Plasticity of Gene Expression and Thermal Tolerance: Implications for Climate Change Vulnerability in a Tropical Forest Lizard.

AbstractTropical ectotherms are thought to be especially vulnerable to climate change because they have evolved in temporally stable thermal environments and therefore have decreased tolerance for thermal variability. Thus, they are expected to have narrow thermal tolerance ranges, live close to their upper thermal tolerance limits, and have decreased thermal acclimation capacity. Although models often predict that tropical forest ectotherms are especially vulnerable to rapid environmental shifts, these models rarely include the potential for plasticity of relevant traits. We measured phenotypic plasticity of thermal tolerance and thermal preference as well as multitissue transcriptome plasticity in response to warmer temperatures in a species that previous work has suggested is highly vulnerable to climate warming, the Panamanian slender anole lizard (Anolis apletophallus). We found that many genes, including heat shock proteins, were differentially expressed across tissues in response to short-term warming. Under long-term warming, the voluntary thermal maxima of lizards also increased, although thermal preference exhibited only limited plasticity. Using these data, we modeled changes in the activity time of slender anoles through the end of the century under climate change and found that plasticity should delay declines in activity time by at least two decades. Our results suggest that slender anoles, and possibly other tropical ectotherms, can alter the expression of genes and phenotypes when responding to shifting environmental temperatures and that plasticity should be considered when predicting the future of organisms under a changing climate.

Colonization during a key developmental window reveals microbiota-dependent shifts in growth and immunity during undernutrition.

BACKGROUND: Childhood undernutrition is a major global health challenge with devastating lifelong consequences. Linear growth stunting due to undernutrition has been linked to poor health outcomes, and mothers who experience growth stunting in childhood are more likely to give birth to stunted children later in life. Based on these findings, we hypothesized that intergenerational colonization of mice with microbiota from human donors with undernutrition may recapitulate certain immune and growth changes observed in this disorder. RESULTS: To test this hypothesis, we developed a gnotobiotic murine model of undernutrition using microbiota from human infants with healthy or stunted growth trajectories. Intergenerational colonization with microbiota derived from children with growth stunting lead to less linear growth and the development of immune features of undernutrition and enteropathy, including intestinal villus blunting, lower liver IGF-1 and accumulation of intraepithelial lymphocytes and plasma cells in the small intestine. In contrast, colonization after weaning lead to fewer host phenotypic changes between these distinct microbial communities. CONCLUSIONS: These results are broadly consistent with previous findings demonstrating that exposure of the immune system to microbial products during the weaning phase is a critical determinant of later life immune function. Overall, our results suggest intergenerational colonization with human microbiota samples is a useful approach with which to investigate microbiota-dependent changes in growth and immunity in early life. Murine models that capture the intergenerational and multifactorial nature of undernutrition are critical to understanding the underlying biology of this disorder. Video Abstract.

A comprehensive investigation of the association between menopause symptoms and problematic eating behavior in peri- and post-menopause cisgender women.

Midlife individuals assigned female at birth are at risk for problematic eating behavior, associated with negative health outcomes. Little is known about how menopausal symptoms may increase risk in this population. The current study aimed to understand how a comprehensive range of menopause symptoms were globally associated with problematic eating behaviors. A total of 281 cisgender women (176 post-menopause, 105 peri-menopause) from the United States aged 40 to 64 were recruited utilizing Prolific, an online survey platform. Participants answered questionnaires about menopause symptoms and problematic eating. Participants were selected using demographic and health information provided in a screener survey. Participants also completed the Eating Disorder Questionnaire (EDE-Q), Women's Health Questionnaire (WHQ), Patient Health Questionnaire-8 (PHQ-8), Generalized Anxiety Disorder-7 (GAD-7), and Pittsburgh Sleep Quality Index (PSQI). Using Structural Equation Modeling, menopause symptoms explained 16.7 percent of the variance in problematic eating. Higher frequency and severity of anxiety, depression, sleep concerns, cognitive complaints, pain, and vasomotor symptoms was associated with greater frequency and severity of problematic eating behaviors, ß = .40, p < .001. Invariance testing showed no significant differences between peri- and postmenopausal women. These findings support the association between menopause symptoms and problematic eating in Midlife cisgender women and highlight the need for continued investigation.

