Effect of a probiotic formula on gastrointestinal health, immune responses and metabolic health in adults with functional constipation or functional diarrhea.

Objective: Our aim was to determine the efficacy of four-week probiotic supplementation on gastrointestinal health. The secondary objectives were to assess probiotic effects on immune reaction, as well as weight control and metabolic health. Methods: We conducted two randomized sub-trials, respectively, among subjects who were diagnosed with functional constipation (FC) or functional diarrhea (FDr) according to the Rome IV criteria. In each sub-trial, 70 eligible Chinese adults were randomized to receive a multi-strain probiotic combination or a placebo. Gastrointestinal symptoms, defecation habits, stool characteristics, blood and fecal biochemistry markers, anthropometrics measures, stress-associated responses, and intestinal flora changes were assessed at baseline and after probiotics intervention. Results: Four weeks of probiotic supplementation reduced overall gastrointestinal symptoms scores in FC participants (p < 0.0001). Their mean weekly stool frequency increased from 3.3 times to 6.2 times; immune response and inflammation markers improved with increases in serum IgA, IFN-γ and fecal sIgA, and decrease in hsCRP; most components of lipid profile were significantly ameliorated, with increases in HDL-C and reductions in TC and TG; body weight, body mass index and basal metabolic rate decreased following probiotics consumption. For FDr participants, probiotics consumption markedly reduced overall gastrointestinal symptom scores (p < 0.0001); decreased stool frequency by 3 times per week; increased IgA, IFN-γ, sIgA concentrations, while lowered hsCRP and IL-4 levels. Both FC and FDr participants had improvement in the scores of defecation habits, anxiety or depression, and perceived stress. Probiotics supplementation promoted the production of all three major short-chain fatty acids. No changes were observed in LDL-C, IgG, IgM, IL-8, IL-10 and motilin. Conclusion: Supplementation with the probiotic formula over a four-week period could help relieving gastrointestinal symptoms, improving satisfaction with defecation habits, emotional state and immune response, and ameliorating dysbacteriosis in participants with FC or FDr. It also had beneficial effects on lipid metabolism and weight control for FC participants.

Race and Ethnicity With Atherosclerotic Cardiovascular Disease Outcomes Within a Universal Health Care System: Insights From the CARTaGENE Study.

BACKGROUND: It remains unclear whether racial and ethnic disparities for atherosclerotic cardiovascular disease (ASCVD) persist within universal health care systems. We aimed to explore long-term ASCVD outcomes within a single-payer health care system with extensive drug coverage in Québec, Canada. METHODS: CARTaGENE (CaG) is a population-based prospective cohort study of individuals aged 40 to 69 years. We included only participants without previous ASCVD. The primary composite endpoint was time to the first ASCVD event (cardiovascular death, acute coronary syndrome, ischemic stroke-transient ischemic attack, or peripheral arterial vascular event). RESULTS: The study cohort included 18,880 participants followed for a median of 6.6 years (2009 to 2016). The mean age was 52 years, and 52.4% were female. After further adjustment for socioeconomic and cardiovascular factors, the increase in ASCVD risk for South Asians (SAs) was attenuated (hazard ratio [HR], 1.41; 95% confidence interval [CI], 0.75, 2.67), whereas Black participants' risk was lower (HR, 0.52; 95% CI, 0.29, 0.95) compared with White participants. After similar adjustments, there were no significant differences in ASCVD outcomes among the Middle Eastern, Hispanic, East-Southeast Asian, Indigenous, and mixed race-ethnicities participants and the White participants. CONCLUSIONS: After adjustment for CV risk factors, the risk of ASCVD was attenuated in the SA CaG participants. Intensive risk-factor modification may mitigate the ASCVD risk of the SAs. Within a universal health care context and comprehensive drug coverage, the ASCVD risk was lower among Black compared with White CaG participants. Future studies are needed to confirm whether universal and liberal access to health care and medications can reduce the rates of ASCVD among the Black population.

Attitudes About Artificially Intelligent Interactive Voice Response Systems Using Amazon Alexa in Cardiovascular Clinics: Insights from the VOICE-COVID-19 Study.

