Abstract

BACKGROUND Decolonisation is considered a valuable means to reduce Staphylococcus aureus infection rates. However, previous topical strategies targeting the nose or skin had little success, and oral antibiotic-based decolonisation is ill advised because of eradication of the microbiota and development of antibiotic resistance. We previously showed that the probiotic Bacillus subtilis significantly diminished S aureus at the main intestinal colonisation site via specific bacterial interaction in mice; in this study, we tested this probiotic approach to control S aureus colonisation in humans. METHODS We did a single-centre, phase 2, double-blind, randomised, placebo-controlled trial in adults from the Songkhla region of Thailand who were colonised by S aureus. Eligible participants were adults (aged ≥18 years) without history of intestinal disease, antibiotic treatment, or hospital admission within the previous 90 days. Participants were excluded if they were pregnant, breastfeeding, taking probiotics, or had diarrhoea. Participants were allocated (1:1) to groups by computer randomisation in blocks of four, and research coordinators were masked to group allocation. Participants received 250 mg of probiotic B subtilis MB40 or placebo once per day for 30 days and S aureus colonisation was determined after the last dose was received. The primary outcome was colonisation by S aureus (continuous, mean decrease in colony-forming-unit count) in the intestine (by faecal counts) and nares (by nasal swabs) after intervention (30-day regimen of B subtilis probiotic). This trial is registered with the Thai Clinical Trials Registry, TCTR20210128003. FINDINGS The trial was done between Jan 29 and June 30, 2021, with enrolment taking place from Jan 29 to April 6, 2021. 115 participants were colonised by S aureus, either in the intestine (n=84), nose (n=50), or both (n=19), and were randomly assigned to treatment (n=55) and placebo groups (n=60). Oral probiotic B subtilis resulted in significant reduction of S aureus in stool (96·8%; p<0·0001) and nose (65·4%; p=0·0002). There were no differences in adverse effects or significant microbiome changes between the intervention and placebo groups. INTERPRETATION B subtilis probiotic eliminated more than 95% of the total S aureus colonising the human body without altering the microbiota. This probiotic strategy offers several key advantages over presently used decolonisation strategies for potential use in people with chronic or long-term risk of S aureus infection. Furthermore, by establishing a defining role of the intestinal colonisation site, our findings call for revisiting fundamental notions about S aureus colonisation. FUNDING National Research Council of Thailand and US National Institutes of Health.

Abstract

DISCLOSURE SUMMARY Dr. Yadav is Chief Scientific Officer and Co-Founder of Postbiotics Inc and has no conflict of interest with this work. All other authors have no conflicts of interest to disclose. BACKGROUND Metformin is the only approved first-line oral glucose lowering agent for youth with type 2 diabetes mellitus (Y-T2DM) but often causes gastrointestinal (GI) side effects, which may contribute to reduced treatment adherence and efficacy. Prebiotic intake may reduce metformin's side effects by shifting microbiota composition and activity. OBJECTIVE The aims of this study were to determine the feasibility and tolerability of a prebiotic supplement to improve metformin-induced GI symptoms and explore the changes in glycemia and shifts in the microbiota diversity. METHODS In a two-phase pilot clinical trial, we compared, stool frequency and stool form every 1-2 days, and composite lower GI symptoms (weekly) at initiation of daily metformin combined with either a daily prebiotic or a placebo shake in a 1-week randomized double-blind crossover design (Phase 1), followed by a 1-month open-labeled extension (Phase 2). Plasma glycemic markers and stool samples were collected before and after each phase. RESULTS Six Y-T2DM (17.2 ± 1.7y (mean ± SD), 67% male, BMI (42 ± 9 kg/m2), HbA1c (6.4 ± 0.6%)) completed the intervention. Stool frequency, stool composition, and GI symptom scores did not differ by group or study phase. There were no serious or severe adverse events reported, and no differences in metabolic or glycemic markers. After one week Phase 1metformin/placebo Proteobacteria, Enterobacteriaceae, and Enterobacteriales were identified as candidate biomarkers of metformin effects. Principle coordinate analyses of beta diversity suggested that the metformin/prebiotic intervention was associated with distinct shifts in the microbiome signatures at one week and one month. CONCLUSION Administration of a prebiotic fiber supplement during short-term metformin therapy was well tolerated in Y-T2DM and associated with modest shifts in microbial composition. This study provides a proof-of-concept for feasibility exploring prebiotic-metformin-microbiome interactions as a basis for adjunctive metformin therapy. CLINICAL TRIAL REGISTRATION https://clinicaltrials.gov/, identifier NCT04209075.