Wild Blueberry Extract Intervention in Healthy Older Adults: A Multi-Study, Randomised, Controlled Investigation of Acute Cognitive and Cardiovascular Effects.

BACKGROUND: Circadian and homeostatic declines in cognitive performance are observed during the day, most commonly at 14:00. Additionally, postprandial reductions in cognitive ability have been widely demonstrated 1 h after lunch consumption, affecting domains of executive functioning (EF), episodic memory (EM), and attention. Existing evidence shows that anthocyanin-rich foods such as berries may improve or attenuate the decline in EF and EM in ageing adults. Further research is required to assess whether extracts such as wild blueberry extract (WBE) may be beneficial for cognitive function across an acute timeframe, including known periods of reduced functioning. OBJECTIVES: (1) Study 1: ROAB: To investigate the efficacy of WBE in maintaining EF and EM throughout the day alongside measures of cardiovascular outcomes in healthy older adults. A range of WBE doses were utilised to identify the optimal dose at which cognitive and cardiovascular effects occur. (2) Study 2: BEAT: To replicate alleviation of cognitive decline during a predicted post-lunch dip whilst also improving cardiovascular outcomes following acute WBE 222 mg supplementation. METHODS: Both studies employed a randomised, double-blind, cross-over, placebo-controlled design to explore the effects of WBE intervention versus placebo on several outcomes, including EM, EF, blood pressure, and heart rate in a healthy older adult population (aged 68-75). In ROAB, 28 participants received a single dose of WBE 111 mg, 222 mg, 444 mg, or 888 mg or placebo over a 5-week period, each separated by a 1-week washout. Outcomes were measured at 0 h, 2 h, 4 h, and 6 h post intervention, with intervention occurring immediately after baseline (0 h). In BEAT, 45 participants received WBE 222 mg and placebo (1-week washout). Outcomes were measured at 0 h and 6 h (14:00) when a post-lunch dip was anticipated. This was further enhanced by consumption of lunch 1 h prior to cognitive testing. The WBE 222 mg intervention aligned with known peaks in plasma blueberry polyphenol metabolites at 2 h post dosing, which would coincide with a predicted drop in post-lunch performance. RESULTS: ROAB: A significant dip in executive function was apparent at the 4 h timepoint for placebo only, indicating attenuation for WBE doses. Strikingly, WBE 222 mg produced acute reductions in both systolic and diastolic blood pressure compared with placebo. BEAT: EF reaction time was found to be significantly faster for WBE 222 compared to placebo at the predicted post-lunch dip (14:00), with no other notable benefits on a range of cognitive and cardiovascular outcomes. CONCLUSION: These two studies indicate that WBE may have cardiovascular benefits and attenuate the natural cognitive decline observed over the course of the day, particularly when a decline is associated with a circadian rhythm-driven postprandial dip. However, it is important to acknowledge that effects were subtle, and benefits were only observed on a small number of outcomes. Further research is required to explore the utility of WBE in populations already experiencing mild cognitive impairments.

Lifetime effects and cost-effectiveness of standard and higher-intensity statin therapy across population categories in the UK: a microsimulation modelling study.