The acceptability of artificially intelligent interactive voice response (AI-IVR) systems in cardiovascular research settings is unclear. As a result, we evaluated peoples' attitudes regarding the Amazon Echo Show 8 device when used for electronic data capture in cardiovascular clinics. Participants were recruited following the Voice-Based Screening for SARS-CoV-2 Exposure in Cardiovascular clinics study. Overall, 215 people enrolled and underwent screening (mean age 46.1; 55% females) in the VOICE-COVID study and 58 people consented to participate in a post-screening survey. Following thematic analysis, four key themes affecting AI-IVR acceptability were identified. These were difficulties with communication (44.8%), limitations with available interaction modalities (41.4%), barriers with the development of therapeutic relationships (25.9%), and concerns with universality and accessibility (8.6%). While there are potential concerns with the use of AI-IVR technologies, these systems appeared to be well accepted in cardiovascular clinics. Increased development of these technologies could significantly improve healthcare access and efficiency.

External validation and extension of the TIMI risk score for heart failure in diabetes for patients with recent acute coronary syndrome: An analysis of the EXAMINE trial.

AIMS: The Thrombolysis in Myocardial Infarction Risk Score for Heart Failure (HF) in Diabetes (TRS-HFDM ) prognosticates HF hospitalization in people with type 2 diabetes (T2D). This study aimed to externally validate and extend its use for those with recent acute coronary syndrome (ACS). MATERIALS AND METHODS: The TRS-HFDM was externally validated in the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial (n = 5380) and extended with natriuretic biomarkers. Missing data were multiply imputed. Initial TRS-HFDM variables were previous HF (2 points), atrial fibrillation (1 point), coronary artery disease (1 point), estimated glomerular filtration rate <60 ml/min/1.73 m2 (1 point), and urine albumin-to-creatinine ratio 30-300 mg/g (1 point) and >300 mg/g (2 points). RESULTS: In total, HF hospitalization occurred in 193 (3.6%) patients. Based on the TRS-HFDM , 25% of patients were classified as intermediate risk (1 point), 30% were classified as high risk (2 points), 19% were classified as very-high risk (3 points) and 26% were classified as severe risk (≥4 points). Before model extension, discrimination (C-index 0.76, 95%·CI 0.73-0.80) and calibration (calibration slope 0.82, 95%·CI 0.65-1.0; calibration-in-the-large -0.15, 95%·CI -0.37-0.64) were moderate-to-good in individuals with T2D and recent ACS. The extension of TRS-HFDM with the addition of N-terminal pro-B-type natriuretic peptide (NT-ProBNP) improved discrimination (C-index 0.82, 95%·CI 0.79-0.85) and calibration (calibration slope 0.84, 95%·CI 0.66-1.02; calibration-in-the-large -0.12, 95%·CI -0.33-0.081) for this higher-risk population. CONCLUSION: The TRS-HFDM with the extension of NT-ProBNP improves risk stratification and generalizes the use of the risk score for patients with T2D and ACS. Future validation studies in ACS populations may be warranted.

Lotka-Volterra models for extraterrestrial self-replicating probes.

A sufficiently advanced extraterrestrial civilization can send out a swarm of self-replicating probes for space exploration. Given the fast-growing number of such a probe, even if there is only one extraterrestrial civilization sending out such probes in the Milky Way galaxy, we should still expect to see them. The fact that we do not consist part of the Fermi paradox. The suggestion that self-replicating probes will eventually mutate to consume their progenitors and therefore significantly reduce the number of total probes has been investigated and dismissed in the literature. In this work, we revisit this question with a more realistic Lotka-Volterra model and show that mutated probes would drive the progenitor probes into "extinction," thereby replacing them to spread throughout the galaxy. Thus, the efficiency of mutated probes in reducing the total number of self-replicating probes is even less than previously thought. As part of the analysis, we also suggest that, somewhat counter-intuitively, in designing self-replicating probes, one should not program them to stop replicating when sufficient mutation causes the probes to fail to recognize the progenitor probes as "self."

Personalized Nutrition Intervention Improves Health Status in Overweight/Obese Chinese Adults: A Randomized Controlled Trial.

