The Effect of Iron Supplements on the Gut Microbiome of Females of Reproductive Age: A Randomized Controlled Trial.

BACKGROUND: Iron deficiency is the most common nutritional deficiency worldwide, particularly for young children and females of reproductive age. Although oral iron supplements are routinely recommended and generally considered safe, iron supplementation has been shown to alter the fecal microbiota in low-income countries. Little is known about the effect of iron supplementation on the fecal microbiota in high-income settings. OBJECTIVES: To assess the effect of oral iron supplementation compared with placebo on the gut microbiome in nonpregnant females of reproductive age in a high-income country. METHODS: A 21-d prospective parallel design double-blind, randomized control trial conducted in South Australia, Australia. Females (18-45 y) were randomly assigned to either iron (65.7 mg ferrous fumarate) or placebo. Fecal samples were collected prior to commencing supplements and after 21 d of supplementation. The primary outcome was microbiota ß-diversity (paired-sample weighted unique fraction metric dissimilarity) between treatment and placebo groups after 21 d of supplementation. Exploratory outcomes included changes in the relative abundance of bacterial taxa. RESULTS: Of 82 females randomly assigned, 80 completed the trial. There was no significant difference between the groups for weighted unique fraction metric dissimilarity (mean difference: 0.003; 95% confidence interval: -0.007, 0.014; P = 0.52) or relative abundance of common bacterial taxa or Escherichia-Shigella (q > 0.05). CONCLUSIONS: Iron supplementation did not affect the microbiome of nonpregnant females of reproductive age in Australia. This trial was registered at clinicaltrials.gov as NCT05033483.

The gut microbiome and mental health: advances in research and emerging priorities.

The gut microbiome exerts a considerable influence on human neurophysiology and mental health. Interactions between intestinal microbiology and host regulatory systems have now been implicated both in the development of psychiatric conditions and in the efficacy of many common therapies. With the growing acceptance of the role played by the gut microbiome in mental health outcomes, the focus of research is now beginning to shift from identifying relationships between intestinal microbiology and pathophysiology, and towards using this newfound insight to improve clinical outcomes. Here, we review recent advances in our understanding of gut microbiome-brain interactions, the mechanistic underpinnings of these relationships, and the ongoing challenge of distinguishing association and causation. We set out an overarching model of the evolution of microbiome-CNS interaction and examine how a growing knowledge of these complex systems can be used to determine disease susceptibility and reduce risk in a targeted manner.

Acute feeding with almonds compared to a carbohydrate-based snack improves appetite-regulating hormones with no effect on self-reported appetite sensations: a randomised controlled trial.

PURPOSE: Early satiety has been identified as one of the mechanisms that may explain the beneficial effects of nuts for reducing obesity. This study compared postprandial changes in appetite-regulating hormones and self-reported appetite ratings after consuming almonds (AL, 15% of energy requirement) or an isocaloric carbohydrate-rich snack bar (SB). METHODS: This is a sub-analysis of baseline assessments of a larger parallel-arm randomised controlled trial in overweight and obese (Body Mass Index 27.5-34.9 kg/m2) adults (25-65 years). After an overnight fast, 140 participants consumed a randomly allocated snack (AL [n = 68] or SB [n = 72]). Appetite-regulating hormones and self-reported appetite sensations, measured using visual analogue scales, were assessed immediately before snack food consumption, and at 30, 60, 90 and 120 min following snack consumption. A sub-set of participants (AL, n = 49; SB, n = 48) then consumed a meal challenge buffet ad libitum to assess subsequent energy intake. An additional appetite rating assessment was administered post buffet at 150 min. RESULTS: Postprandial C-peptide area under the curve (AUC) response was 47% smaller with AL compared to SB (p < 0.001). Glucose-dependent insulinotropic polypeptide, glucagon and pancreatic polypeptide AUC responses were larger with AL compared to SB (18%, p = 0.005; 39% p < 0.001; 45% p < 0.001 respectively). Cholecystokinin, ghrelin, glucagon-like peptide-1, leptin and polypeptide YY AUCs were not different between groups. Self-reported appetite ratings and energy intake following the buffet did not differ between groups. CONCLUSION: More favourable appetite-regulating hormone responses to AL did not translate into better self-reported appetite or reduced short-term energy consumption. Future studies should investigate implications for longer term appetite regulation. ANZCTR REFERENCE NUMBER: ACTRN12618001861246 2018.