Background: Cardiovascular disease incidence and mortality have declined across developed economies and granular up-to-date cost-effectiveness evidence is required for treatments targeting large populations. To assess the health benefits and cost-effectiveness of standard and higher intensity statin therapy in the contemporary UK population 40-70 years old. Methods: A cardiovascular disease microsimulation model, developed using the Cholesterol Treatment Trialists' Collaboration data (117,896 participants; 5 years follow-up), and calibrated in the UK Biobank cohort (501,854 participants; 9 years follow-up), projected risks of myocardial infarction, stroke, coronary revascularization, diabetes, cancer and vascular and nonvascular death for all UK Biobank participants without and with statin treatment. Meta-analyses of trials and cohort studies informed statins' relative effects on cardiovascular events, incident diabetes, myopathy and rhabdomyolysis. UK healthcare perspective was taken (2020/2021 UK£) with costs per 28 tablets of £1.10 for standard (35%-45% LDL cholesterol (LDL-C) reduction) and £1.68 for higher intensity (≥45% LDL-C reduction) generic statin. Findings: Across categories by sex, age, LDL-C, and cardiovascular disease history/10-year cardiovascular risk, lifetime standard statin increased survival by 0.28-1.85 years (0.20-1.09 quality-adjusted life years (QALYs)), and higher intensity statin by further 0.06-0.40 years (0.03-0.20 QALYs) per person. Standard statin was cost-effective across all categories with incremental cost per QALY from £280 to £8530, with higher intensity statin cost-effective at higher cardiovascular risks and higher LDL-C levels. Stopping statin early reduced benefits and was not cost-effective. Interpretation: Lifetime low-cost statin therapy is cost-effective across all 40-70 years old in UK. Strengthening and widening statin treatment could cost-effectively improve population health. Funding: UK NIHR Health Technology Assessment Programme (17/140/02).

Long-term cardiovascular risks and the impact of statin treatment on socioeconomic inequalities: a microsimulation model.

BACKGROUND: UK cardiovascular disease (CVD) incidence and mortality have declined in recent decades but socioeconomic inequalities persist. AIM: To present a new CVD model, and project health outcomes and the impact of guideline-recommended statin treatment across quintiles of socioeconomic deprivation in the UK. DESIGN AND SETTING: A lifetime microsimulation model was developed using 117 896 participants in 16 statin trials, 501 854 UK Biobank (UKB) participants, and quality-of-life data from national health surveys. METHOD: A CVD microsimulation model was developed using risk equations for myocardial infarction, stroke, coronary revascularisation, cancer, and vascular and non-vascular death, estimated using trial data. The authors calibrated and further developed this model in the UKB cohort, including further characteristics and a diabetes risk equation, and validated the model in UKB and Whitehall II cohorts. The model was used to predict CVD incidence, life expectancy, quality-adjusted life years (QALYs), and the impact of UK guideline-recommended statin treatment across socioeconomic deprivation quintiles. RESULTS: Age, sex, socioeconomic deprivation, smoking, hypertension, diabetes, and cardiovascular events were key CVD risk determinants. Model-predicted event rates corresponded well to observed rates across participant categories. The model projected strong gradients in remaining life expectancy, with 4-5-year (5-8 QALYs) gaps between the least and most socioeconomically deprived quintiles. Guideline-recommended statin treatment was projected to increase QALYs, with larger gains in quintiles of higher deprivation. CONCLUSION: The study demonstrated the potential of guideline-recommended statin treatment to reduce socioeconomic inequalities. This CVD model is a novel resource for individualised long-term projections of health outcomes of CVD treatments.

Caffeine gum improves 5 km running performance in recreational runners completing parkrun events.

PURPOSE: The purpose of this study was to determine whether caffeine gum improves the performance of recreational runners completing parkruns (weekly, 5 km, mass participant running events). METHODS: Thirty-six recreational runners (M = 31, F = 5; age 33.7 ± 10.7 y; BMI 23.1 ± 2.4 kg/m2) capable of running 5 km in < 25 min were recruited to a study at the Sheffield Hallam parkrun, UK. Runners were block randomized into one of three double-blind, placebo-controlled, cross-over intervention trials with caffeine gum as the treatment (n = 6 per intervention trial) or into one of three non-intervention trials that ran concurrently with the intervention trials (n = 6 per non-intervention trial). Changes in conditions across different parkruns were adjusted for using data from the non-intervention trials. Runners in the randomized cross-over intervention trials chewed gum supplying 300 mg of caffeine or a placebo gum for 5 min, starting 30 min before each parkrun. RESULTS: Caffeine gum improved 5 km parkrun performance by a mean of 17.28 s (95% CI 4.19, 30.37; P = 0.01). Adjustment for environmental conditions using data from the non-intervention trials attenuated the statistical significance (P = 0.04). Caffeine gum also decreased RPE by 1.21 (95% CI 0.30, 2.13; P = 0·01) units relative to placebo. CONCLUSIONS: A 300 mg dose of caffeine supplied in chewing gum improved the performance of recreational runners completing 5 km parkruns by an average of 17 s. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov: NCT02473575 before recruitment commenced.