Abstract

BACKGROUND The popularity of the gluten-free diet and sales of gluten-free products have increased immensely. AIMS To investigate whether gluten induces gastrointestinal symptoms, measured by self-reported questionnaires, as well as mental health symptoms in adolescents from a population-based cohort. METHODS The eligible participants (n = 273) were recruited from a population-based cohort of 1266 adolescents and had at least four different gastrointestinal symptoms. Phase one (n = 54) was a run-in phase where the participants lived gluten-free for 2 weeks. If they improved they continued to phase 2 (n = 33), a blinded randomised cross-over trial. Participants were blindly randomised either to start with 7 days of gluten, eating two granola bars containing 10 g of gluten or to 7 days on placebo, eating two granola bars without gluten, followed by the reverse and separated by a 7-day washout period. The effects of the intervention on gastrointestinal symptoms and mental health symptoms were assessed. RESULTS In total, 54/273 participants entered the run-in phase and 35 were eligible for randomization. A total of 33 were randomised and 32 completed the trial. The median age was 20.3 (IQR 19.2-20.9) and 32/33 participants were females. Compared with a placebo, gluten did not induce gastrointestinal symptoms. The difference in the average VAS was -0.01 (95% confidence interval -2.07 to 2.05). Nor did we find a difference in the outcomes measuring mental health. CONCLUSION Compared with placebo, adding gluten to the diet did not induce gastrointestinal symptoms or worsened mental health in adolescents recruited from a population-based cohort. The trial registration number is NCT04639921.

Abstract

OBJECTIVE We aim to investigate the effect of curcumin on preventing cancer anorexia-cachexia syndrome (CACS) via through mechanism of inhibition on NF-kB signal pathway. Outcome measurement for primary end point was improvement of body tissue composition, and the secondary end points were body weight and body mass index, hand grip muscle strengthening, and safety. METHODS This is randomized, double-blind, placebo-controlled phase ll a study, 33 patients with CACS in solid malignancy were enrolled and randomized in 1:1 to receive oral curcumin (at a dose of 800 mg twice daily) or placebo for 8 weeks. RESULTS All parameters of body compositions were not statistically significant different between two groups, which were consist body fat mass [-1.25(SEM 0.87) vs. +0.63(SEM 0.55); p=0.119], skeletal muscle mass [-0.35(SEM 0.60) vs.+0.33(SEM 0.42); p=0.408] and percent body fat [-0.47(SEM 0.95) vs. -0.29(SEM 0.82); p=0.893] including with basal metabolic rate [-13.47(SEM 21.94) vs. +15.30(13.76); p=0.336]. The average of weight loss was also not statistically significant different between two groups. [-1.4 kg(SEM 0.89) in curcumin vs-1.12 kg(SEM 0.73), p=0.810]. Notably, patient with curcumin had less reduction of hand-grip muscle strength on both hands [Rt. handed: -2.47 in curcumin vs. -5.36 in placebo; p=0.318] [Lt. handed: -1.98 vs. -5.43; p=0.317], and basal metabolic rate than placebo group. Most adverse events were grade 1 on both groups similarly. CONCLUSION Curcumin was not shown to be superior to placebo with regard to increasing the body composition in cancer patients with CACS. However, curcumin might show some clinical benefits, including slow progression of hand-grip muscle strength loss, and basal metabolic rate. Further investigations should be explored.

Abstract

BACKGROUND Seventy percent of patients suffering from birch pollen allergy (BPA) develop a pollen-related food allergy (prFA), especially to apples, due to a clinically relevant cross-reactivity between the major allergen in birch Bet v 1 and Mal d 1 in apples. Therefore allergen-specific immunotherapy with fresh apples (AITA) could be a promising natural treatment of both BPA and prFA. OBJECTIVE To assess the clinical efficacy of immunotherapy by daily apple consumption for patients with BPA and prFA. METHODS A daily defined increasing amount of selected cultivars (Red Moon®, Pink Lady®, Topaz, Golden Delicious) was continuously consumed by 16 patients (12 female; median age; 50; range, 23-68 years), leading to increased intake of allergen over a period of at least 8 months. Specific IgE and IgG4 to Bet v 1 and Mal d 1, conjunctival and oral provocation tests, skin reactivity, and the average daily rhinoconjunctivitis combined symptom and medication score (CSMS) were measured during the peak birch pollen season. RESULTS After 8 months of therapy, patients showed increased tolerance to apples (p < .001) and a decreased skin reactivity to apples. Oral allergy syndrome to other birch prFA than apple also decreased (p < .05). Moreover, daily rhinoconjunctivitis CSMS declined by 34% (p < .001), as did conjunctival reactivity to birch pollen extract by 27% (p < .01), while specific IgG4 to Mal d 1 and Bet v 1 increased (p < .01).

