the effects of consuming farmed salmon, raised on different feeding regimes, on nutrient status and health outcomes in healthy subjects. METHODS: Salmon were grown on feeds containing mainly fish oil (FO) or rapeseed oil (RO), resulting in an eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) content of fillets of 2.1 or 0.9 g/100 g, respectively. In a randomized parallel controlled trial, 51 healthy subjects were allocated to consume 2 portions/week of FO salmon (n = 17), RO salmon (n = 17) or no additional salmon (Control, n = 17) as part of their habitual diet, for 18 weeks. We collected blood at 0, 9 and 18 weeks to measure omega-3 index (O3I) in red blood cells, plasma markers of cardiovascular risk, serum 25(OH)-vitamin D3 (25(OH)D3) and plasma trace elements. RESULTS: After 18 weeks, O3I was similarly increased in subjects consuming 2 portions/week of FO or RO salmon compared to control (both p < 0.05). Serum 25(OH)D3 was significantly higher, whereas plasma triacylglycerols were significantly lower in subjects consuming RO salmon compared to control (both p < 0.05). Heart rate was significantly lower in subjects consuming FO salmon after 9 weeks, compared to control (p < 0.01). Salmon consumption did not affect other markers. CONCLUSION: Consuming two portions/week of salmon raised on rapeseed oil rather than fish oil increased the O3I and vitamin D status, and decreased plasma triacylglycerols. These outcomes endorse opportunities for developing more sustainable feeds within aquaculture food systems. CLINICAL TRIAL REGISTRY: This trial was registered at clinicaltrials.gov as NCT01916434.

Randomized Trial of Ciprofloxacin Doxycycline and Hydroxychloroquine Versus Budesonide in Active Crohn's Disease.

BACKGROUND: Increased mucosa-associated E. coli are present in Crohn's disease, but their role in pathogenesis is uncertain. AIMS: To assess efficacy and safety of an antibiotic/hydroxychloroquine combination effective against E. coli inside macrophages. METHODS: Adults with moderately active disease (CDAI > 220-450 plus C reactive protein ≥ 5 mg/l and/or fecal calprotectin > 250 µg/g) were randomized to receive (open-label) oral budesonide (Entocort CR 9 mg/day 8 weeks, 6 mg/day 2 weeks, 3 mg/day 2 weeks) or oral ciprofloxacin 500 mg bd, doxycycline 100 mg bd, hydroxychloroquine 200 mg tds for 4 weeks, followed by doxycycline 100 mg bd and hydroxychloroquine 200 mg tds for 20 weeks. Primary endpoints were remission (CDAI ≤ 150) at 10 weeks, remission maintained to 24 weeks, and remission maintained to 52 weeks. Patients not responding (CDAI fall by > 70) by 10 weeks were invited to crossover onto the alternative therapy. RESULTS: Fifty-nine patients were recruited across 8 sites. Including crossover, 39 patients received antibiotics/hydroxychloroquine and 39 received budesonide. At 10 weeks, 24 weeks, and 52 weeks on initial therapy, only 2/27, 2/27, and 1/27 were in remission on antibiotics/hydroxychloroquine compared with 8/32, 1/32, and 1/32 on budesonide (P = 0.092 at 10 weeks). Withdrawals by 10 weeks due to adverse events were seen in 15 receiving antibiotics/hydroxychloroquine and 6 budesonide. Results including crossover were more promising with 9/24 patients receiving antibiotics/hydroxychloroquine per protocol in remission by 24 weeks. No correlation was seen between response to antibiotics/hydroxychloroquine and ASCA/OmpC antibody status or disease location. CONCLUSION: Overall results with this antibiotic/hydroxychloroquine combination were unimpressive, but long-term remission is seen in some patients and justifies further study.

A Theory- and Evidence-Based Digital Intervention Tool for Weight Loss Maintenance (NoHoW Toolkit): Systematic Development and Refinement Study.