A biphasic response to blueberry supplementation on depressive symptoms in emerging adults: a double-blind randomized controlled trial.

PURPOSE: The aim of the present study was to examine the acute and chronic effects of wild blueberry supplementation on mood, executive function, and serum biomarkers of neuroplasticity, inflammation, and oxidative stress in emerging adults with moderate-to-severe depressive symptoms. METHODS: In this double-blind trial, 60 emerging adults (Mage = 20.0 years, 32% male) with self-reported depressive symptoms were randomly assigned to receive a single blueberry drink (acute phase), followed by 6 weeks of daily blueberry supplementation (chronic phase), or a matched placebo drink. The primary outcome was Beck Depression Inventory-II (BDI-II) scores at 6-week follow-up. Further measures included momentary affect (PANAS-X) and accuracy on an executive function task. The data were analyzed using ANCOVAs adjusted for baseline values, sex, and habitual fruit and vegetable intake. Estimated marginal means were calculated to compare the treatment arms. RESULTS: The blueberry drink significantly improved positive affect (p = 0.026) and executive function (p = 0.025) at 2 h post-ingestion, with change scores being positively correlated in the blueberry group (r = 0.424, p = 0.017). However, after six weeks of supplementation the reduction in BDI-II scores was greater in the placebo group by 5.8 points (95% CI: 0.8-10.7, p = 0.023). Generalized anxiety and anhedonia also decreased significantly more in the placebo group. No significant differences were found for any of the biomarkers. CONCLUSIONS: Six weeks of wild blueberry supplementation were inferior to placebo in reducing depressive symptoms. Nevertheless, the correlated improvements in positive affect and executive function after a single dose of blueberries point to a beneficial, albeit transient, psychological effect. These contrasting results suggest a biphasic, hormetic-like response that warrants further investigation. TRIAL REGISTRATION: NCT04647019, dated 30 November, 2020.

The Relationship between Mushroom Intake and Cognitive Performance: An Epidemiological Study in the European Investigation of Cancer-Norfolk Cohort (EPIC-Norfolk).

The previous literature suggests that regular consumption of edible mushrooms may confer neuroprotective cognitive health benefits. To further investigate the possible association between mushrooms and brain function during ageing, data from a population-based study of diet and chronic disease (EPIC-Norfolk cohort) were analysed. Changes in mushroom intake were measured using a food frequency questionnaire at three health check (HC) points over an 18-year period, with participants categorised based on their consumption frequency. Cognitive performance was assessed at the final health check (3HC) via a battery of validated tests assessing a range of different cognitive domains. The findings revealed a significant reduction in mushroom intake over time, with 4.12% of the cohort giving up mushrooms after previously consuming them. At 3HC, mushroom consumers displayed better cognitive performance than non-consumers across multiple cognitive domains. This relationship was observed to be dose-dependent, with those consuming 1 or more portions per week showing the highest cognitive scores. These findings suggest that regular mushroom consumption may be beneficial for cognitive function during aging. Further randomised controlled trials will be needed to confirm any potential benefits of mushrooms on long-term cognitive health, alongside public health initiatives to promote mushroom consumption in this older-adult demographic.

A review of the effects of mushrooms on mood and neurocognitive health across the lifespan.

