Characterization of heterogeneous skin constructs for full thickness skin regeneration in murine wound models.

An autologous heterogeneous skin construct (AHSC) has been developed and used clinically as an alternative to traditional skin grafting techniques for treatment of cutaneous defects. AHSC is manufactured from a small piece of healthy skin in a manner that preserves endogenous regenerative cellular populations. To date however, specific cellular and non-cellular contributions of AHSC to the epidermal and dermal layers of closed wounds have not been well characterized given limited clinical opportunity for graft biopsy following wound closure. To address this limitation, a three-part mouse full-thickness excisional wound model was developed for histologic and macroscopic graft tracing. First, fluorescent mouse-derived AHSC (mHSC) was allografted onto non-fluorescent recipient mice to enable macroscopic and histologic time course evaluation of wound closure. Next, mHSC-derived from haired pigmented mice was allografted onto gender- and major histocompatibility complex (MHC)-mismatched athymic nude mouse recipients. Resulting grafts were distinguished from recipient murine skin via immunohistochemistry. Finally, human-derived AHSC (hHSC) was xenografted onto athymic nude mice to evaluate engraftment and hHSC contribution to wound closure. Experiments demonstrated that mHSC and hHSC facilitated wound closure through production of viable, proliferative cellular material and promoted full-thickness skin regeneration, including hair follicles and glands in dermal compartments. This combined macroscopic and histologic approach to tracing AHSC-treated wounds from engraftment to closure enabled robust profiling of regenerated architecture and further understanding of processes underlying AHSC mechanism of action. These models may be applied to a variety of wound care investigations, including those requiring longitudinal assessments of healing and targeted identification of donor and recipient tissue contributions.

Quality evaluation of nutrition policies in early childhood education and care services in Nerang, QLD.

ISSUE ADDRESSED: Food environments in early childhood, such as early childhood education and care services, influence the development of dietary patterns and behaviours that traverse into adulthood, where they affect health and longevity. Nutrition policies are mandatory in early childhood education and care services in Australia and can positively or negatively shape the food environment. However, the quality of such nutrition policies is unknown. This study aimed to evaluate the comprehensiveness and strength of nutrition policies of early childhood education and care services among services participating in a university-community alliance in South East Queensland. METHODS: Early childhood education and care services (n = 12) in Nerang, Queensland, Australia, participated in a cross-sectional study evaluating the comprehensiveness and strength of nutrition policies across four domains (Nutrition Education, Nutrition Standards, Promoting Healthy Eating and Communication and Evaluation) of the Wellness in Child Care Assessment Tool. RESULTS: Nutrition policies evaluated in this study had median total comprehensiveness scores of 55 (out of 100) and median total strength scores of 19 (out of 100). 'Nutrition Education' had the highest median scores for comprehensiveness (67 out of 100) and strength (33 out of 100), while 'Nutrition Standards' had the lowest comprehensiveness score (41 out of 100), and 'Communication and Evaluation' had the lowest strength score (0 out of 100). CONCLUSIONS: All services have a nutrition policy, but there are opportunities to enhance both the content and linguistic strength of statements within policies related to nutrition domains. SO WHAT?: There is a clear need to improve the comprehensiveness and strength of written statements in nutrition policies across all four domains, particularly 'Nutrition Standards' and 'Communication and Evaluation'.

Detailed survey of an in vitro intestinal epithelium model by single-cell transcriptomics.

The co-culture of two adult human colorectal cancer cell lines, Caco-2 and HT29, on Transwell is commonly used as an in vitro gut mimic, yet the translatability of insights from such a system to adult human physiological contexts is not fully characterized. Here, we used single-cell RNA sequencing on the co-culture to obtain a detailed survey of cell type heterogeneity in the system and conducted a holistic comparison with human physiology. We identified the intestinal stem cell-, transit amplifying-, enterocyte-, goblet cell-, and enteroendocrine-like cells in the system. In general, the co-culture was fetal intestine-like, with less variety of gene expression compared to the adult human gut. Transporters for major types of nutrients were found in the majority of the enterocytes-like cells in the system. TLR 4 was not expressed in the sample, indicating that the co-culture model is incapable of mimicking the innate immune aspect of the human epithelium.

Field-evolved pyrethroid resistance in Tychius picirostris (Coleoptera: Curculionidae) populations in Oregon white clover seed crops.