Background: Overweight and obesity increase the risk of noncommunicable diseases (NCDs). Personalized nutrition (PN) approaches may provide tailored nutritional advice/service by focusing on individual's unique characteristics to prevent against NCDs. Objective: We aimed to compare the effect of PN intervention with the traditional "one size fits all" intervention on health status in overweight/obese Chinese adults. Methods: In this 12-week randomized controlled trial, 400 adults with BMI ≥24 kg/m2 were randomized to control group (CG, n = 200) and PN group (PNG, n = 200). The CG received conventional health guidance according to the Dietary Guidelines for Chinese Residents and Chinese DRIs Handbook, whereas the PNG experienced PN intervention that was developed by using decision trees based on the subjects' anthropometric measurements, blood samples (phenotype), buccal cells (genotype), and dietary and physical activity (PA) assessments (baseline and updated). Results: Compared with the conventional intervention, PN intervention significantly improved clinical outcomes of anthropometric (e.g., body mass index (BMI), body fat percentage, waist circumference) and blood biomarkers (e.g., blood lipids, uric acid, homocysteine). The improvement in clinical outcomes was achieved through behavior change in diet and PA. The subjects in the PNG had higher China dietary guidelines index values and PA levels. Personalized recommendations of "lose weight," "increase fiber" and "take multivitamin/mineral supplements" were the major contributors to the decrease of BMI and improvement of lipid profile. Conclusion: We provided the first evidence that PN intervention was more beneficial than conventional nutrition intervention to improve health status in overweight/obese Chinese adults. This study provides a model of framework for developing personalized advice in Chinese population.Chictr.org.cn (ChiCTR1900026226).

A randomized controlled trial of renin-angiotensin-aldosterone system inhibitor management in patients admitted in hospital with COVID-19.

BACKGROUND: Renin-angiotensin aldosterone system inhibitors (RAASi) are commonly used among patients hospitalized with a severe acute respiratory syndrome coronavirus 2 infection coronavirus disease 2019 (COVID-19). We evaluated whether continuation versus discontinuation of RAASi were associated with short term clinical or biochemical outcomes. METHODS: The RAAS-COVID-19 trial was a randomized, open label study in adult patients previously treated with RAASi who are hospitalized with COVID-19 (NCT04508985). Participants were randomized 1:1 to discontinue or continue RAASi. The primary outcome was a global rank score calculated from baseline to day 7 (or discharge) incorporating clinical events and biomarker changes. Global rank scores were compared between groups using the Wilcoxon test statistic and the negative binomial test (using incident rate ratio [IRR]) and the intention-to-treat principle. RESULTS: Overall, 46 participants were enrolled; 21 participants were randomized to discontinue RAASi and 25 to continue. Patients' mean age was 71.5 years and 43.5% were female. Discontinuation of RAASi, versus continuation, resulted in a non-statistically different mean global rank score (discontinuation 6 [standard deviation [SD] 6.3] vs continuation 3.8 (SD 2.5); P = .60). The negative binomial analysis identified that discontinuation increased the risk of adverse outcomes (IRR 1.67 [95% CI 1.06-2.62]; P = .027); RAASi discontinuation increased brain natriuretic peptide levels (% change from baseline: +16.7% vs -27.5%; P = .024) and the incidence of acute heart failure (33% vs 4.2%, P = .016). CONCLUSION: RAASi continuation in participants hospitalized with COVID-19 appears safe; discontinuation increased brain natriuretic peptide levels and may increase risk of acute heart failure; where possible, RAASi should be continued.

Real-World Safety of Sacubitril/Valsartan in Women and Men With Heart Failure and Reduced Ejection Fraction: A Meta-analysis.

BACKGROUND: Sacubitril/valsartan (SV) is a novel and effective therapy for heart failure with reduced ejection fraction (HFrEF). Despite several sex-specific particularities that may influence drug effects, there has been no prior study evaluating the safety of SV in women with HFrEF in the "real-world." METHODS: We performed a literature search to identify observational studies evaluating SV. We contacted all authors to obtain sex-specific data on major adverse outcomes. We compared all-cause and cardiovascular (CV) deaths, heart failure hospitalizations, hyperkalemia, and hypotension in men and women. RESULTS: We identified five cohort studies enrolling 8,981 patients; 6,092 men (67.8%) and 2,889 women (32.2%). The mean age was 67 years in both sexes. The rates for all-cause mortality, CV mortality, heart failure hospitalizations, hypotension, and hyperkalemia were similar between women and men. Although the unadjusted aggregate rates of all-cause and CV mortalities were numerically higher in men than in women, these differences did not reach statistical differences. CONCLUSION: Our meta-analysis showed similar rates of major adverse events in men and women with HFrEF treated with SV. Larger observational studies with longer duration and a higher number of women are needed to confirm the long-term safety of SV in women in the clinical practice.

