Protocol for the Gut Bugs in Autism Trial: a double-blind randomised placebo-controlled trial of faecal microbiome transfer for the treatment of gastrointestinal symptoms in autistic adolescents and adults.

INTRODUCTION: Autism (formally autism spectrum disorder) encompasses a group of complex neurodevelopmental conditions, characterised by differences in communication and social interactions. Co-occurring chronic gastrointestinal symptoms are common among autistic individuals and can adversely affect their quality of life. This study aims to evaluate the efficacy of oral encapsulated faecal microbiome transfer (FMT) in improving gastrointestinal symptoms and well-being among autistic adolescents and adults. METHODS AND ANALYSIS: This double-blind, randomised, placebo-controlled trial will recruit 100 autistic adolescents and adults aged 16-45 years, who have mild to severe gastrointestinal symptoms (Gastrointestinal Symptoms Rating Scale (GSRS) score ≥2.0). We will also recruit eight healthy donors aged 18-32 years, who will undergo extensive clinical screening. Recipients will be randomised 1:1 to receive FMT or placebo, stratified by biological sex. Capsules will be administered over two consecutive days following an overnight bowel cleanse with follow-up assessments at 6, 12 and 26 weeks post-treatment. The primary outcome is GSRS score at 6 weeks. Other assessments include anthropometry, body composition, hair cortisol concentration, gut microbiome profile, urine/plasma gut-derived metabolites, plasma markers of gut inflammation/permeability and questionnaires on general well-being, sleep quality, physical activity, food diversity and treatment tolerability. Adverse events will be recorded and reviewed by an independent data monitoring committee. ETHICS AND DISSEMINATION: Ethics approval for the study was granted by the Central Health and Disability Ethics Committee on 24 August 2021 (reference number: 21/CEN/211). Results will be published in peer-reviewed journals and presented to both scientific and consumer group audiences. TRIAL REGISTRATION NUMBER: ACTRN12622000015741.

An open-label pilot trial of faecal microbiome transfer to restore the gut microbiome in anorexia nervosa: protocol.

INTRODUCTION: Individuals with anorexia nervosa (AN) harbour distinct gut microbiomes compared with healthy individuals, which are sufficient to induce weight loss and anxiety-like behaviours when transplanted into germ-free mice. We hypothesise that faecal microbiome transfer (FMT) from healthy donors would help restore the gut microbiome of individuals with AN, which in turn, may aid patient recovery. METHODS: We aim to conduct an open-label pilot study in 20 females aged 16-32 years in Auckland, New Zealand who meet the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) criteria for AN and have a body mass index 13-19 kg/m2. We will recruit four healthy, lean, female donors, aged 18-32 years, who will undergo extensive clinical screening prior to stool donation. Faecal microbiota will be harvested from donors and double encapsulated in delayed release, acid-resistant capsules. All participants will receive a single course of 20 FMT capsules (five from each donor) which they can choose to take over two or four consecutive days. Stool and blood samples will be collected from participants over a period of 3 months to assess their gut microbiome profile, metabolome, levels of intestinal inflammation and nutritional status. Our primary outcome is a shift in the gut microbiome composition at 3 weeks post-FMT (Bray-Curtis dissimilarity). We will also monitor participants' body composition (whole-body dual-energy X-ray absorptiometry scans), eating disorder psychopathology, mental health and assess their views on, and tolerability of, treatment. All adverse events will be recorded and reviewed by an independent data monitoring committee. ETHICS AND DISSEMINATION: Ethics approval was provided by the Central Health and Disability Ethics Committee (Ministry of Health, New Zealand, 21/CEN/212). Results will be published in peer-reviewed journals and presented to both scientific and consumer group audiences. TRIAL REGISTRATION NUMBER: ACTRN12621001504808.

Strain engraftment competition and functional augmentation in a multi-donor fecal microbiota transplantation trial for obesity.