The clover seed weevil, Tychius picirostris Fabricius, a serious pest of white clover, Trifolium repens L., grown for seed in western Oregon, causing feeding damage to flowers and developing seeds. Since 2017, white clover seed producers have anecdotally reported T. picirostris control failures using foliar pyrethroid insecticide applications. This mode of action (MoA) is an important chemical control option for T. picirostris management. To evaluate insecticide resistance selection to pyrethroids (bifenthrin) and other MoAs labeled for T. picirostris management (malathion and chlorantraniliprole), adult populations were collected from 8 commercial white clover grown for seed fields in the Willamette Valley, OR, in 2022 and 2023. Among collected Oregon populations, very high resistance ratios (RR50 = 178.00-725.67) were observed to technical grade bifenthrin and low to high resistance ratios (RR50 = 7.80-32.80) to malathion in surface contact assays compared to a susceptible Canadian field population. Moreover, >2.73 times the labeled rate of formulated product containing bifenthrin as the sole MoA was required to kill >50% of T. picirostris in topical assays. Synergistic assays with a mixed-function oxidase inhibitor, an esterase inhibitor, and a glutathione-S-transferase inhibitor revealed phase I and II detoxification enzymes are present in Oregon T. picirostris populations and confer metabolic resistance to bifenthrin. This is the first report of T. picirostris insecticide resistance selection to pyrethroid and organophosphate insecticides. Results will inform continued monitoring and insecticide resistance management strategies to slow the evolution of T. picirostris insecticide resistance selection in Oregon's white clover seed production.

Impaired perceptual discrimination of complex objects in older adults at risk for dementia.

Tau pathology accumulates in the perirhinal cortex (PRC) of the medial temporal lobe (MTL) during the earliest stages of the Alzheimer's disease (AD), appearing decades before clinical diagnosis. Here, we leveraged perceptual discrimination tasks that target PRC function to detect subtle cognitive impairment even in nominally healthy older adults. Older adults who did not have a clinical diagnosis or subjective memory complaints were categorized into "at-risk" (score <26; n = 15) and "healthy" (score ≥26; n = 23) groups based on their performance on the Montreal Cognitive Assessment. The task included two conditions known to recruit the PRC: faces and complex objects (greebles). A scene condition, known to recruit the hippocampus, and a size control condition that does not rely on the MTL were also included. Individuals in the at-risk group were less accurate than those in the healthy group for discriminating greebles. Performance on either the face or size control condition did not predict group status above and beyond that of the greeble condition. Visual discrimination tasks that are sensitive to PRC function may detect early cognitive decline associated with AD.

Blocking methionine catabolism induces senescence and confers vulnerability to GSK3 inhibition in liver cancer.

Availability of the essential amino acid methionine affects cellular metabolism and growth, and dietary methionine restriction has been implicated as a cancer therapeutic strategy. Nevertheless, how liver cancer cells respond to methionine deprivation and underlying mechanisms remain unclear. Here we find that human liver cancer cells undergo irreversible cell cycle arrest upon methionine deprivation in vitro. Blocking methionine adenosyl transferase 2A (MAT2A)-dependent methionine catabolism induces cell cycle arrest and DNA damage in liver cancer cells, resulting in cellular senescence. A pharmacological screen further identified GSK3 inhibitors as senolytics that selectively kill MAT2A-inhibited senescent liver cancer cells. Importantly, combined treatment with MAT2A and GSK3 inhibitors therapeutically blunts liver tumor growth in vitro and in vivo across multiple models. Together, methionine catabolism is essential for liver tumor growth, and its inhibition can be exploited as an improved pro-senescence strategy for combination with senolytic agents to treat liver cancer.

Characterizing the alternative feedback mechanisms in the hypothalamic-pituitary-adrenal (HPA) axis and determining a stressed state in the African wild dog (Lycaon pictus).