Cohort profile: GRACE - a residential aged care cohort examining factors influencing antimicrobial resistance carriage.

BACKGROUND: The emergence of antimicrobial-resistant bacteria represents a considerable threat to human health, particularly for vulnerable populations such as those living in residential aged care. However, antimicrobial resistance carriage and modes of transmission remain incompletely understood. The Generating evidence on antimicrobial Resistance in the Aged Care Environment (GRACE) study was established to determine principal risk factors of antimicrobial resistance carriage and transmission in residential aged care facilities (RACFs). This article describes the cohort characteristics, national representation, and planned analyses for this study. METHODS: Between March 2019 and March 2020, 279 participants were recruited from five South Australian RACFs. The median age was 88.6 years, the median period in residence was 681 days, and 71.7% were female. A dementia diagnosis was recorded in 54.5% and more than two thirds had moderate to severe cognitive impairment (68.8%). 61% had received at least one course of antibiotics in the 12 months prior to enrolment. RESULTS: To investigate the representation of the GRACE cohort to Australians in residential aged care, its characteristics were compared to a subset of the historical cohort of the Registry of Senior Australians (ROSA). This included 142,923 individuals who were permanent residents of RACFs on June 30th, 2017. GRACE and ROSA cohorts were similar in age, sex, and duration of residential care, prevalence of health conditions, and recorded dementia diagnoses. Differences were observed in care requirements and antibiotic exposure (both higher for GRACE participants). GRACE participants had fewer hospital visits compared to the ROSA cohort, and a smaller proportion were prescribed psycholeptic medications. CONCLUSIONS: We have assembled a cohort of aged care residents that is representative of the Australian aged care population, and which provides a basis for future analyses. Metagenomic data isolated from participants and built environments will be used to determine microbiome and resistome characteristics of an individual and the facility. Individual and facility risk exposures will be aligned with metagenomic data to identify principal determinants for antimicrobial resistance carriage. Ultimately, this analysis will inform measures aimed at reducing the emergence and spread of antimicrobial resistant pathogens in this high-risk population.

Assessment of Long-Term Macrolide Exposure on the Oropharyngeal Microbiome and Macrolide Resistance in Healthy Adults and Consequences for Onward Transmission of Resistance.

While the use of long-term macrolide therapy to prevent exacerbations in chronic respiratory diseases is widespread, its impact on the oropharyngeal microbiota and macrolide resistance, and the potential for onward transmission of resistance to close contacts are poorly understood. We determined the effects of long-term exposure to azithromycin or erythromycin on phenotypic and genotypic macrolide resistance within the oropharyngeal microbiome of healthy adults and their close contacts in a randomized, single-blinded, parallel-group trial of 4 weeks of twice-daily oral 400 mg erythromycin ethylsuccinate or twice-daily oral 125 mg azithromycin. Using oropharyngeal swabs collected from 20 index healthy adults and 20 paired close contacts, the oropharyngeal microbial composition and macrolide resistance in streptococci were assessed by 16S rRNA sequencing and antibiotic susceptibility testing of oropharyngeal cultures, respectively, at baseline and weeks 4 and 8 (washout). Targeted quantitative PCR of antibiotic resistance genes was performed to evaluate paired changes in resistance gene levels in index patients and close contacts and to relate the potential transmission of antibiotic resistance. Neither azithromycin nor erythromycin altered oropharyngeal microbiota characteristics significantly. Proportional macrolide resistance in oropharyngeal streptococci increased with both erythromycin and azithromycin, remaining above baseline levels for the azithromycin group at washout. Levels of resistance genes increased significantly with azithromycin[erm(B) and mef] and erythromycin (mef), returning to baseline levels at washout only for the erythromycin group. We found no evidence of onward transmission of resistance to close contacts, as indicated by the lack of concomitant changes in resistance gene levels detected in close contacts. (This study has been registered with the Australian and New Zealand Clinical Trials Registry under identifier ACTRN12617000278336.).

R othia mucilaginosa is an anti-inflammatory bacterium in the respiratory tract of patients with chronic lung disease.