CONTEXTE: Le sacubitril/valsartan (SV) est un médicament novateur et efficace contre l'insuffisance cardiaque à fraction d'éjection réduite (ICFER). Malgré le fait que plusieurs particularités sexospécifiques peuvent influencer les effets du médicament, aucune étude préalable n'a été menée pour évaluer l'innocuité du SV chez les femmes atteintes d'ICFER dans la "vraie vie". MÉTHODOLOGIE: Nous avons effectué une recherche de la littérature pour recenser les études observationnelles évaluant le SV Nous avons communiqué avec tous les auteurs pour obtenir des données sexospécifiques sur les principaux issus défavorables. Nous avons comparé les données sur les décès toutes causes confondues et les décès d'origine cardiovasculaire (CV), les hospitalisations pour cause d'insuffisance cardiaque, l'hyperkaliémie et l'hypotension tant chez les hommes que chez les femmes. RÉSULTATS: Nous avons recensé cinq études de cohortes auxquelles ont participé 8 981 patients, soit 6 092 hommes (67,8 %) et 2 889 femmes (32,2 %). L'âge moyen était de 67 ans chez les patients des deux sexes. Les taux de décès toutes causes confondues, de décès d'origine CV, d'hospitalisation pour cause d'insuffisance cardiaque, d'hypotension et d'hyperkaliémie chez les femmes étaient similaires à ceux notés chez les hommes. Les taux globaux non ajustés de décès toutes causes confondues et de décès d'origine CV étaient numériquement plus élevés chez les hommes que chez les femmes, mais il n'y avait pas de différence sur le plan statistique. CONCLUSION: Notre méta-analyse a mis en évidence des taux similaires d'événements indésirables majeurs chez les hommes et chez les femmes atteints d'ICFER traités par le SV. Des études observationnelles à plus grande échelle avec de plus longue durée et un nombre plus élevé de femmes devront être menées pour confirmer l'innocuité à long terme du SV en pratique clinique chez les femmes.

Voice-based screening for SARS-CoV-2 exposure in cardiovascular clinics.

Aims: Artificial intelligence (A.I) driven voice-based assistants may facilitate data capture in clinical care and trials; however, the feasibility and accuracy of using such devices in a healthcare environment are unknown. We explored the feasibility of using the Amazon Alexa ('Alexa') A.I. voice-assistant to screen for risk factors or symptoms relating to SARS-CoV-2 exposure in quaternary care cardiovascular clinics. Methods and results: We enrolled participants to be screened for signs and symptoms of SARS-CoV-2 exposure by a healthcare provider and then subsequently by the Alexa. Our primary outcome was interrater reliability of Alexa to healthcare provider screening using Cohen's Kappa statistic. Participants rated the Alexa in a post-study survey (scale of 1 to 5 with 5 reflecting strongly agree). This study was approved by the McGill University Health Centre ethics board. We prospectively enrolled 215 participants. The mean age was 46 years [17.7 years standard deviation (SD)], 55% were female, and 31% were French speakers (others were English). In total, 645 screening questions were delivered by Alexa. The Alexa mis-identified one response. The simple and weighted Cohen's kappa statistic between Alexa and healthcare provider screening was 0.989 [95% confidence interval (CI) 0.982-0.997] and 0.992 (955 CI 0.985-0.999), respectively. The participants gave an overall mean rating of 4.4 (out of 5, 0.9 SD). Conclusion: Our study demonstrates the feasibility of an A.I. driven multilingual voice-based assistant to collect data in the context of SARS-CoV-2 exposure screening. Future studies integrating such devices in cardiovascular healthcare delivery and clinical trials are warranted. Registration: https://clinicaltrials.gov/ct2/show/NCT04508972.

Prediction of heart failure outcomes in patients with type 2 diabetes mellitus: Validation of the Thrombolysis in Myocardial Infarction Risk Score for Heart Failure in Diabetes (TRS-HFDM ) in patients in the ACCORD trial.