Glucocorticoids are regulated by the hypothalamic-pituitary-adrenal (HPA) axis and are important in responding to various psychological and physiological stressors. For the African wild dog (Lycaon pictus) only one aspect of the HPA axis has been investigated with no information present on cortisol insufficiency. Here, a pilot study involving both HPA feedback mechanisms is characterized by dynamic function tests (i.e., stimulation and suppression) and a cutoff value for a stressed state is established. Results showed a mean plasma cortisol increase of 40.7% after the administration of Synacthen from initial values, with females recording higher concentrations than males. Using Youden's index, this adaptive response was able to determine a cutoff value of 80.72 ng/ml that infers a stress state. The observed response in the suppression test was similar to that reported in domestic dogs. These results expand the basic knowledge of adrenal function in this endangered species and provide a means in which to determine whether animals are stressed or not. The method used also has application to other species in gauging the degree of stress they are experiencing, which can assist in improving welfare outcomes for captive animals.

The Effects of Systemic Lupus-Related Cognitive Impairments on Activities of Daily Living and Life Role Participation: A Qualitative Framework Study.

OBJECTIVE: Cognitive impairment (CI) in systemic lupus erythematosus (SLE) negatively impacts health-related quality of life leading to activity limitations. This qualitative study aimed to (1) explore the effect of SLE-related CI on activities of daily living and life role participation and (2) describe factors influencing activity restriction and life role participation. METHODS: Semistructured, in-depth interviews of lived experience of CI in SLE were conducted with 24 participants with SLE. Sociodemographic and clinical data, and objective and subjective cognitive function, were collected to characterize participants. A qualitative thematic content analysis was undertaken guided by a framework analytical approach. RESULTS: Participants reported problems in multiple cognitive domains, with multiple perceived causes. CI was felt to impact work, social, domestic, and family life, health, and independence. Five overarching themes were represented in the data: (1) characterization of SLE-reported CI, (2) perceived cause of CI, (3) perceived impact of CI on activities of daily living and life role participation, (4) adaptations for managing CI, and (5) influence of CI adaptations on activities of daily living and life role participation. CONCLUSION: This study provides a better understanding of the patient experience of CI in SLE, how it impacts their lives, and what coping strategies they employ. It highlights the long-term challenges those with CI in SLE undergo and provides evidence for the urgent need to implement multidisciplinary treatment options. When managing CI, it may be beneficial to evaluate and understand available psychosocial support resources to help identify and reinforce relevant adaptations to improve health-related quality of life.

Consuming Mushrooms When Adopting a Healthy Mediterranean-Style Dietary Pattern Does Not Influence Short-Term Changes of Most Cardiometabolic Disease Risk Factors in Healthy Middle-Aged and Older Adults.

BACKGROUND: Mushrooms are a nutritious food, though knowledge of the effects of mushroom consumption on cardiometabolic risk factors is limited and inconsistent. OBJECTIVE: We assessed the effects of consuming mushrooms as part of a healthy United States Mediterranean-style dietary pattern (MED) on traditional and emerging cardiometabolic disease (CMD) risk factors. We hypothesized that adopting a MED diet with mushrooms would lead to greater improvements in multiple CMD risk factors. METHODS: Using a randomized, parallel study design, 60 adults (36 females, 24 males; aged 46 ± 12 y; body mass index 28.3 ± 2.84 kg/m2, mean ± standard deviation) without diagnosed CMD morbidities consumed a MED diet (all foods provided) without (control with breadcrumbs) or with 84 g/d of Agaricus bisporus (White Button, 4 d/wk) and Pleurotus ostreatus (Oyster, 3 d/wk) mushrooms for 8 wk. Fasting baseline and postintervention outcome measurements were traditional CMD risk factors, including blood pressure and fasting serum lipids, lipoproteins, glucose, and insulin. Exploratory CMD-related outcomes included lipoprotein particle sizes and indexes of inflammation. RESULTS: Adopting the MED-mushroom diet compared with the MED-control diet without mushrooms improved fasting serum glucose (change from baseline -2.9 ± 1.18 compared with 0.6 ± 1.10 mg/dL; time × group P = 0.034). Adopting the MED diet, independent of mushroom consumption, reduced serum total cholesterol (-10.2 ± 3.77 mg/dL; time P = 0.0001). Concomitantly, there was a reduction in high-density lipoprotein (HDL) cholesterol, buoyant HDL2b, and apolipoprotein A1, and an increase in lipoprotein(a) concentrations (main effect of time P < 0.05 for all). There were no changes in other measured CMD risk factors. CONCLUSIONS: Consuming a Mediterranean-style healthy dietary pattern with 1 serving/d of whole Agaricus bisporus and Pleurotus ostreatus mushrooms improved fasting serum glucose but did not influence other established or emerging CMD risk factors among middle-aged and older adults classified as overweight or obese but with clinically normal cardiometabolic health. TRIAL REGISTRATION NUMBER: https://www. CLINICALTRIALS: gov/study/NCT04259229?term=NCT04259229&rank=1.