BACKGROUND: Many weight loss programs show short-term effectiveness, but subsequent weight loss maintenance is difficult to achieve. Digital technologies offer a promising means of delivering behavior change approaches at low costs and on a wide scale. The Navigating to a Healthy Weight (NoHoW) project, which was funded by the European Union's Horizon 2020 research and innovation program, aimed to develop, test, and evaluate a digital toolkit designed to promote successful long-term weight management. The toolkit was tested in an 18-month, large-scale, international, 2×2 factorial (motivation and self-regulation vs emotion regulation) randomized controlled trial that was conducted on adults with overweight or obesity who lost ≥5% of their body weight in the preceding 12 months before enrollment into the intervention. OBJECTIVE: This paper aims to describe the development of the NoHoW Toolkit, focusing on the logic models, content, and specifications, as well as the results from user testing. METHODS: The toolkit was developed by using a systematic approach, which included the development of the theory-based logic models, the selection of behavior change techniques, the translation of these techniques into a web-based app (NoHoW Toolkit components), technical development, and the user evaluation and refinement of the toolkit. RESULTS: The toolkit included a set of web-based tools and inputs from digital tracking devices (smart scales and activity trackers) and modules that targeted weight, physical activity, and dietary behaviors. The final toolkit comprised 34 sessions that were distributed through 15 modules and provided active content over a 4-month period. The motivation and self-regulation arm consisted of 8 modules (17 sessions), the emotion regulation arm was presented with 7 modules (17 sessions), and the combined arm received the full toolkit (15 modules; 34 sessions). The sessions included a range of implementations, such as videos, testimonies, and questionnaires. Furthermore, the toolkit contained 5 specific data tiles for monitoring weight, steps, healthy eating, mood, and sleep. CONCLUSIONS: A systematic approach to the development of digital solutions based on theory, evidence, and user testing may significantly contribute to the advancement of the science of behavior change and improve current solutions for sustained weight management. Testing the toolkit by using a 2×2 design provided a unique opportunity to examine the effect of motivation and self-regulation and emotion regulation separately, as well as the effect of their interaction in weight loss maintenance.

Myocardial and Systemic Inflammation in Acute Stress-Induced (Takotsubo) Cardiomyopathy.

BACKGROUND: Acute stress-induced (takotsubo) cardiomyopathy can result in a heart failure phenotype with a prognosis comparable with that of myocardial infarction. In this study, we hypothesized that inflammation is central to the pathophysiology and natural history of takotsubo cardiomyopathy. METHODS: In a multicenter study, we prospectively recruited 55 patients with takotsubo cardiomyopathy and 51 age-, sex-, and comorbidity-matched control subjects. During the index event and at the 5-month follow-up, patients with takotsubo cardiomyopathy underwent multiparametric cardiac magnetic resonance imaging, including ultrasmall superparamagnetic particles of iron oxide (USPIO) enhancement for detection of inflammatory macrophages in the myocardium. Blood monocyte subpopulations and serum cytokines were assessed as measures of systemic inflammation. Matched control subjects underwent investigation at a single time point. RESULTS: Subjects were predominantly middle-aged (64±14 years) women (90%). Compared with control subjects, patients with takotsubo cardiomyopathy had greater USPIO enhancement (expressed as the difference between pre-USPIO and post-USPIO T2*) in both ballooning (14.3±0.6 milliseconds versus 10.5±0.9 milliseconds; P<0.001) and nonballooning (12.9±0.6 milliseconds versus 10.5±0.9 milliseconds; P=0.02) left ventricular myocardial segments. Serum interleukin-6 (23.1±4.5 pg/mL versus 6.5±5.8 pg/mL; P<0.001) and chemokine (C-X-C motif) ligand 1 (1903±168 pg/mL versus 1272±177 pg/mL; P=0.01) concentrations and classic CD14++CD16- monocytes (90±0.5% versus 87±0.9%; P=0.01) were also increased whereas intermediate CD14++CD16+ (5.4±0.3% versus 6.9±0.6%; P=0.01) and nonclassic CD14+CD16++ (2.7±0.3% versus 4.2±0.5%; P=0.006) monocytes were reduced in patients with takotsubo cardiomyopathy. At 5 months, USPIO enhancement was no longer detectable in the left ventricular myocardium, although persistent elevations in serum interleukin-6 concentrations ( P=0.009) and reductions in intermediate CD14++CD16+ monocytes (5.6±0.4% versus 6.9±0.6%; P=0.01) remained. CONCLUSIONS: We demonstrate for the first time that takotsubo cardiomyopathy is characterized by a myocardial macrophage inflammatory infiltrate, changes in the distribution of monocyte subsets, and an increase in systemic proinflammatory cytokines. Many of these changes persisted for at least 5 months, suggesting a low-grade chronic inflammatory state. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02897739.