AIM: To investigate the ability of the Thrombolysis in Myocardial Infarction Risk Score for Heart Failure in Diabetes (TRS-HFDM ) to stratify patients with type 2 diabetes mellitus (T2DM) and high cardiovascular risk for heart failure (HF) hospitalization. MATERIALS AND METHODS: We used data from the control group of the Action to Control Cardiovascular Risk in Diabetes Study Group (ACCORD) trial (n = 5123; mean follow-up 4.8 years). The TRS-HFDM includes: prior HF (2 points), atrial fibrillation (1 point), coronary artery disease (1 point), estimated glomerular filtration rate <60 mL/min/1.73 m2 (1 point), and urine albumin-to-creatinine ratio (>300 mg/g: 2 points; 30-300 mg/g: 1 point). We evaluated the discrimination (Harrell's C-index) and calibration (Nam-D'Agostino calibration statistic) of the TRS-HFDM with regard to time to HF hospitalization or death due to HF. RESULTS: The mean age of the participants was 62.8 ± 6.6 years, and 38% were women. The prevalences of TRS-HFDM 0, 1, 2, 3 and ≥4 were 42.1%, 34.9%, 14.6%, 6.0% and 2.5%, respectively. Increasing TRS-HFDM corresponded to an increasing HF risk: 1.3 per 1000 person-years for a TRS-HFDM of 0 to 64.7 per 1000 person-years for TRS-HFDM of ≥4. The TRS-HFDM demonstrated robust discrimination of HF outcomes (C-index 0.78). Furthermore, the score was well calibrated for HF outcomes (calibration statistic P = 0.13). Similar results were seen in participants without baseline HF (C-index 0.75). CONCLUSION: The TRS-HFDM discriminates HF-specific risk among people with T2DM. The use of TRS-HFDM to identify those who would maximally benefit from therapies that reduce HF risk warrants evaluation.

Effects of Conventional Milk Versus Milk Containing Only A2 ß-Casein on Digestion in Chinese Children: A Randomized Study.

OBJECTIVES: In this study, we hypothesized that replacing conventional milk, which contains A1 and A2 ß-casein proteins, with milk that contains only A2 ß-casein in the diet of dairy or milk-intolerant preschoolers (age 5 to 6 years) would result in reduced gastrointestinal symptoms associated with milk intolerance, and that this would correspond with cognitive improvements. METHODS: This randomized, double-blind, crossover study aimed to compare the effects of 5 days' consumption of conventional milk versus milk containing only A2 ß-casein on gastrointestinal symptoms, as assessed via visual analog scales, average stool frequency and consistency, and serum inflammatory and immune biomarkers in healthy preschoolers with mild-to-moderate milk intolerance. The study also aimed to compare changes in the cognitive behavior of preschoolers, based on Subtle Cognitive Impairment Test scores. RESULTS: Subjects who consumed milk containing only A2 ß-casein had significantly less severe gastrointestinal symptoms as measured by visual analog scales, reduced stool frequency, and improvements in stool consistency, compared with subjects consuming conventional milk. There were significant increases from baseline in serum interleukin-4, immunoglobulins G, E, and G1, and beta-casomorphin-7 coupled to lower glutathione levels, in subjects consuming conventional milk compared with milk containing only A2 ß-casein. Subtle Cognitive Impairment Test analysis showed significant improvements in test accuracy after consumption of milk containing only A2 ß-casein. There were no severe adverse events related to consumption of either milk product. CONCLUSIONS: Replacing conventional milk with milk containing only A2 ß-casein reduced gastrointestinal symptoms associated with milk intolerance in Chinese preschool children, with corresponding improvements in aspects of cognitive performance.

Comparing external and internal validation methods in correcting outcome misclassification bias in logistic regression: A simulation study and application to the case of postsurgical venous thromboembolism following total hip and knee arthroplasty.