Effect of High-Intensity Interval Training and Moderate-Intensity Continuous Training in People With Poststroke Gait Dysfunction: A Randomized Clinical Trial.

Background The exercise strategy that yields the greatest improvement in both cardiorespiratory fitness (V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$) and walking capacity poststroke has not been determined. This study aimed to determine whether conventional moderate-intensity continuous training (MICT) or high-intensity interval training (HIIT) have different effects on V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ and 6-minute walk distance (6MWD). Methods and Results In this 24-week superiority trial, people with poststroke gait dysfunction were randomized to MICT (5 days/week) or HIIT (3 days/week with 2 days/week of MICT). MICT trained to target intensity at the ventilatory anaerobic threshold. HIIT trained at the maximal tolerable treadmill speed/grade using a novel program of 2 work-to-recovery protocols: 30:60 and 120:180 seconds. V̇O2 and heart rate was measured during performance of the exercise that was prescribed at 8 and 24 weeks for treatment fidelity. Main outcomes were change in V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ and 6MWD. Assessors were blinded to the treatment group for V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ but not 6MWD. Secondary outcomes were change in ventilatory anaerobic threshold, cognition, gait-economy, 10-meter gait-velocity, balance, stair-climb performance, strength, and quality-of-life. Among 47 participants randomized to either MICT (n=23) or HIIT (n=24) (mean age, 62±11 years; 81% men), 96% completed training. In intention-to-treat analysis, change in V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ for MICT versus HIIT was 2.4±2.7 versus 5.7±3.1 mL·kg-1·min-1 (mean difference, 3.2 [95% CI, 1.5-4.8]; P<0.001), and change in 6MWD was 70.9±44.3 versus 83.4±53.6 m (mean difference, 12.5 [95% CI, -17 to 42]; P=0.401). HIIT had greater improvement in ventilatory anaerobic threshold (mean difference, 2.07 mL·kg-1·min-1 [95% CI, 0.59-3.6]; P=0.008). No other between-group differences were observed. During V̇O2 monitoring at 8 and 24 weeks, MICT reached 84±14% to 87±18% of V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ while HIIT reached 101±22% to 112±14% of V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ (during peak bouts). Conclusions HIIT resulted in more than a 2-fold greater and clinically important change in V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ than MICT. Training to target (ventilatory anaerobic threshold) during MICT resulted in ~3 times the minimal clinically important difference in 6MWD, which was similar to HIIT. These findings show proof of concept that HIIT yields greater improvements in cardiorespiratory fitness than conventional MICT in appropriately screened individuals. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03006731.

Using co-creation focus groups to customise a remote multidomain programme designed to increase dementia literacy.

OBJECTIVES: To adapt the content and functionalities of Brain Health PRO, a web-based multidomain program designed to increase dementia literacy, to the context and needs of users, providers and community organisations across Québec, Canada. DESIGN: Five consecutive qualitative co-creation focus group sessions 30-90 min in duration each, exploring potential barriers and facilitators to usability, accessibility, comprehensibility, participant recruitment and retention. SETTING: Virtual meetings. PARTICIPANTS: A 15-member team based in Québec and Ontario, Canada, consisting of 9 researchers (including a graduate student and the project coordinator), representing occupational therapy, sensory rehabilitation, neuropsychology, psychology, health science and research methods, 3 informal caregivers of older adults living with cognitive decline and 3 members of the Federation of Quebec Alzheimer Societies. DATA ANALYSIS: Session recordings were summarised through both qualitative description and thematic analysis. RESULTS: The synthesised recommendations included adjustments around diversity, the complexity and presentation styles of the materials, suggestions on refining the web interface and the measurement approaches; it influenced aspects of participant recruitment, retention efforts and engagement with the content of Brain Health PRO. CONCLUSIONS: Co-creation in dementia prevention research is important because it involves collaboration between researchers, community support and service providers, and persons with lived experience as care providers, in the design and implementation of clinical studies. This approach helps to ensure that the content and presentation of educational material is relevant and meaningful to the target population and those involved in its delivery, and it leads to a greater understanding of their needs and perspectives.