BACKGROUND: Donor selection is an important factor influencing the engraftment and efficacy of fecal microbiota transplantation (FMT) for complex conditions associated with microbial dysbiosis. However, the degree, variation, and stability of strain engraftment have not yet been assessed in the context of multiple donors. METHODS: We conducted a double-blinded randomized control trial of FMT in 87 adolescents with obesity. Participants were randomized to receive multi-donor FMT (capsules containing the fecal microbiota of four sex-matched lean donors) or placebo (saline capsules). Following a bowel cleanse, participants ingested a total of 28 capsules over two consecutive days. Capsules from individual donors and participant stool samples collected at baseline, 6, 12, and 26 weeks post-treatment were analyzed by shotgun metagenomic sequencing allowing us to track bacterial strain engraftment and its functional implications on recipients' gut microbiomes. RESULTS: Multi-donor FMT sustainably altered the structure and the function of the gut microbiome. In what was effectively a microbiome competition experiment, we discovered that two donor microbiomes (one female, one male) dominated strain engraftment and were characterized by high microbial diversity and a high Prevotella to Bacteroides (P/B) ratio. Engrafted strains led to enterotype-level shifts in community composition and provided genes that altered the metabolic potential of the community. Despite our attempts to standardize FMT dose and origin, FMT recipients varied widely in their engraftment of donor strains. CONCLUSION: Our study provides evidence for the existence of FMT super-donors whose microbiomes are highly effective at engrafting in the recipient gut. Dominant engrafting male and female donor microbiomes harbored diverse microbial species and genes and were characterized by a high P/B ratio. Yet, the high variability of strain engraftment among FMT recipients suggests the host environment also plays a critical role in mediating FMT receptivity. TRIAL REGISTRATION: The Gut Bugs trial was registered with the Australian New Zealand Clinical Trials Registry ( ACTRN12615001351505 ). TRIAL PROTOCOL: The trial protocol is available at https://bmjopen.bmj.com/content/9/4/e026174 . Video Abstract.

Effects of Fecal Microbiome Transfer in Adolescents With Obesity: The Gut Bugs Randomized Controlled Trial.

Importance: Treatment of pediatric obesity is challenging. Preclinical studies in mice indicated that weight and metabolism can be altered by gut microbiome manipulation. Objective: To assess efficacy of fecal microbiome transfer (FMT) to treat adolescent obesity and improve metabolism. Design, Setting, and Participants: This randomized, double-masked, placebo-controlled trial (October 2017-March 2019) with a 26-week follow-up was conducted among adolescents aged 14 to 18 years with a body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 30 or more in Auckland, New Zealand. A total of 87 individuals took part-565 individuals responded to advertisements, 328 were ineligible, and 150 declined participation. Clinical data were analyzed from September 2019 to May 2020. Interventions: Single course of oral encapsulated fecal microbiome from 4 healthy lean donors of the same sex or saline placebo. Main Outcomes and Measures: Primary outcome was BMI standard deviation score at 6 weeks using intention-to-treat analysis. Secondary outcomes included body composition, cardiometabolic parameters, well-being, and gut microbiome composition. Results: Eighty-seven participants (59% female adolescents, mean [SD] age 17.2 [1.4] years) were randomized 1:1, in groups stratified by sex, to FMT (42 participants) or placebo (45 participants). There was no effect of FMT on BMI standard deviation score at 6 weeks (adjusted mean difference [aMD] -0.026; 95% CI -0.074, 0.022). Reductions in android-to-gynoid-fat ratio in the FMT vs placebo group were observed at 6, 12, and 26 weeks, with aMDs of -0.021 (95% CI, -0.041 to -0.001), -0.023 (95% CI, -0.043 to -0.003), and -0.029 (95% CI, -0.049 to -0.008), respectively. There were no observed effects on insulin sensitivity, liver function, lipid profile, inflammatory markers, blood pressure, total body fat percentage, gut health, and health-related quality of life. Gut microbiome profiling revealed a shift in community composition among the FMT group, maintained up to 12 weeks. In post-hoc exploratory analyses among participants with metabolic syndrome at baseline, FMT led to greater resolution of this condition (18 to 4) compared with placebo (13 to 10) by 26 weeks (adjusted odds ratio, 0.06; 95% CI, 0.01-0.45; P = .007). There were no serious adverse events recorded throughout the trial. Conclusions and Relevance: In this randomized clinical trial of adolescents with obesite, there was no effect of FMT on weight loss in adolescents with obesity, although a reduction in abdominal adiposity was observed. Post-hoc analyses indicated a resolution of undiagnosed metabolic syndrome with FMT among those with this condition. Further trials are needed to confirm these results and identify organisms and mechanisms responsible for mediating the observed benefits. Trial Registration: Australian New Zealand Clinical Trials Registry Identifier: ACTRN12615001351505.