Consistent sleep onset and maintenance of body weight after weight loss: An analysis of data from the NoHoW trial.

BACKGROUND: Several studies have suggested that reduced sleep duration and quality are associated with an increased risk of obesity and related metabolic disorders, but the role of sleep in long-term weight loss maintenance (WLM) has not been thoroughly explored using prospective data. METHODS AND FINDINGS: The present study is an ancillary study based on data collected on participants from the Navigating to a Healthy Weight (NoHoW) trial, for which the aim was to test the efficacy of an evidence-based digital toolkit, targeting self-regulation, motivation, and emotion regulation, on WLM among 1,627 British, Danish, and Portuguese adults. Before enrolment, participants had achieved a weight loss of ≥5% and had a BMI of ≥25 kg/m2 prior to losing weight. Participants were enrolled between March 2017 and March 2018 and followed during the subsequent 12-month period for change in weight (primary trial outcome), body composition, metabolic markers, diet, physical activity, sleep, and psychological mediators/moderators of WLM (secondary trial outcomes). For the present study, a total of 967 NoHoW participants were included, of which 69.6% were women, the mean age was 45.8 years (SD 11.5), the mean baseline BMI was 29.5 kg/m2 (SD 5.1), and the mean weight loss prior to baseline assessments was 11.4 kg (SD 6.4). Objectively measured sleep was collected using the Fitbit Charge 2 (FC2), from which sleep duration, sleep duration variability, sleep onset, and sleep onset variability were assessed across 14 days close to baseline examinations. The primary outcomes were 12-month changes in body weight (BW) and body fat percentage (BF%). The secondary outcomes were 12-month changes in obesity-related metabolic markers (blood pressure, low- and high-density lipoproteins [LDL and HDL], triglycerides [TGs], and glycated haemoglobin [HbA1c]). Analysis of covariance and multivariate linear regressions were conducted with sleep-related variables as explanatory and subsequent changes in BW, BF%, and metabolic markers as response variables. We found no evidence that sleep duration, sleep duration variability, or sleep onset were associated with 12-month weight regain or change in BF%. A higher between-day variability in sleep onset, assessed using the standard deviation across all nights recorded, was associated with weight regain (0.55 kg per hour [95% CI 0.10 to 0.99]; P = 0.016) and an increase in BF% (0.41% per hour [95% CI 0.04 to 0.78]; P = 0.031). Analyses of the secondary outcomes showed that a higher between-day variability in sleep duration was associated with an increase in HbA1c (0.02% per hour [95% CI 0.00 to 0.05]; P = 0.045). Participants with a sleep onset between 19:00 and 22:00 had the greatest reduction in diastolic blood pressure (DBP) (P = 0.02) but also the most pronounced increase in TGs (P = 0.03). The main limitation of this study is the observational design. Hence, the observed associations do not necessarily reflect causal effects. CONCLUSION: Our results suggest that maintaining a consistent sleep onset is associated with improved WLM and body composition. Sleep onset and variability in sleep duration may be associated with subsequent change in different obesity-related metabolic markers, but due to multiple-testing, the secondary exploratory outcomes should be interpreted cautiously. TRIAL REGISTRATION: The trial was registered with the ISRCTN registry (ISRCTN88405328).

Association between objectively measured sleep duration, adiposity and weight loss history.