Nutrition risk and cognitive performance in community-living older adults without cognitive impairment: a cross-sectional analysis of the Canadian Longitudinal Study on Aging.

Malnutrition is correlated with poor cognition; however, an understanding of the association between nutrition risk, which precedes malnutrition, and cognition is lacking. This study aimed to determine if nutrition risk measured with the SCREEN-8 tool is associated with cognitive performance among cognitively healthy adults aged 55+, after adjusting for demographic and lifestyle covariates. Sex- and age-stratified analyses were also explored. Baseline data from the Canadian Longitudinal Study on Aging was used. Cognition was determined using a 6-measure composite score based on four executive functions and two memory tasks, taking into account age, sex, and education. Multivariable linear regression was performed while adjusting for body mass index (BMI), lifestyle, and health covariates in the entire sample (n = 11 378) and then stratified by sex and age. Approximately half of participants were female (54.5%) aged 65+ (54.1%). Greater nutrition risk was associated with poorer cognitive performance in the entire sample (F[1, 11 368] = 5.36, p = 0.021) and among participants aged 55-64 (n = 5227; F[1, 5217] = 5.45, p = 0.020). Sex differences in lifestyle and health factors associated with cognition were apparent, but nutrition risk was not associated with cognition in sex-stratified models. Based on this analysis, there may be an association between nutrition risk and cognitive performance in older adults. When screening for either cognitive impairment or nutrition risk, complementary assessments for these conditions is warranted, as early intervention may provide benefit.

Effect of sex on the APOE4-aging interaction in the white matter microstructure of cognitively normal older adults using diffusion-tensor MRI with orthogonal-tensor decomposition (DT-DOME).

The influence of the apolipoprotein E ε4 allele (APOE4) on brain microstructure of cognitively normal older adults remains incompletely understood, in part due to heterogeneity within study populations. In this study, we examined white-matter microstructural integrity in cognitively normal older adults as a function of APOE4 carrier status using conventional diffusion-tensor imaging (DTI) and the novel orthogonal-tensor decomposition (DT-DOME), accounting for the effects of age and sex. Age associations with white-matter microstructure did not significantly depend on APOE4 status, but did differ between sexes, emphasizing the importance of accounting for sex differences in APOE research. Moreover, we found the DT-DOME to be more sensitive than conventional DTI metrics to such age-related and sex effects, especially in crossing WM fiber regions, and suggest their use in further investigation of white matter microstructure across the life span in health and disease.

A comprehensive single cell data analysis of lymphoblastoid cells reveals the role of super-enhancers in maintaining EBV latency.

We probed the lifecycle of Epstein-Barr virus (EBV) on a cell-by-cell basis using single cell RNA sequencing (scRNA-seq) data from nine publicly available lymphoblastoid cell lines (LCLs). While the majority of LCLs comprised cells containing EBV in the latent phase, two other clusters of cells were clearly evident and were distinguished by distinct expression of host and viral genes. Notably, both were high expressors of EBV LMP1/BNLF2 and BZLF1 compared to another cluster that expressed neither gene. The two novel clusters differed from each other in their expression of EBV lytic genes, including glycoprotein gene GP350. The first cluster, comprising GP350- LMP1hi cells, expressed high levels of HIF1A and was transcriptionally regulated by HIF1-α. Treatment of LCLs with Pevonedistat, a drug that enhances HIF1-α signaling, markedly induced this cluster. The second cluster, containing GP350+ LMP1hi cells, expressed EBV lytic genes. Host genes that are controlled by super-enhancers (SEs), such as transcription factors MYC and IRF4, had the lowest expression in this cluster. Functionally, the expression of genes regulated by MYC and IRF4 in GP350+ LMP1hi cells were lower compared to other cells. Indeed, induction of EBV lytic reactivation in EBV+ AKATA reduced the expression of these SE-regulated genes. Furthermore, CRISPR-mediated perturbation of the MYC or IRF4 SEs in LCLs induced the lytic EBV gene expression, suggesting that host SEs and/or SE target genes are required for maintenance of EBV latency. Collectively, our study revealed EBV-associated heterogeneity among LCLs that may have functional consequence on host and viral biology.