BACKGROUND: Chronic airway inflammation is the main driver of pathogenesis in respiratory diseases such as severe asthma, chronic obstructive pulmonary disease, cystic fibrosis (CF) and bronchiectasis. While the role of common pathogens in airway inflammation is widely recognised, the influence of other microbiota members is still poorly understood. METHODS: We hypothesised that the lung microbiota contains bacteria with immunomodulatory activity which modulate net levels of immune activation by key respiratory pathogens. Therefore, we assessed the immunomodulatory effect of several members of the lung microbiota frequently reported as present in CF lower respiratory tract samples. RESULTS: We show that Rothia mucilaginosa, a common resident of the oral cavity that is also often detectable in the lower airways in chronic disease, has an inhibitory effect on pathogen- or lipopolysaccharide-induced pro-inflammatory responses, in vitro (three-dimensional cell culture model) and in vivo (mouse model). Furthermore, in a cohort of adults with bronchiectasis, the abundance of Rothia species was negatively correlated with pro-inflammatory markers (interleukin (IL)-8 and IL-1ß) and matrix metalloproteinase (MMP)-1, MMP-8 and MMP-9 in sputum. Mechanistic studies revealed that R. mucilaginosa inhibits NF-κB pathway activation by reducing the phosphorylation of IκBα and consequently the expression of NF-κB target genes. CONCLUSIONS: These findings indicate that the presence of R. mucilaginosa in the lower airways potentially mitigates inflammation, which could in turn influence the severity and progression of chronic respiratory disorders.

Ear microbiota and middle ear disease: a longitudinal pilot study of Aboriginal children in a remote south Australian setting.

BACKGROUND: Otitis media (OM) is a major disease burden in Australian Aboriginal children, contributing to serious long-term health outcomes. We report a pilot analysis of OM in children attending an outreach ear and hearing clinic in a remote south Australian community over a two-year period. Our study focuses on longitudinal relationships between ear canal microbiota characteristics with nasopharyngeal microbiota, and clinical and treatment variables. RESULTS: Middle ear health status were assessed in 19 children (aged 3 months to 8 years) presenting in remote western South Australia and medical interventions were recorded. Over the two-year study period, chronic suppurative OM was diagnosed at least once in 7 children (37%), acute OM with perforation in 4 children (21%), OM with effusion in 11 children (58%), while only 1 child had no ear disease. Microbiota analysis of 19 children (51 sets of left and right ear canal swabs and nasopharyngeal swabs) revealed a core group of bacterial taxa that included Corynebacterium, Alloiococcus, Staphylococcus, Haemophilus, Turicella, Streptococcus, and Pseudomonas. Within-subject microbiota similarity (between ears) was significantly greater than inter-subject similarity, regardless of differences in ear disease (p = 0.0006). Longitudinal analysis revealed changes in diagnosis to be associated with more pronounced changes in microbiota characteristics, irrespective of time interval. Ear microbiota characteristics differed significantly according to diagnosis (P (perm) = 0.0001). Diagnoses featuring inflammation with tympanic membrane perforation clustering separately to those in which the tympanic membrane was intact, and characterised by increased Proteobacteria, particularly Haemophilus influenzae, Moraxella catarrhalis, and Oligella. While nasopharyngeal microbiota differed significantly in composition to ear microbiota (P (perm) = 0.0001), inter-site similarity was significantly greater in subjects with perforated tympanic membranes, a relationship that was associated with the relative abundance of H. influenzae in ear samples (rs = - 0.71, p = 0.0003). Longitudinal changes in ear microbiology reflected changes in clinical signs and treatment. CONCLUSIONS: Children attending the ear and hearing clinic in a remote Aboriginal community present with a broad spectrum of OM conditions and severities, consistent with other remote Aboriginal communities. Ear microbiota characteristics align with OM diagnosis and change with disease course. Nasopharyngeal microbiota characteristics are consistent with the contribution of acute upper respiratory infection to OM aetiology.

Targeted reduction of airborne viral transmission risk in long-term residential aged care.

COVID-19 has demonstrated the devastating consequences of the rapid spread of an airborne virus in residential aged care. We report the use of CO2-based ventilation assessment to empirically identify potential 'super-spreader' zones within an aged care facility, and determine the efficacy of rapidly implemented, inexpensive, risk reduction measures.

The gut microbiome regulates host glucose homeostasis via peripheral serotonin.