BACKGROUND: An association between sleep and obesity has been suggested in several studies, but many previous studies relied on self-reported sleep and on BMI as the only adiposity measure. Moreover, a relationship between weight loss history and attained sleep duration has not been thoroughly explored. DESIGN: The study comprised of 1202 participants of the European NoHoW trial who had achieved a weight loss of ≥5% and had a BMI of ≥25 kg/m2 prior to losing weight. Information was available on objectively measured sleep duration (collected during 14 days), adiposity measures, weight loss history and covariates. Regression models were conducted with sleep duration as the explanatory variable and BMI, fat mass index (FMI), fat-free mass index (FFMI) and waist-hip ratio (WHR) as response variables. Analyses were conducted with 12-month weight loss, frequency of prior weight loss attempts or average duration of weight maintenance after prior weight loss attempts as predictors of measured sleep duration. RESULTS: After adjusting for physical activity, perceived stress, smoking, alcohol consumption, education, sex and age, sleep duration was associated to BMI (P < 0.001), with the highest BMI observed in the group of participants sleeping <6 h a day [34.0 kg/m2 (95% CI: 31.8-36.1)]. Less difference in BMI was detected between the remaining groups, with the lowest BMI observed among participants sleeping 8-<9 h a day [29.4 kg/m2 (95% CI: 28.8-29.9)]. Similar results were found for FMI (P = 0.008) and FFMI (P < 0.001). We found no association between sleep duration and WHR. Likewise, we found no associations between weight loss history and attained sleep duration. CONCLUSION: In an overweight population who had achieved a clinically significant weight loss, short sleep duration was associated with higher BMI, with similar associations for fat and lean mass. We found no evidence of association between weight loss history and attained sleep duration.

Nondigestible Carbohydrates Affect Metabolic Health and Gut Microbiota in Overweight Adults after Weight Loss.

BACKGROUND: The composition of diets consumed following weight loss (WL) can have a significant impact on satiety and metabolic health. OBJECTIVE: This study was designed to test the effects of including a nondigestible carbohydrate to achieve weight maintenance (WM) following a period of WL. METHODS: Nineteen volunteers [11 females and 8 males, aged 20-62 y; BMI (kg/m2): 27-42] consumed a 3-d maintenance diet (15%:30%:55%), followed by a 21-d WL diet (WL; 30%:30%:40%), followed by 2 randomized 10-d WM diets (20%:30%:50% of energy from protein:fat:carbohydrate) containing either resistant starch type 3 (RS-WM; 22 or 26 g/d for females and males, respectively) or no RS (C-WM) in a within-subject crossover design without washout periods. The primary outcome, WM after WL, was analyzed by body weight. Secondary outcomes of fecal microbiota composition and microbial metabolite concentrations and gut hormones were analyzed in fecal samples and blood plasma, respectively. All outcomes were assessed at the end of each dietary period. RESULTS: Body weight was similar after the RS-WM and C-WM diets (90.7 and 90.8 kg, respectively), with no difference in subjectively rated appetite. During the WL diet period plasma ghrelin increased by 36% (P < 0.001), glucose-dependent insulinotropic polypeptide (GIP) decreased by 33% (P < 0.001), and insulin decreased by 46% (P < 0.001), but no significant differences were observed during the RS-WM and C-WM diet periods. Fasting blood glucose was lower after the RS-WM diet (5.59 ± 0.31 mmol/L) than after the C-WM diet [5.75 ± 0.49 mmol/L; P = 0.015; standard error of the difference between the means (SED): 0.09]. Dietary treatments influenced the fecal microbiota composition (R2 = 0.054, P = 0.031) but not diversity. CONCLUSIONS: The metabolic benefits, for overweight adults, from WL were maintained through a subsequent WM diet with higher total carbohydrate intake. Inclusion of resistant starch in the WM diet altered gut microbiota composition positively and resulted in lower fasting glucose compared with the control, with no apparent change in appetite. This trial was registered at clinicaltrials.gov as NCT01724411.