PURPOSE: We assessed the validity of postsurgery venous thromboembolism (VTE) diagnoses identified from administrative databases and compared Bayesian and multiple imputation (MI) approaches in correcting for outcome misclassification in logistic regression models. METHODS: Sensitivity and specificity of postsurgery VTE among patients undergoing total hip or knee replacement (THR/TKR) were assessed against chart review in six Montreal hospitals in 2009 to 2010. Administrative data on all THR/TKR Quebec patients in 2009 to 2010 were obtained. The performance of Bayesian external, Bayesian internal, and MI approaches to correct the odds ratio (OR) of postsurgery VTE in tertiary versus community hospitals was assessed using simulations. Bayesian external approach used prior information from external sources, while Bayesian internal and MI approaches used chart review. RESULTS: In total, 17 319 patients were included, 2136 in participating hospitals, among whom 75 had VTE in administrative data versus 81 in chart review. VTE sensitivity was 0.59 (95% confidence interval, 0.48-0.69) and specificity was 0.99 (0.98-0.99), overall. The adjusted OR of VTE in tertiary versus community hospitals was 1.35 (1.12-1.64) using administrative data, 1.45 (0.97-2.19) when MI was used for misclassification correction, and 1.53 (0.83-2.87) and 1.57 (0.39-5.24) when Bayesian internal and external approaches were used, respectively. In simulations, all three approaches reduced the OR bias and had appropriate coverage for both nondifferential and differential misclassification. CONCLUSION: VTE identified from administrative data had low sensitivity and high specificity. The Bayesian external approach was useful to reduce outcome misclassification bias in logistic regression; however, it required accurate specification of the misclassification properties and should be used with caution.

Correcting hazard ratio estimates for outcome misclassification using multiple imputation with internal validation data.

OBJECTIVE: Outcome misclassification may occur in observational studies using administrative databases. We evaluated a two-step multiple imputation approach based on complementary internal validation data obtained from two subsamples of study participants to reduce bias in hazard ratio (HR) estimates in Cox regressions. METHODS: We illustrated this approach using data from a surveyed sample of 6247 individuals in a study of statin-diabetes association in Quebec. We corrected diabetes status and onset assessed from health administrative data against self-reported diabetes and/or elevated fasting blood glucose (FBG) assessed in subsamples. The association between statin use and new onset diabetes was evaluated using administrative data and the corrected data. By simulation, we assessed the performance of this method varying the true HR, sensitivity, specificity, and the size of validation subsamples. RESULTS: The adjusted HR of new onset diabetes among statin users versus non-users was 1.61 (95% confidence interval: 1.09-2.38) using administrative data only, 1.49 (0.95-2.34) when diabetes status and onset were corrected based on self-report and undiagnosed diabetes (FBG ≥ 7 mmol/L), and 1.36 (0.92-2.01) when corrected for self-report and undiagnosed diabetes/impaired FBG (≥ 6 mmol/L). In simulations, the multiple imputation approach yielded less biased HR estimates and appropriate coverage for both non-differential and differential misclassification. Large variations in the corrected HR estimates were observed using validation subsamples with low participation proportion. The bias correction was sometimes outweighed by the uncertainty introduced by the unknown time of event occurrence. CONCLUSION: Multiple imputation is useful to correct for outcome misclassification in time-to-event analyses if complementary validation data are available from subsamples. Copyright © 2017 John Wiley & Sons, Ltd.

Clinical evaluation of glutathione concentrations after consumption of milk containing different subtypes of ß-casein: results from a randomized, cross-over clinical trial.

This study reports the plasma glutathione concentrations in a double-blind, randomized, controlled, 2 × 2 cross-over study in which healthy participants consumed conventional milk (2 × 250 mL per day) containing both A1 and A2 types of ß-casein, or milk containing only A2 type ß-casein. Beta-casomorphin-7 (BCM-7), a peptide uniquely derived from the A1 type of ß-casein, was previously reported to downregulate glutathione expression in human gut epithelial and neuronal cell lines by limiting cysteine uptake. The current human study demonstrates that consumption of milk containing only A2 ß-casein was associated with a greater increase in plasma glutathione concentrations compared with the consumption of milk containing both ß-casein types, and did not increase plasma BCM-7 concentrations compared with the washout diet in the study participants. Thus, milk containing only A2 ß-casein and not A1 ß-casein has the potential to promote the production of the antioxidant glutathione in humans. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; identifier: NCT02406469.

Effects of milk containing only A2 beta casein versus milk containing both A1 and A2 beta casein proteins on gastrointestinal physiology, symptoms of discomfort, and cognitive behavior of people with self-reported intolerance to traditional cows' milk.