High prevalence of undiagnosed comorbidities among adolescents with obesity.

Metabolic diseases are increasing among adolescents with obesity. Although the reported prevalence of metabolic syndrome is approximately 30% worldwide, its prevalence is largely unknown among New Zealand adolescents. Therefore, we assessed the health of adolescents with obesity (BMI ≥ 30 kg/m2) enrolled in a randomised clinical trial (Gut Bugs Trial), to identify the prevalence of undiagnosed comorbidities. Assessments included anthropometry, 24-h ambulatory blood pressure monitoring, and insulin sensitivity. We report on baseline data (pre-randomisation) on 87 participants (14-18 years; 59% females), with mean BMI 36.9 ± 5.3 kg/m2 (BMI SDS 3.33 ± 0.79). Approximately 40% of participants had undiagnosed metabolic syndrome, which was twice as common among males. Half (53%) had pre-diabetes and 92% a reduction in insulin sensitivity. Moreover, 31% had pre-hypertension/hypertension, 69% dyslipidaemia, and 25% abnormal liver function. Participants with class III obesity had a greater risk of metabolic syndrome than those with classes I/II [relative risk 1.99 (95% CI 1.19, 3.34)]. Risks for pre-hypertension/hypertension and inflammation were also greater among those with class III obesity. We identified a high prevalence of undiagnosed comorbidities among adolescents with obesity in New Zealand. As adolescent obesity tracks into adulthood, early interventions are needed to prevent progression to overt cardiometabolic diseases.

Crown preparations by undergraduate dental students: A comparison of conventional versus digital assessment via an intraoral scanner.

PURPOSE: This study aims to assess the effectiveness of the 3Shape TRIOS intraoral scanner (IOS) in student crown preparation evaluation. DESIGN: Students were tasked to perform a full metal crown preparation on the upper left first molar on a patient simulator within 45 minutes. Marginal Width, Occlusal Reduction, Presence of Undercuts, Taper, Planes of Reduction, Line Angles, Conformity to Gingival Contour, and Smoothness were evaluated via 3 assessment modes: (a) Conventional assessment by 2 supervisors; (b) Conventional assessment by students; (c) Digital assessment by students. Agreement between assessment modes was investigated using Kappa (κ), with a threshold set at κ > 0.4. Effectiveness of IOS for objective parameters was determined via physical verification, while that for subjective parameters was defined by agreement with the stricter supervisor grade. RESULTS: Substantial agreement (κ = 0.631) was found between IOS measurement of Marginal Width and physical verification. Two of 5 subjective parameters met κ > 0.4 for agreement between IOS and the stricter supervisor grade. Agreement between supervisors ranged from slight (κ = 0.103) for Occlusal Reduction to Fair (κ = 0.399) for Marginal Width. Agreement between conventional assessments of supervisors and students ranged from less than chance (κ = -0.142) for Occlusal Reduction to moderate (κ = 0.577) for Line Angles. Agreement between conventional assessments of supervisors and digital assessments of students ranged from slight (κ = 0.130) for Planes of Reduction to moderate (κ = 0.538) for Line Angles. CONCLUSIONS: IOS may be used to overcome limitations in conventional assessment of objective parameters and some subjective parameters. Digital assessment of crown preparations cannot completely replace conventional assessment.

Gut microbiome transfer-Finding the perfect fit.