Mushrooms contain bioactive compounds with documented antioxidant and anti-inflammatory actions. Here, we present a systematic evaluation of epidemiological and clinical studies that investigate the role of mushrooms, either as a separate or integral dietary component, on neurocognition and mood. Following a search of four databases, a total of 34 human studies examining the effect of different mushrooms across varying age cohorts and health statuses were selected for inclusion. Epidemiological studies included in this review (n = 24) revealed a significant benefit of dietary patterns that included mushrooms of any species on cognition and mood in both healthy and compromised populations. However, the results obtained from intervention studies (n = 10) were mixed. Studies mainly investigated Lion's Mane (Hericium erinaceus), showing some enhancement of mood and cognitive function in middle-aged and older adults. Further acute and chronic human intervention studies are needed, using adequate sample sizes, employing appropriately sensitive neurocognitive tests, and investigating a range of dietary mushrooms, to confirm the effects of mushroom supplementation on neurocognition and mood in humans.

Estimating Costs Associated with Disease Model States Using Generalized Linear Models: A Tutorial.

Estimates of costs associated with disease states are required to inform decision analytic disease models to evaluate interventions that modify disease trajectory. Increasingly, decision analytic models are developed using patient-level data with a focus on heterogeneity between patients, and there is a demand for costs informing such models to reflect individual patient costs. Statistical models of health care costs need to recognize the specific features of costs data which typically include a large number of zero observations for non-users, and a skewed and heavy right-hand tailed distribution due to a small number of heavy healthcare users. Different methods are available for modelling costs, such as generalized linear models (GLMs), extended estimating equations and latent class approaches. While there are tutorials addressing approaches to decision modelling, there is no practical guidance on the cost estimation to inform such models. Therefore, this tutorial aims to provide a general guidance on estimating healthcare costs associated with disease states in decision analytic models. Specifically, we present a step-by-step guide to how individual participant data can be used to estimate costs over discrete periods for participants with particular characteristics, based on the GLM framework. We focus on the practical aspects of cost modelling from the conceptualization of the research question to the derivation of costs for an individual in particular disease states. We provide a practical example with step-by-step R code illustrating the process of modelling the hospital costs associated with disease states for a cardiovascular disease model.

Transdermal Blood Sampling for C-Peptide Is a Minimally Invasive, Reliable Alternative to Venous Sampling in Children and Adults With Type 1 Diabetes.

OBJECTIVE: C-peptide and islet autoantibodies are key type 1 diabetes biomarkers, typically requiring venous sampling, which limits their utility. We assessed transdermal capillary blood (TCB) collection as a practical alternative. RESEARCH DESIGN AND METHODS: Ninety-one individuals (71 with type 1 diabetes, 20 control; individuals with type 1 diabetes: aged median 14.8 years [interquartile range (IQR) 9.1-17.1], diabetes duration 4.0 years [1.5-7.7]; control individuals: 42.2 years [38.0-52.1]) underwent contemporaneous venous and TCB sampling for measurement of plasma C-peptide. Participants with type 1 diabetes also provided venous serum and plasma, and TCB plasma for measurement of autoantibodies to glutamate decarboxylase, islet antigen-2, and zinc transporter 8. The ability of TCB plasma to detect significant endogenous insulin secretion (venous C-peptide ≥200 pmol/L) was compared along with agreement in levels, using Bland-Altman. Venous serum was compared with venous and TCB plasma for detection of autoantibodies, using established thresholds. Acceptability was assessed by age-appropriate questionnaire. RESULTS: Transdermal sampling took a mean of 2.35 min (SD 1.49). Median sample volume was 50 µL (IQR 40-50) with 3 of 91 (3.3%) failures, and 13 of 88 (14.7%) <35 µL. TCB C-peptide showed good agreement with venous plasma (mean venous ln[C-peptide] - TCB ln[C-peptide] = 0.008, 95% CI [-0.23, 0.29], with 100% [36 of 36] sensitivity/100% [50 of 50] specificity to detect venous C-peptide ≥200 pmol/L). Where venous serum in multiple autoantibody positive TCB plasma agreed in 22 of 32 (sensitivity 69%), comparative specificity was 35 of 36 (97%). TCB was preferred to venous sampling (type 1 diabetes: 63% vs. 7%; 30% undecided). CONCLUSIONS: Transdermal capillary testing for C-peptide is a sensitive, specific, and acceptable alternative to venous sampling; TCB sampling for islet autoantibodies needs further assessment.