Superior Capsule Reconstruction Using Acellular Dermal Allograft Secured at 45° of Glenohumeral Abduction Improves the Superior Stability of the Glenohumeral Joint in Irreparable Massive Posterosuperior Rotator Cuff Tears.

PURPOSE: The purpose of the current study was to create a dynamic cadaveric shoulder model to determine the effect of graft fixation angle on shoulder biomechanics following SCR and to assess which commonly used fixation angle (30° vs 45° of abduction) results in superior glenohumeral biomechanics. METHODS: Twelve fresh-frozen cadaveric shoulders were evaluated using a dynamic shoulder testing system. Humeral head translation, subacromial and glenohumeral contact pressures were compared among 4 conditions: 1) Intact, 2) Irreparable supra- and infraspinatus tendon tear, 3) SCR using acellular dermal allograft (ADA) fixation at 30° of abduction, and 4) SCR with ADA fixation at 45° of abduction. RESULTS: SCR at both 30° (0.287 mm, CI: -0.480 - 1.05 mm; P < .0001) and 45° (0.528 mm, CI: -0.239-1.305 mm; P = .0006) significantly decreased superior translation compared to the irreparably torn state. No significant changes in subacromial peak contact pressure were observed between any states. The average glenohumeral contact pressure increased significantly following creation of an irreparable RCT (373 kPa, CI: 304-443 vs 283 kPa, CI 214-352; P = .0147). The SCR performed at 45° (295 kPa, CI: 226-365, P = .0394) of abduction significantly decreased the average glenohumeral contact pressure compared to the RCT state. There was no statistically significant difference between the average glenohumeral contact pressure of the intact state and SCR at 30° and 45°. CONCLUSION: SCR improved the superior stability of the glenohumeral joint when the graft was secured at 30° or 45° of glenohumeral abduction. Fixation at 45° of glenohumeral abduction provided more stability than did fixation at 30°. CLINICAL RELEVANCE: Grafts attached at 45° of glenohumeral abduction biomechanically restore the glenohumeral stability after SCR using ADA better than fixation at 30° of glenohumeral abduction.

Association of mycophenolate and azathioprine use with cognitive function in systemic lupus.

OBJECTIVES: Cognitive dysfunction (CD) is a common manifestation of SLE that can have detrimental consequences for those affected. To date, no treatments have been approved for SLE-CD. This study aims to assess the association of azathioprine (AZA) and mycophenolate (MMF) use with SLE-CD, given that these medications have demonstrated neuroprotective qualities in prior studies. METHODS: Consecutive adult SLE patients presenting to a single healthcare center were considered for participation. The ACR neuropsychological battery for SLE was administered to consenting patients at 0, 6 and 12 months. Scores were compared with age- and sex-matched controls. Primary outcome was CD, defined as a z-score ≤-1.5 in two or more cognitive domains. Mixed-effects logistic regression models were constructed to estimate the odds of CD with respect to AZA and MMF use. RESULTS: A total of 300 participants representing 676 patient visits completed the study; 114 (38%) met criteria for CD at baseline. The cumulative AZA dose (g/kg) was associated with reduced odds of CD [odds ratio (OR) 0.76 (95% CI 0.58, 0.98), P = 0.04]. Years of AZA treatment was also associated with reduced odds of CD [OR 0.72 (95% CI 0.54, 0.97), P = 0.03]. MMF use was not associated with CD. CONCLUSION: AZA use was associated with significantly lower odds of SLE-CD, while MMF use was not. Additional studies are warranted to further investigate the relationship of AZA and SLE-CD.

The Role of the Gut Microbiome in Diet and Exercise Effects on Cognition: A Review of the Intervention Literature.