Gut microbiome transfer (GMT; also referred to as faecal microbiota transplantation or FMT) has been propelled from fringe therapy to mainstream science as a highly effective treatment for recurrent Clostridioides difficile infection. As a result, there has been great interest in the potential efficacy and safety of GMT in treating other medical conditions, for example inflammatory bowel disease, and more recently as a novel therapy for obesity and metabolic diseases. For these chronic conditions, the results from clinical trials have been mixed. Further, specifically in obesity and metabolic diseases, there are limited available data, with only a few published studies with a small number of participants and short duration of follow-up. Therefore, this review aims to explore the human, microbial and formulation factors that may affect the success of GMT. This includes various aspects in the preparation and administration of GMT, such as stool processing, modes of delivery, pretreatment with antibiotics and/or bowel lavage, frequency of GMT and possible use of precision bacteriotherapy. In addition, we examine the potential use of GMT in obesity, type 2 diabetes and metabolic diseases based on current available literature, highlighting some recent advances in GMT research in this area, as well as potential adverse effects after GMT therapy.

Associations of Prenatal and Childhood Antibiotic Exposure With Obesity at Age 4 Years.

Importance: Although antibiotics are associated with obesity in animal models, the evidence in humans is conflicting. Objective: To assess whether antibiotic exposure during pregnancy and/or early childhood is associated with the development of childhood obesity, focusing particularly on siblings and twins. Design, Setting, and Participants: This cross-sectional national study included 284 211 participants (132 852 mothers and 151 359 children) in New Zealand. Data analyses were performed for 150 699 children for whom data were available, 30 696 siblings, and 4188 twins using covariate-adjusted analyses, and for 6249 siblings and 522 twins with discordant outcomes using fixed-effects analyses. Data analysis was performed November 2017 to March 2019. Exposure: Exposure to antibiotics during pregnancy and/or early childhood. Main Outcomes and Measures: The main outcome is odds of obesity at age 4 years. Anthropometric data from children born between July 2008 and June 2011 were obtained from the B4 School Check, a national health screening program that records the height and weight of 4-year-old children in New Zealand. These data were linked to antibiotics (pharmaceutical records) dispensed to women before conception and during all 3 trimesters of pregnancy and to their children from birth until age 2 years. Results: The overall study population consisted of 132 852 mothers and 151 359 children (77 610 [51.3%] boys) who were aged 4 to 5 years when their anthropometrical measurements were assessed. Antibiotic exposure was common, with at least 1 course dispensed to 35.7% of mothers during pregnancy and 82.3% of children during the first 2 years of life. Results from covariate-adjusted analyses showed that both prenatal and early childhood exposures to antibiotics were independently associated with obesity at age 4 years, in a dose-dependent manner. Every additional course of antibiotics dispensed to the mothers yielded an adjusted odds ratio (aOR) of obesity in their children (siblings) of 1.02 (95% CI, 0.99-1.06), which was similar to the odds across pregnancy for the whole population (aOR, 1.06; 95% CI, 1.04-1.07). For the child's exposure, the aOR for the association between antibiotic exposure and obesity was 1.04 (95% CI, 1.03-1.05) among siblings and 1.05 (95% CI, 1.02-1.09) among twins. However, fixed-effects analyses of siblings and twins showed no associations between antibiotic exposure and obesity, with aORs of 0.95 (95% CI, 0.90-1.00) for maternal exposure, 1.02 (95% CI, 0.99-1.04) for child's exposure, and 0.91 (95% CI, 0.81-1.02) for twins' exposure. Conclusions and Relevance: Although covariate-adjusted analyses demonstrated an association between antibiotic exposure and odds of obesity, further analyses of siblings and twins with discordant outcomes showed no associations. Thus, these discordant results likely reflect unmeasured confounding factors.

Protocol for the Gut Bugs Trial: a randomised double-blind placebo-controlled trial of gut microbiome transfer for the treatment of obesity in adolescents.