BACKGROUND: Cows' milk generally contains two types of ß-casein, A1 and A2 types. Digestion of A1 type can yield the peptide ß-casomorphin-7, which is implicated in adverse gastrointestinal effects of milk consumption, some of which resemble those in lactose intolerance. This study aimed to compare the effects of milk containing A1 ß-casein with those of milk containing only A2 ß-casein on inflammation, symptoms of post-dairy digestive discomfort (PD3), and cognitive processing in subjects with self-reported lactose intolerance. METHODS: Forty-five Han Chinese subjects participated in this double-blind, randomized, 2 × 2 crossover trial and consumed milk containing both ß-casein types or milk containing only A2 ß-casein. Each treatment period was 14 days with a 14-day washout period at baseline and between treatment periods. Outcomes included PD3, gastrointestinal function (measured by smart pill), Subtle Cognitive Impairment Test (SCIT), serum/fecal laboratory biomarkers, and adverse events. RESULTS: Compared with milk containing only A2 ß-casein, the consumption of milk containing both ß-casein types was associated with significantly greater PD3 symptoms; higher concentrations of inflammation-related biomarkers and ß-casomorphin-7; longer gastrointestinal transit times and lower levels of short-chain fatty acids; and increased response time and error rate on the SCIT. Consumption of milk containing both ß-casein types was associated with worsening of PD3 symptoms relative to baseline in lactose tolerant and lactose intolerant subjects. Consumption of milk containing only A2 ß-casein did not aggravate PD3 symptoms relative to baseline (i.e., after washout of dairy products) in lactose tolerant and intolerant subjects. CONCLUSIONS: Consumption of milk containing A1 ß-casein was associated with increased gastrointestinal inflammation, worsening of PD3 symptoms, delayed transit, and decreased cognitive processing speed and accuracy. Because elimination of A1 ß-casein attenuated these effects, some symptoms of lactose intolerance may stem from inflammation it triggers, and can be avoided by consuming milk containing only the A2 type of beta casein. TRIAL REGISTRATION: ClinicalTrials.gov/NCT02406469.

α-Galacto-oligosaccharides Dose-Dependently Reduce Appetite and Decrease Inflammation in Overweight Adults.

BACKGROUND: Dietary fibers have been associated with a reduction in appetite and energy intake. Although a few studies suggest that nonviscous fibers can exert such effects, likely through colonic fermentation, limited data are available. OBJECTIVE: The objective of this study was to determine whether α-galacto-oligosaccharides (α-GOSs), fermentable soluble fibers extracted from legumes, could reduce appetite, food intake, and inflammation in overweight subjects. METHODS: In 2 single-center, double-blind, randomized, placebo-controlled trials, 88 overweight adults [50% men and 50% women; 18-60 y old; body mass index (in kg/m(2)): 25-28] were supplemented for 14 d with tea that contained α-GOSs with different α-GOS dosages (6, 12, or 18 g α-GOSs/d), formulas (12 g α-GOSs/d with >80% of molecules with a degree of polymerization of 2, 3, or 4), or a control substance (glucose syrup). Appetite scores (5 appetite dimensions were assessed on visual analog scales during a preload test meal), food intake (test meal and 24-h food recall), and inflammatory markers [plasma lipopolysaccharide (LPS) and C-reactive protein (CRP)] were evaluated at day 0 (baseline) and day 15. RESULTS: Changes in appetite scores from day 0 to day 15 were significantly higher after α-GOS intake, with areas under the curve for the satiety score of +121 ± 108, +218 ± 218, and +306 ± 205 score · min for 6, 12, and 18 g α-GOSs/d, respectively, and -5 ± 64 score · min for the control group. We observed dose-dependent effects that did not vary by α-GOS composition. The administration of 6, 12, or 18 g α-GOSs/d significantly and dose-dependently increased the change in energy intake from day 0 to day 15 during a test meal (-13 ± 19, -26 ± 22, and -32 ± 22 kcal, respectively; +6 ± 21 kcal for the control group). Reductions in energy intake during lunch and dinner were also higher in the α-GOS groups in the dose-effect study. At day 15, LPS was dose-dependently reduced without an association with α-GOS composition (0.16 ± 0.02, 0.12 ± 0.08, and 0.08 ± 0.05 EU/mL for 6, 12, and 18 g α-GOSs/d, respectively, and 0.06 ± 0.04 EU/mL for the control group) and CRP was significantly lower in the α-GOS groups than in the control group in the formulation-effect study. CONCLUSIONS: Consumption of α-GOSs for 14 d dose-dependently reduced appetite, food intake, and inflammation in overweight adults with no impact of α-GOS composition. Consequently, α-GOSs appear to promote long-term weight loss and mitigate metabolic disorders.