Interest in the gut-brain axis and its implications for neurodegenerative diseases, such as Alzheimer's disease and related dementias, is growing. Microbial imbalances in the gastrointestinal tract, which are associated with impaired cognition, may represent a therapeutic target for lowering dementia risk. Multicomponent lifestyle interventions are a promising dementia risk reduction strategy and most often include diet and exercise, behaviors that are also known to modulate the gut microbiome. A better understanding of the role of the gut microbiome in diet and exercise effects on cognition may help to optimize these lifestyle interventions. The purpose of this review is to summarize findings from diet and exercise interventions that have investigated cognitive changes via effects on the microbiome. We aim to discuss the underlying mechanisms, highlight current gaps in the field, and provide new research directions. There is evidence mainly from rodent studies supporting the notion that microbiota changes mediate the effects of diet and exercise on cognition, with potential mechanisms including end-product metabolites and regulation of local and systemic inflammation. The field lacks whole diet and exercise interventions, especially those involving human participants. It is further limited by heterogeneous rodent models, outcome assessments, and the absence of proper mediation analyses. Trials including older adults with dementia risk factors, factorial designs of diet and exercise, and pre and post measures of microbiota, end-product metabolites, and inflammation would help to elucidate and potentially leverage the role of the microbiome in lowering dementia risk through lifestyle modification.

Strategy-training post-stroke via tele-rehabilitation: a pilot randomized controlled trial.

PURPOSE: Long-term limitations in social participation are common after stroke. Whether these can be attenuated through a tele-rehabilitation approach is unknown. We were particularly interested in examining transfer of learning effects which could result in broader improvements in social participation. METHODS: We adapted a strategy training rehabilitation approach (tele-CO-OP) for remote delivery. Participants with chronic stroke were randomized to receive the intervention (EXPT) or to a wait list (Control). Feasibility and acceptability were measured via attendance scores, satisfaction with the training and therapist evaluation of engagement with the training. The primary outcome measure was the Canadian Occupational Performance Measure (COPM), a standardized semi-structured interview which elicits difficulties in day-to-day life. RESULTS: Seventeen participants were randomized. Tele-CO-OP was found to be feasible and acceptable: participants reported high satisfaction and engagement, and missed few sessions. Large effect sizes for transfer of learning effects were observed in favor of receiving tele-CO-OP vs being waitlisted. Significant benefits were also conferred to the Control group following receipt of tele-CO-OP. The intervention also appeared to improve mood. CONCLUSIONS: This exploratory study demonstrates the feasibility and acceptability of tele-CO-OP and provides preliminary evidence for transfer of learning effects to untrained everyday social participation activities. Trial registration number: NCT02724813.

Stroke results in long-term limitations in social participation.The Cognitive Orientation to daily Occupational Performance (CO-OP) Approach provides a potential avenue for ameliorating these limitations.This pilot randomized controlled trial demonstrated that it is feasible to deliver tele-CO-OP and that positive benefits may accrue to those receiving the intervention for both trained and untrained activities.Tele-CO-OP is a promising intervention for addressing long-term participation limitations in individuals with chronic stroke.

IL-1ß promotes IL-9-producing Th cell differentiation in IL-2-limiting conditions through the inhibition of BCL6.

IL-9-producing CD4+ T helper cells, termed Th9 cells, differentiate from naïve precursor cells in response to a combination of cytokine and cell surface receptor signals that are elevated in inflamed tissues. After differentiation, Th9 cells accumulate in these tissues where they exacerbate allergic and intestinal disease or enhance anti-parasite and anti-tumor immunity. Previous work indicates that the differentiation of Th9 cells requires the inflammatory cytokines IL-4 and TGF-ß and is also dependent of the T cell growth factor IL-2. While the roles of IL-4 and TGF-ß-mediated signaling are relatively well understood, how IL-2 signaling contributes to Th9 cell differentiation outside of directly inducing the Il9 locus remains less clear. We show here that murine Th9 cells that differentiate in IL-2-limiting conditions exhibit reduced IL-9 production, diminished NF-kB activation and a reduced NF-kB-associated transcriptional signature, suggesting that IL-2 signaling is required for optimal NF-kB activation in Th9 cells. Interestingly, both IL-9 production and the NF-kB transcriptional signature could be rescued by addition of the NF-kB-activating cytokine IL-1ß to IL-2-limiting cultures. IL-1ß was unique among NF-kB-activating factors in its ability to rescue Th9 differentiation as IL-2 deprived Th9 cells selectively induced IL-1R expression and IL-1ß/IL-1R1 signaling enhanced the sensitivity of Th9 cells to limiting amounts of IL-2 by suppressing expression of the Th9 inhibitory factor BCL6. These data shed new light on the intertwined nature of IL-2 and NF-kB signaling pathways in differentiating Th cells and elucidate the potential mechanisms that promote Th9 inflammatory function in IL-2-limiting conditions.