A novel, high-performance, low-volume, rapid luciferase immunoprecipitation system (LIPS) assay to detect autoantibodies to zinc transporter 8.

BACKGROUND: Zinc transporter 8 autoantibodies (ZnT8A) are thought to appear close to type 1 diabetes (T1D) onset and can identify high-risk multiple (≥2) autoantibody positive individuals. Radiobinding assays (RBA) are widely used for ZnT8A measurement but have limited sustainability. We sought to develop a novel, high-performance, non-radioactive luciferase immunoprecipitation system (LIPS) assay to replace RBA. METHODS: A custom dual C-terminal ZnT8 (aa268-369; R325/W325) heterodimeric antigen, tagged with a NanoluciferaseTM (Nluc-ZnT8) reporter, and LIPS assay was developed. Assay performance was evaluated by testing sera from new onset T1D (n = 573), healthy schoolchildren (n = 521), and selected first-degree relatives (FDRs) from the Bart's Oxford family study (n = 617; 164 progressed to diabetes). RESULTS: In new-onset T1D, ZnT8A levels by LIPS strongly correlated with RBA (Spearman's r = 0.89; P < 0.0001), and positivity was highly concordant (94.3%). At a high specificity (95%), LIPS and RBA had comparable assay performance [LIPS pROC-AUC(95) 0.032 (95% CI: 0.029-0.036); RBA pROC-AUC(95) 0.031 (95% CI: 0.028-0.034); P = 0.376]. Overall, FDRs found positive by LIPS or RBA had a comparable 20-year diabetes risk (52.6% and 59.7%, respectively), but LIPS positivity further stratified T1D risk in FDRs positive for at least one other islet autoantibody detected by RBA (P = 0.0346). CONCLUSION: This novel, high-performance, cheaper, quicker, higher throughput, low blood volume Nluc-ZnT8 LIPS assay is a safe, non-radioactive alternative to RBA with enhanced sensitivity and ability to discriminate T1D progressors. This method offers an advanced approach to current strategies to screen the general population for T1D risk for immunotherapy trials and to reduce rates of diabetic ketoacidosis at diagnosis.

The role of diet and host species in shaping the seasonal dynamics of the gut microbiome.

The gut microbiome plays an important role in the health and fitness of hosts. While previous studies have characterized the importance of various ecological and evolutionary factors in shaping the composition of the gut microbiome, most studies have been cross-sectional in nature, ignoring temporal variation. Thus, it remains unknown how these same factors might affect the stability and dynamics of the gut microbiome over time, resulting in variation across the tree of life. Here, we used samples collected in each of four seasons for three taxa: the herbivorous southern white rhinoceros (Ceratotherium simum simum, n = 5); the carnivorous Sumatran tiger (Panthera tigris sumatrae, n = 5); and the red panda (Ailurus fulgens, n = 9), a herbivorous carnivore that underwent a diet shift in its evolutionary history from carnivory to a primarily bamboo-based diet. We characterize the variability of the gut microbiome among these three taxa across time to elucidate the influence of diet and host species on these dynamics. Altogether, we found that red pandas exhibit marked seasonal variation in their gut microbial communities, experiencing both high microbial community turnover and high variation in how individual red panda's gut microbiota respond to seasonal changes. Conversely, while the gut microbiota of rhinoceros change throughout the year, all individuals respond in the same way to seasonal changes. Tigers experience relatively low levels of turnover throughout the year, yet the ways in which individuals respond to seasonal transitions are highly varied. We highlight how the differences in microbiome richness and network connectivity between these three species may affect the level of temporal stability in the gut microbiota across the year.