The gut microbiome is an established regulator of aspects of host metabolism, such as glucose handling. Despite the known impacts of the gut microbiota on host glucose homeostasis, the underlying mechanisms are unknown. The gut microbiome is also a potent mediator of gut-derived serotonin synthesis, and this peripheral source of serotonin is itself a regulator of glucose homeostasis. Here, we determined whether the gut microbiome influences glucose homeostasis through effects on gut-derived serotonin. Using both pharmacological inhibition and genetic deletion of gut-derived serotonin synthesis, we find that the improvements in host glucose handling caused by antibiotic-induced changes in microbiota composition are dependent on the synthesis of peripheral serotonin.

National Trends in Antibiotic Use in Australian Residential Aged Care Facilities, 2005-2016.

BACKGROUND: Understanding current patterns of antibiotic use in residential aged care facilities (RACFs) is essential to inform stewardship activities, but limited utilization data exist. This study examined changes in prevalence and consumption of antibiotics in Australian RACFs between 2005-2006 and 2015-2016. METHODS: This population-based, repeated cross-sectional analysis included all long-term permanent residents of Australian RACFs between July 2005 and June 2016 who were aged ≥ 65 years. The yearly prevalence rate of antibiotic use and number of defined daily doses (DDDs) of systemic antibiotics per 1000 resident-days were determined annually from linked pharmaceutical claims data. Trends were assessed using ordinary least squares regression. RESULTS: This study included 502 752 residents from 3218 RACFs, with 424.9 million resident-days analyzed. Antibiotics were dispensed on 5 608 126 occasions during the study period, of which 88% were for oral use. Cefalexin, amoxicillin-clavulanic acid, and trimethoprim were the most commonly dispensed antibiotics. The annual prevalence of antibiotic use increased from 63.8% (95% confidence interval [CI], 63.3%-64.4%) to 70.3% (95% CI, 69.9%-70.7%) between 2005-2006 and 2015-2016 (0.8% average annual increase, P < .001). There was a 39% relative increase in total consumption of systemic antibiotics, with utilization increasing from 67.6 to 93.8 DDDs/1000 resident-days during the study period (average annual increase of 2.8 DDDs/1000 resident-days, P < .001). CONCLUSIONS: This nationwide study showed substantial increases in both prevalence of use and total consumption of antibiotics in Australian RACFs between 2005 and 2016. The increasingly widespread use of antibiotics in Australian RACFs is concerning and points to a need for enhanced efforts to optimize antibiotic use in this setting.

Neutrophils in asthma: the good, the bad and the bacteria.

Airway inflammation plays a key role in asthma pathogenesis but is heterogeneous in nature. There has been significant scientific discovery with regard to type 2-driven, eosinophil-dominated asthma, with effective therapies ranging from inhaled corticosteroids to novel biologics. However, studies suggest that approximately 1 in 5 adults with asthma have an increased proportion of neutrophils in their airways. These patients tend to be older, have potentially pathogenic airway bacteria and do not respond well to classical therapies. Currently, there are no specific therapeutic options for these patients, such as neutrophil-targeting biologics.Neutrophils comprise 70% of the total circulatory white cells and play a critical defence role during inflammatory and infective challenges. This makes them a problematic target for therapeutics. Furthermore, neutrophil functions change with age, with reduced microbial killing, increased reactive oxygen species release and reduced production of extracellular traps with advancing age. Therefore, different therapeutic strategies may be required for different age groups of patients.The pathogenesis of neutrophil-dominated airway inflammation in adults with asthma may reflect a counterproductive response to the defective neutrophil microbial killing seen with age, resulting in bystander damage to host airway cells and subsequent mucus hypersecretion and airway remodelling. However, in children with asthma, neutrophils are less associated with adverse features of disease, and it is possible that in children, neutrophils are less pathogenic.In this review, we explore the mechanisms of neutrophil recruitment, changes in cellular function across the life course and the implications this may have for asthma management now and in the future. We also describe the prevalence of neutrophilic asthma globally, with a focus on First Nations people of Australia, New Zealand and North America.

Add-on azithromycin reduces sputum cytokines in non-eosinophilic asthma: an AMAZES substudy.

Add-on azithromycin (AZM) significantly reduces exacerbations in poorly controlled asthma irrespective of disease phenotype. In a predefined substudy of the original AMAZES protocol (500 mg, three times a week for 48 weeks), we report that AZM treatment reduces key sputum inflammatory proteins (interleukin (IL)-6, IL-1ß and extracellular DNA), which is more evident in non-eosinophilic asthma (NEA). Moreover, AZM reduced Haemophilus influenzae load only in NEA. Our data support the anti-inflammatory effects of AZM in poorly controlled asthma. Prospective studies are required to identify patients that derive greatest benefit from AZM add-on therapy.