INTRODUCTION: Animal studies showed that germ-free mice inoculated with normal mouse gut bacteria developed obesity, insulin resistance and higher triglyceride levels, despite similar food intake. In humans, an association has been found between obesity and gut microbiome dysbiosis. However, gut microbiome transfer has not been evaluated for the treatment of human obesity. We will examine the effectiveness of gut microbiome transfer using encapsulated material for the treatment of obesity in adolescents. METHODS AND ANALYSIS: A two-arm, double-blind, placebo-controlled, randomised clinical trial of a single course of gut microbiome transfer will be conducted in 80 obese [body mass index (BMI) ≥30 kg/m2] adolescents (males and females, aged 14-18 years) in Auckland, New Zealand. Healthy lean donors (males and females, aged 18-28 years) will provide fresh stool samples from which bacteria will be isolated and double encapsulated. Participants (recipients) will be randomised at 1:1 to control (placebo) or treatment (gut microbiome transfer), stratified by sex. Recipients will receive 28 capsules over two consecutive mornings (~14 mL of frozen microbial suspension or saline). Clinical assessments will be performed at baseline, 6, 12 and 26 weeks, and will include: anthropometry, blood pressure, fasting metabolic markers, dietary intake, physical activity levels and health-related quality of life. Insulin sensitivity (Matsuda index), gut microbiota population structure characterised by 16S rRNA amplicon sequencing and body composition (using dual-energy X-ray absorptiometry) will be assessed at baseline, 6, 12 and 26 weeks. 24-hour ambulatory blood pressure monitoring will be performed at baseline and at 6 weeks. The primary outcome is BMI SD scores (SDS) at 6 weeks, with BMI SDS at 12 and 26 weeks as secondary outcomes. Other secondary outcomes include insulin sensitivity, adiposity (total body fat percentage) and gut microbial composition at 6, 12 and 26 weeks. Statistical analysis will be performed on the principle of intention to treat. ETHICS AND DISSEMINATION: Ethics approval was provided by the Northern A Health and Disability Ethics Committee (Ministry of Health, New Zealand; 16/NTA/172). The trial results will be published in peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBER: ACTRN12615001351505; Pre-results.

Acceptability of a multilevel intervention to improve blood pressure control among patients with chronic kidney disease in a public health care delivery system.

BACKGROUND: The Kidney Awareness Registry and Education (KARE) trial examined the impact of a multilevel intervention on blood pressure control among patients with chronic kidney disease (CKD) in a public health care delivery system. KARE consisted of a clinic-based intervention (a primary care CKD registry with point-of-care provider notifications and quarterly feedback related to CKD management) and a patient-directed intervention [a CKD self-management support (CKD-SMS) program that included low literacy educational materials, automated telephone-administered self-management modules and telephone health coaching]. We explored the acceptability of these interventions among end users. METHODS: At trial conclusion, we surveyed 39 primary care providers (PCPs) to identify preferences about components of the clinic intervention, conducted two focus groups among non-PCP staff to elicit in-depth attitudes and experiences with operationalizing the team-based CKD registry, and conducted eight focus groups with English- and Spanish-speaking patients to hear about their experiences with the CKD-SMS program. Focus group transcripts were analyzed using thematic analysis. Self-reported participation and data from the automated telephone program were used to evaluate patient engagement. RESULTS: Most PCPs (94%) believed that the point-of-care notifications benefited clinic workflow and agreed that quarterly feedback enhanced their ability to identify (89.5%) and manage (73.7%) CKD. Staff confirmed usefulness of point-of-care notifications. Patients suggested the automated telephone system was impersonal, though easy to use; that frequent automated calls were helpful to reinforce self-management behaviors; and that telephone health coaching was convenient. Nearly 40% of patients completed >80% of automated phone calls, 95% participated in calls with their health coach and 77% created at least one action plan. CONCLUSIONS: A CKD registry is acceptable to primary care health care teams and has potential to enhance identification and management of CKD in primary care. Low-income patients appreciated and engaged with a telephone-based CKD-SMS program, demonstrating its potential for increasing awareness and health engagement among populations with CKD within a public health care delivery system.

Antibiotics, gut microbiome and obesity.