Abstract

Obesity adversely impacts overall and cancer-specific survival among breast cancer patients. Preclinical studies demonstrate negative energy balance inhibits cancer progression; however, feasibility and effects in patients are unknown. A two-arm, single-blinded, randomized controlled weight-loss trial was undertaken presurgery among 32 overweight/obese, Stage 0-II breast cancer patients. The attention control arm (AC) received basic nutritional counseling and upper-body progressive resistance training whereas the weight loss intervention (WLI) arm received identical guidance, plus counseling on caloric restriction and aerobic exercise to promote 0.68-0.92 kg/week weight loss. Anthropometrics, body composition, blood and survey data were collected at baseline and presurgery ∼30 days later. Tumor markers (e.g., Ki67) and gene expression were assessed on biopsy and surgical specimens; sera were analyzed for cytokines, growth and metabolic factors. Significant WLI vs. AC differences were seen in baseline-to-follow-up changes in weight (-3.62 vs. -0.52 kg), %body fat (-1.3 vs. 0%), moderate-to-vigorous physical activity (+224 vs. +115 min/week), caloric density (-0.3 vs. 0 kcal/g), serum leptin (-12.3 vs. -4.0 ng/dl) and upregulation of tumor PI3Kinase signaling and cell cycle-apoptosis related genes (CC-ARG; all p-values <0.05). Cytolytic CD56dim NK cell expression was positively associated with weight loss; CC-ARG increased with physical activity. Increased tumor (nuclear) TNFα and IL-1β, CX3CL1 and CXCL1 gene expression was observed in the WLI. Tumor Ki67 did not differ between arms. Feasibility benchmarks included 80% accrual, 100% retention, no adverse effects and excellent adherence. Short-term weight loss interventions are feasible; however, mixed effects on tumor biology suggest unclear benefit to presurgical caloric restriction, but possible benefits of physical activity.

Abstract

Here we aimed at determining the therapeutic effect of a very low-calorie diet in overweight episodic migraine patients during a weight-loss intervention in which subjects alternated randomly between a very low-calorie ketogenic diet (VLCKD) and a very low-calorie non-ketogenic diet (VLCnKD) each for one month. In a nutritional program, 35 overweight obese migraine sufferers were allocated blindly to 1-month successive VLCKD or VLCnKD in random order (VLCKD-VLCnKD or VLCnKD-VLCD). The primary outcome measure was the reduction of migraine days each month compared to a 1-month pre-diet baseline. Secondary outcome measures were 50% responder rate for migraine days, reduction of monthly migraine attacks, abortive drug intake and body mass index (BMI) change. Only data from the intention-to-treat cohort (n = 35) will be presented. Patients who dropped out (n = 6) were considered as treatment failures. Regarding the primary outcome, during the VLCKD patients experienced -3.73 (95% CI: -5.31, -2.15) migraine days respect to VLCnKD (p < 0.0001). The 50% responder rate for migraine days was 74.28% (26/35 patients) during the VLCKD period, but only 8.57% (3/35 patients) during VLCnKD. Migraine attacks decreased by -3.02 (95% CI: -4.15, -1.88) during VLCKD respect to VLCnKD (p < 0.00001). There were no differences in the change of acute anti-migraine drug consumption (p = 0.112) and BMI (p = 0.354) between the 2 diets. A VLCKD has a preventive effect in overweight episodic migraine patients that appears within 1 month, suggesting that ketogenesis may be a useful therapeutic strategy for migraines.