Contribution of facility level factors to variation in antibiotic use in long-term care facilities: a national cohort study.

OBJECTIVES: To examine national variation in systemic antibiotic use in long-term care facilities (LTCFs) and identify facility characteristics associated with antibiotic utilization. METHODS: This retrospective cohort study included 312 375 residents of 2536 Australian LTCFs between 2011 and 2016. LTCFs were categorized as low, medium or high antibiotic use facilities according to tertiles of DDDs of systemic antibiotics dispensed per 1000 resident-days. Multivariable logistic regression estimated the associations between facility characteristics (ownership, size, location, medication quality indicator performance, prevalence of after-hours medical practitioner services) and antibiotic use (low versus high). RESULTS: LTCFs in the lowest and highest antibiotic use categories received a median of 54.3 (IQR 46.5-60.5) and 106.1 (IQR 95.9-122.3) DDDs/1000 resident-days, respectively. Compared with not-for-profit LTCFs in major cities, government-owned non-metropolitan LTCFs were less likely to experience high antibiotic use [adjusted OR (aOR) 0.47, 95% CI 0.24-0.91]. LTCFs with 69-99 residents were less likely to experience high antibiotic use (aOR 0.69, 95% CI 0.49-0.97) than those with 25-47 residents annually. Greater prevalence of medical practitioner services accessed after-hours was associated with high antibiotic use [aOR 1.10 (per 10% increase in after-hours services), 95% CI 1.01-1.21]. South Australian LTCFs (aOR 2.17, 95% CI 1.38-3.39) were more likely, while Queensland (0.43, 95% CI 0.30-0.62) and Western Australian (aOR 0.34, 95% CI 0.21-0.57) LTCFs were less likely to experience high antibiotic use than New South Wales LTCFs. CONCLUSIONS: Considerable facility level variation in systemic antibiotic use was observed across Australian LTCFs. Identification of facility characteristics associated with antibiotic use provides a basis for targeted stewardship initiatives.

The effects of increasing fruit and vegetable intake in children with asthma: A randomized controlled trial.

BACKGROUND: A high fruit and vegetable (F&V) diet reduces asthma exacerbations in adults; this has not been examined in children to date. OBJECTIVE: To investigate the effect of a 6-month, high F&V diet on the time to first asthma exacerbation in children with asthma, in a parallel-group, randomized, controlled trial. METHODS: Children (aged 3-11 years) with asthma, history of exacerbations and usual low F&V intake (≤3 serves/day) were randomized to the intervention (high F&V diet) or control group (usual diet) for 6 months. The primary outcome was time to first exacerbation requiring medical intervention. Secondary outcomes included exacerbation rate, lung function, plasma TNF-α, CRP, and IL-6, faecal microbiota and peripheral blood mononuclear cell (PBMC) histone deacetylase (HDAC) activity and G-protein coupled receptor (GPR) 41/43 and HDAC (1-11) expression. RESULTS: 67 children were randomized between September 2015 and July 2018. F&V intake (difference in change (∆): 3.5 serves/day, 95% CI: [2.6, 4.4] p < 0.001) and plasma total carotenoids (∆: 0.44 µg/ml [0.19, 0.70] p = 0.001) increased after 6 months (intervention vs control). Time to first exacerbation (HR: 0.81, 95% CI: [0.38, 1.69], p = 0.569; control vs. intervention) and exacerbation rate (IRR: 0.84, [0.47, 1.49], p = 0.553; control vs. intervention) were similar between groups. In per-protocol analysis, airway reactance z-scores increased in the intervention versus control group (X5 ∆: 0.76 [0.04, 1.48] p = 0.038, X20 ∆: 0.93 [0.23, 1.64] p = 0.009) and changes in faecal microbiota were observed though there was no difference between groups in systemic inflammation or molecular mechanisms. In the control group, CRP and HDAC enzyme activity increased, while GPR41 expression decreased. No adverse events attributable to the interventions were observed. CONCLUSION & CLINICAL RELEVANCE: A high F&V diet did not affect asthma exacerbations over the 6-month intervention, though warrants further investigation as a strategy for improving lung function and protecting against systemic inflammation in children with asthma.