Resolution of dysglycaemia after treatment of monoclonal gammopathy of endocrine significance.

In very rare cases of monoclonal gammopathy, insulin-binding paraprotein can cause disabling hypoglycaemia. We report a 67-year-old man re-evaluated for hyperinsulinaemic hypoglycaemia that persisted despite distal pancreatectomy. He had no medical history of diabetes mellitus or autoimmune disease but was being monitored for an IgG kappa monoclonal gammopathy of undetermined significance. On glucose tolerance testing, hyperglycaemia occurred at 60 min (glucose 216 mg/dL) and hypoglycaemia at 300 min (52 mg/dL) concurrent with an apparent plasma insulin concentration of 52 850 pmol/L on immunoassay. Laboratory investigation revealed an IgG2 kappa with very high binding capacity but low affinity (Kd 1.43 × 10-6 mol/L) for insulin. The monoclonal gammopathy was restaged as smouldering myeloma not warranting plasma cell-directed therapy from a haematological standpoint. Plasma exchange reduced paraprotein levels and improved fasting capillary glucose concentrations. Lenalidomide was used to treat disabling hypoglycaemia, successfully depleting paraprotein and leading to resolution of symptoms.

Impact of New Cardiovascular Events on Quality of Life and Hospital Costs in People With Cardiovascular Disease in the United Kingdom and United States.

BACKGROUND: Despite optimized risk factor control, people with prior cardiovascular disease remain at high cardiovascular disease risk. We assess the immediate- and longer-term impacts of new vascular and nonvascular events on quality of life (QoL) and hospital costs among participants in the REVEAL (Randomized Evaluation of the Effects of Anacetrapib Through Lipid Modification) trial in secondary prevention. METHODS AND RESULTS: Data on demographic and clinical characteristics, health-related quality of life (QoL: EuroQoL 5-Dimension-5-Level), adverse events, and hospital admissions during the 4-year follow-up of the 21 820 participants recruited in Europe and North America informed assessments of the impacts of new adverse events on QoL and hospital costs from the UK and US health systems' perspectives using generalized linear regression models. Reductions in QoL were estimated in the years of event occurrence for nonhemorrhagic stroke (-0.067 [United Kingdom], -0.069 [US]), heart failure admission (-0.072 [United Kingdom], -0.103 [US]), incident cancer (-0.064 [United Kingdom], -0.068 [US]), and noncoronary revascularization (-0.071 [United Kingdom], -0.061 [US]), as well as in subsequent years following these events. Myocardial infarction and coronary revascularization (CRV) procedures were not found to affect QoL. All adverse events were associated with additional hospital costs in the years of events and in subsequent years, with the highest additional costs in the years of noncoronary revascularization (£5830 [United Kingdom], $14 133 [US Medicare]), of myocardial infarction with urgent CRV procedure (£5614, $24722), and of urgent/nonurgent CRV procedure without myocardial infarction (£4674/£4651 and $15 251/$17 539). CONCLUSIONS: Stroke, heart failure, and noncoronary revascularization procedures substantially reduce QoL, and all cardiovascular disease events increase hospital costs. These estimates are useful in informing cost-effectiveness of interventions to reduce cardiovascular disease risk in secondary prevention. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01252953; https://www.Isrctn.com. Unique identifier: ISRCTN48678192; https://www.clinicaltrialsregister.eu. Unique identifier: 2010-023467-18.

Inulin-type fructans and 2'fucosyllactose alter both microbial composition and appear to alleviate stress-induced mood state in a working population compared to placebo (maltodextrin): the EFFICAD Trial, a randomized, controlled trial.