Antibiotics have been hailed by many as "miracle drugs" that have been effectively treating infectious diseases for over a century, leading to a marked reduction in morbidity and mortality. However, with the increasing use of antibiotics, we are now faced not only with the increasing threat of antibiotic resistance, but also with a rising concern about potential long-term effects of antibiotics on human health, including the development of obesity. The obesity pandemic continues to increase, a problem that affects both adults and children alike. Disruptions to the gut microbiome have been linked to a multitude of adverse conditions, including obesity, type 2 diabetes, inflammatory bowel diseases, anxiety, autism, allergies, and autoimmune diseases. This review focuses on the association between antibiotics and obesity, and the role of the gut microbiome. There is strong evidence supporting the role of antibiotics in the development of obesity in well-controlled animal models. However, evidence for this link in humans is still inconclusive, and we need further well-designed clinical trials to clarify this association.

Linking High Risk Postpartum Women with a Technology Enabled Health Coaching Program to Reduce Diabetes Risk and Improve Wellbeing: Program Description, Case Studies, and Recommendations for Community Health Coaching Programs.

Background. Low-income minority women with prior gestational diabetes mellitus (pGDM) or high BMIs have increased risk for chronic illnesses postpartum. Although the Diabetes Prevention Program (DPP) provides an evidence-based model for reducing diabetes risk, few community-based interventions have adapted this program for pGDM women. Methods. STAR MAMA is an ongoing randomized control trial (RCT) evaluating a hybrid HIT/Health Coaching DPP-based 20-week postpartum program for diabetes prevention compared with education from written materials at baseline. Eligibility includes women 18-39 years old, ≥32 weeks pregnant, and GDM or BMI > 25. Clinic- and community-based recruitment in San Francisco and Sonoma Counties targets 180 women. Sociodemographic and health coaching data from a preliminary sample are presented. Results. Most of the 86 women included to date (88%) have GDM, 80% were identified as Hispanic/Latina, 78% have migrant status, and most are Spanish-speaking. Women receiving the intervention indicate high engagement, with 86% answering 1+ calls. Health coaching callbacks last an average of 9 minutes with range of topics discussed. Case studies presented convey a range of emotional, instrumental, and health literacy-related supports offered by health coaches. Discussion. The DPP-adapted HIT/health coaching model highlights the possibility and challenge of delivering DPP content to postpartum women in community settings. This trial is registered with ClinicalTrials.gov NCT02240420.

Reliability of objective voice measures of normal speaking voices.

OBJECTIVE: To determine the reliability of objective voice measures used commonly in clinical practice. SUBJECTS: Eighteen healthy volunteers (nine males and nine females). METHODS: Objective voice measures were performed on 18 healthy volunteers on 10 occasions under similar conditions over a 30-day period. Consistency of measures was analyzed to determine reliability. RESULTS: Using currently accepted normative values, intraclass correlation coefficients were moderate (>0.6) for consistency over the 10 testing sessions for most acoustic measures that do not depend on intensity, measures of laryngeal efficiency, and perturbation measures of fundamental frequency (F0) for both genders. For females, cepstral peak prominence (CPP) had moderate reliability, whereas for males, the smoothed CPP was reliable. Other than F0, none of the perturbation measures are reliable for females. However, jitter, relative average perturbation, and standard deviation of F0 are reliable for males. Noise-to-harmonic ratios (NHRs) had the lowest consistency of all measures over the course of the 10 sessions. CONCLUSIONS: Clinicians should be cautious in their use of acoustic voice measures that depend on the intensity and in their use of most perturbation measures. NHR was found to be the least reliable measure. Additionally, the reliability of CPP measure varies by gender. Understanding the degree of within-person variability on some objective voice measures and whether that variation is due to biological differences or measurement error will lead clinicians to consider the need for a more standardized testing protocol. Additional research is needed to investigate what factors within the testing protocol and/or changes to the measurement instruments may lead to more consistent test results.

Neuroendocrine adenoma of the middle ear (NAME).

Neuroendocrine adenoma of the middle ear (NAME) is a rare tumor. We report a case of NAME, the clinical and pathologic findings of which illustrate the biologic behavior of adenomatous tumors of the middle ear and their relationship with rare carcinoid tumors of the middle ear. A 29-year-old man presented with a history of recurrent otitis media, right conductive hearing loss, and aural fullness. The tumor was removed in its entirety. Otolaryngologists should be familiar with this unusual but important entity.