In vivo evaluation of the antitussive, expectorant and bronchodilating effects of extract and fractions from aerial parts of Peganum harmala linn.

ETHNOPHARMACOLOGICAL RELEVANCE: Aerial parts of Peganum harmala Linn (APP) is used as traditional medical herb in Uighur medicine in China, and it is traditionally used for treatment of cough and asthma.The aim of the present study is to evaluate the antitussive, expectorant and bronchodilating effects of extract and fractions (alkaloids and flavonoids) from APP, and to support its folk use with scientific evidence, and lay a foundation for its further researches. MATERIALS AND METHODS: APP was extracted with 50% ethanol by reflux, extracts were concentrated in vacuum to afford total extract of APP (EXT). EXT was separated to provide alkaloid fraction (ALK) and flavonoid fraction (FLA) by macroporous resin. Antitussive evaluations were carried out with cough models in mice and guinea pigs induced by ammonia liquor, capsaicin, and citric acid. Phenol red secretion experiments in mice were performed to evaluate the expectorant activity. Bronchodilating activities were evaluated with a bronchoconstrictive challenge induced by acetylcholine chloride and histamine in guinea pigs. RESULTS: In all the three antitussive tests, the EXT and ALK could significantly inhibit the frequency of cough, and prolong the cough latent period in animals. High dose of EXT (1650 mg/kg) and ALK (90 mg/kg) in mice and in guinea pigs created therapeutic activities as good as that of codeine phosphate (30 mg/kg). EXT could significantly increase phenol red secretion in mice for 0.64, 1.08 and 1.29 fold averagely at dosages of 183, 550, and 1650 mg/kg, ALK for 0.63, 0.96, 1.06 fold averagely at dosages of 10, 30, and 90 mg/kg, and ammonium chloride (1500 mg/kg, standard expectorant drug) for 0.97 fold, comparing with control group. Aminophylline could dramatically prolong the preconvulsive time for 162.28% in guinea pigs, EXT for 67.34%, 101.96% and 138.00% at dosages of 183, 550, and 1650 mg/kg, ALK for 55.47%, 97.74% and 126.77% at dosages of 10, 30, and 90 mg/kg, and FLA for 84.69%, 95.94% and 154.52% at dosages of 10, 30, and 90 mg/kg, comparing with pretreatment. CONCLUSIONS: APP is an effective traditional folk medicine for the treatment of cough with potent antitussive, expectorant and bronchodilating activities. The alkaloid fraction is proved to be the most effective components of APP. The alkaloids from APP may be valuable lead compounds for drug development of respiratory diseases.

Probiotics reduce symptoms of antibiotic use in a hospital setting: a randomized dose response study.

Probiotics are known to reduce antibiotic associated diarrhea (AAD) and Clostridium difficile associated diarrhea (CDAD) risk in a strain-specific manner. The aim of this study was to determine the dose-response effect of a four strain probiotic combination (HOWARU(®) Restore) on the incidence of AAD and CDAD and severity of gastrointestinal symptoms in adult in-patients requiring antibiotic therapy. Patients (n=503) were randomized among three study groups: HOWARU(®) Restore probiotic 1.70×10(10) CFU (high-dose, n=168), HOWARU(®) Restore probiotic 4.17×10(9) CFU (low-dose, n=168), or placebo (n=167). Subjects were stratified by gender, age, and duration of antibiotic treatment. Study products were administered daily up to 7 days after the final antibiotic dose. The primary endpoint of the study was the incidence of AAD. Secondary endpoints included incidence of CDAD, diarrhea duration, stools per day, bloody stools, fever, abdominal cramping, and bloating. A significant dose-response effect on AAD was observed with incidences of 12.5, 19.6, and 24.6% with high-dose, low-dose, and placebo, respectively (p=0.02). CDAD was the same in both probiotic groups (1.8%) but different from the placebo group (4.8%; p=0.04). Incidences of fever, abdominal pain, and bloating were lower with increasing probiotic dose. The number of daily liquid stools and average duration of diarrhea decreased with higher probiotic dosage. The tested four strain probiotic combination appears to lower the risk of AAD, CDAD, and gastrointestinal symptoms in a dose-dependent manner in adult in-patients.