BACKGROUND: There is increasing interest in the bidirectional relationship existing between the gut and brain and the effects of both oligofructose and 2'fucosyllactose to alter microbial composition and mood state. Yet, much remains unknown about the ability of oligofructose and 2'fucosyllactose to improve mood state via targeted manipulation of the gut microbiota. OBJECTIVES: We aimed to compare the effects of oligofructose and 2'fucosyllactose alone and in combination against maltodextrin (comparator) on microbial composition and mood state in a working population. METHODS: We conducted a 5-wk, 4-arm, parallel, double-blind, randomized, placebo-controlled trial in 92 healthy adults with mild-to-moderate levels of anxiety and depression. Subjects were randomized to oligofructose 8 g/d (plus 2 g/d maltodextrin); maltodextrin 10 g/d; oligofructose 8 g/d plus 2'fucosyllactose (2 g/d) or 2'fucosyllactose 2 g/d (plus 8 g/d maltodextrin). Changes in microbial load (fluorescence in situ hybridization-flow cytometry) and composition (16S ribosomal RNA sequencing) were the primary outcomes. Secondary outcomes included gastrointestinal sensations, bowel habits, and mood state parameters. RESULTS: There were significant increases in several bacterial taxa including Bifidobacterium, Bacteroides, Roseburia, and Faecalibacterium prausnitzii in both the oligofructose and oligofructose/2'fucosyllactose interventions (all P ≤ 0.05). Changes in bacterial taxa were highly heterogenous upon 2'fuscoyllactose supplementation. Significant improvements in Beck Depression Inventory, State Trait Anxiety Inventory Y1 and Y2, and Positive and Negative Affect Schedule scores and cortisol awakening response were detected across oligofructose, 2'fucosyllactose, and oligofructose/2'fucosyllactose combination interventions (all P ≤ 0.05). Both sole oligofructose and oligofructose/2'fuscosyllactose combination interventions outperformed both sole 2'fucosyllactose and maltodextrin in improvements in several mood state parameters (all P ≤ 0.05). CONCLUSION: The results of this study indicate that oligofructose and combination of oligofructose/2'fucosyllactose can beneficially alter microbial composition along with improving mood state parameters. Future work is needed to understand key microbial differences separating individual responses to 2'fucosyllactose supplementation. This trial was registered at clinicaltrials.gov as NCT05212545.

Unconditional cash transfers reduce homelessness.

Homelessness is an economic and social crisis. In a cluster-randomized controlled trial, we address a core cause of homelessness-lack of money-by providing a one-time unconditional cash transfer of CAD$7,500 to each of 50 individuals experiencing homelessness, with another 65 as controls in Vancouver, BC. Exploratory analyses showed that over 1 y, cash recipients spent fewer days homeless, increased savings and spending with no increase in temptation goods spending, and generated societal net savings of $777 per recipient via reduced time in shelters. Additional experiments revealed public mistrust toward the ability of homeless individuals to manage money and demonstrated interventions to increase public support for a cash transfer policy using counter-stereotypical or utilitarian messaging. Together, this research offers a new approach to address homelessness and provides insights into homelessness reduction policies.

Colonization during a key developmental window reveals microbiota-dependent shifts in growth and immunity during undernutrition.

Childhood undernutrition is a major global health challenge with devastating lifelong consequences. Linear growth stunting due to undernutrition has been linked to poor outcomes, and mothers who experience stunting are more likely to give birth to stunted children. Murine models that capture the intergenerational and multifactorial nature of undernutrition are critical to understanding the underlying biology of this disorder. Here we report a gnotobiotic mouse model of undernutrition using microbiota from human infants with healthy or stunted growth trajectories. Intergenerational transmission of microbiota from parents to offspring leads to the development of growth and immune features of undernutrition and enteropathy, including reduced linear growth, intestinal villus blunting and accumulation of intraepithelial lymphocytes. In contrast, colonization after weaning reduces sensitivity to detect changes driven by distinct microbial communities. Overall, these results suggest intergenerational colonization is a useful approach with which to investigate microbiota-dependent growth and immunity in early life.