Abstract

BACKGROUND Existing evidence demonstrates that 1:1 personal training (PT) improves many adverse effects of androgen deprivation therapy (ADT). Whether less resource-intensive exercise delivery models are as effective remains to be established. We determined the feasibility of conducting a multi-center non-inferiority randomized controlled trial comparing PT with supervised group (GROUP) and home-based (HOME) exercise programs, and obtained preliminary efficacy estimates for GROUP and HOME compared to PT on quality of life (QOL) and physical fitness. METHODS Men with prostate cancer on ADT were recruited from one of two experienced Canadian centres and randomized 1:1:1 to PT, GROUP, or HOME. Randomization was stratified by length of ADT use and site. Participants completed moderate intensity aerobic and resistance exercises 4-5 days per week for 6 months with a target 150 min per week of exercise. Exercise prescriptions were individualized and progressed throughout the trial. Feasibility endpoints included recruitment, retention, adherence, and participant satisfaction. The efficacy endpoints QOL, fatigue, and fitness (VO2 peak, grip strength, and timed chair stands) in GROUP and HOME were compared for non-inferiority to PT. Descriptive analyses were used for feasibility endpoints. Between-group differences for efficacy endpoints were examined using Bayesian linear mixed effects models. RESULTS Fifty-nine participants (mean age 69.9 years) were enrolled. The recruitment rate was 25.4% and recruitment was slower than projected. Retention was 71.2%. Exercise adherence as measured through attendance was high for supervised sessions but under 50% by self-report and accelerometry. Satisfaction was high and there was no difference in this measure between all three groups. Between-group differences (comparing both GROUP and HOME to PT) were smaller than the minimum clinically important difference on most measures of QOL, fatigue, and fitness. However, two of six outcomes for GROUP and four of six outcomes for HOME had a > 20% probability of being inferior for GROUP. CONCLUSIONS Feasibility endpoints were generally met. Both GROUP and HOME interventions in men with PC on ADT appeared to be similar to PT for multiple efficacy outcomes, although conclusions are limited by a small sample size and cost considerations have not been incorporated. Efforts need to be targeted to improving recruitment and adherence. A larger trial is warranted. TRIAL REGISTRATION ClinicalTrials.gov: NCT02046837 . Date of registration: January 20, 2014.

Abstract

OBJECTIVE To investigate the feasibility, safety, and efficacy of a ketogenic diet (KD) for superrefractory status epilepticus (SRSE) in adults. METHODS We performed a prospective multicenter study of patients 18 to 80 years of age with SRSE treated with a KD treatment algorithm. The primary outcome measure was significant urine and serum ketone body production as a biomarker of feasibility. Secondary measures included resolution of SRSE, disposition at discharge, KD-related side effects, and long-term outcomes. RESULTS Twenty-four adults were screened for participation at 5 medical centers, and 15 were enrolled and treated with a classic KD via gastrostomy tube for SRSE. Median age was 47 years (interquartile range [IQR] 30 years), and 5 (33%) were male. Median number of antiseizure drugs used before KD was 8 (IQR 7), and median duration of SRSE before KD initiation was 10 days (IQR 7 days). KD treatment delays resulted from intravenous propofol use, ileus, and initial care received at a nonparticipating center. All patients achieved ketosis in a median of 2 days (IQR 1 day) on KD. Fourteen patients completed KD treatment, and SRSE resolved in 11 (79%; 73% of all patients enrolled). Side effects included metabolic acidosis, hyperlipidemia, constipation, hypoglycemia, hyponatremia, and weight loss. Five patients (33%) ultimately died. CONCLUSIONS KD is feasible in adults with SRSE and may be safe and effective. Comparative safety and efficacy must be established with randomized placebo-controlled trials. CLASSIFICATION OF EVIDENCE This study provides Class IV evidence that in adults with SRSE, a KD is effective in inducing ketosis.

Abstract

BACKGROUND Myelodysplastic syndromes (MDS) are characterized by ineffective erythropoiesis with dysplastic bone marrow leading to peripheral cytopenia, risk of infection, and progression to acute myelogenous leukemia. Maitake mushroom beta-glucan, a dietary supplement, stimulates hematopoietic progenitor cell differentiation, granulocyte colony-stimulating factor production, and recovery of peripheral blood leukocytes after bone marrow injury. This phase II trial examined the effects of Maitake on innate immune function in MDS. METHODS Myelodysplastic syndromes patients with International Prognostic Scoring System Low- and Intermediate-1-risk disease received oral Maitake extract at 3 mg/kg twice daily for 12 weeks. Primary endpoints included neutrophil count and function tested as endogenous or stimulated neutrophil production of reactive oxygen species (ROS) by flow cytometry compared with age-matched healthy controls (HC). ROS activators were Escherichia coli, phorbol ester, and the bacterial peptide N-formylmethionyl-leucyl-phenylalanine (fMLP). Complete blood counts, chemistry panels, iron studies, and monocyte function were evaluated. RESULTS Of 21 patients enrolled, 18 completed the study and were evaluable. Maitake increased endogenous (basal) neutrophil (p = 0.005) and monocyte function (p = 0.021). Pre-treatment monocyte response to E. coli was reduced in MDS patients compared with HC (p = 0.002) and increased (p = 0.0004) after treatment. fMLP-stimulated ROS production response also increased (p = 0.03). Asymptomatic eosinophilia occurred in 4 patients (p = 0.014). Other changes in albumin, hemoglobin, and total protein were not clinically relevant. CONCLUSIONS Maitake was well tolerated. Enhanced in vitro neutrophil and monocyte function following treatment demonstrate that Maitake has beneficial immunomodulatory potential in MDS. Further study is warranted.