Lean NAFLD: A Distinct Entity Shaped by Differential Metabolic Adaptation.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the adult population. A significant subset of patients are lean, but their underlying pathophysiology is not well understood. APPROACH AND RESULTS: We investigated the role of bile acids (BAs) and the gut microbiome in the pathogenesis of lean NAFLD. BA and fibroblast growth factor (FGF) 19 levels (a surrogate for intestinal farnesoid X receptor [FXR] activity), patatin-like phospholipase domain containing 3 (PNPLA3), and transmembrane 6 superfamily member 2 (TM6SF2) variants, and gut microbiota profiles in lean and nonlean NAFLD were investigated in a cohort of Caucasian patients with biopsy-proven NAFLD (n = 538), lean healthy controls (n = 30), and experimental murine models. Patients with lean NAFLD had a more favorable metabolic and histological profile compared with those with nonlean NAFLD (P < 0.05 for all). BA levels were significantly higher in NAFLD with advanced compared with earlier stages of liver fibrosis. Patients with lean NAFLD had higher serum secondary BA and FGF19 levels and reduced 7-alpha-hydroxy-4-cholesten-3-one (C4) levels (P < 0.05 for all). These differences were more profound in early compared with advanced stages of fibrosis (P < 0.05 for both). Lean patients demonstrated an altered gut microbiota profile. Similar findings were demonstrated in lean and nonlean murine models of NAFLD. Treating mice with an apical sodium-dependent BA transporter inhibitor (SC-435) resulted in marked increases in fgf15, a shift in the BA and microbiota profiles, and improved steatohepatitis in the lean model. CONCLUSIONS: Differences in metabolic adaptation between patients with lean and nonlean NAFLD, at least in part, explain the pathophysiology and provide options for therapy.

Conventional myelosuppressive chemotherapy for non-haematological malignancy disrupts the intestinal microbiome.

BACKGROUND: The gut microbiota influences many aspects of host physiology, including immune regulation, and is predictive of outcomes in cancer patients. However, whether conventional myelosuppressive chemotherapy affects the gut microbiota in humans with non-haematological malignancy, independent of antibiotic exposure, is unknown. METHODS: Faecal samples from 19 participants with non-haematological malignancy, who were receiving conventional chemotherapy regimens but not antibiotics, were examined prior to chemotherapy, 7-12 days after chemotherapy, and at the end of the first cycle of treatment. Gut microbiota diversity and composition was determined by 16S rRNA gene amplicon sequencing. RESULTS: Compared to pre-chemotherapy samples, samples collected 7-12 days following chemotherapy exhibited increased richness (mean 120 observed species ± SD 38 vs 134 ± 40; p = 0.007) and diversity (Shannon diversity: mean 6.4 ± 0.43 vs 6.6 ± 0.41; p = 0.02). Composition was significantly altered, with a significant decrease in the relative abundance of gram-positive bacteria in the phylum Firmicutes (pre-chemotherapy median relative abundance [IQR] 0.78 [0.11] vs 0.75 [0.11]; p = 0.003), and an increase in the relative abundance of gram-negative bacteria (Bacteroidetes: median [IQR] 0.16 [0.13] vs 0.21 [0.13]; p = 0.01 and Proteobacteria: 0.015 [0.018] vs 0.03 [0.03]; p = 0.02). Differences in microbiota characteristics from baseline were no longer significant at the end of the chemotherapy cycle. CONCLUSIONS: Conventional chemotherapy results in significant changes in gut microbiota characteristics during the period of predicted myelosuppression post-chemotherapy. Further study is indicated to link microbiome changes during chemotherapy to clinical outcomes.

Prevention of SARS-CoV-2 (COVID-19) transmission in residential aged care using ultraviolet light (PETRA): a two-arm crossover randomised controlled trial protocol.

BACKGROUND: SARS-CoV-2 poses a considerable threat to those living in residential aged care facilities (RACF). RACF COVID-19 outbreaks have been characterised by the rapid spread of infection and high rates of severe disease and associated mortality. Despite a growing body of evidence supporting airborne transmission of SARS-CoV-2, current infection control measures in RACF including hand hygiene, social distancing, and sterilisation of surfaces, focus on contact and droplet transmission. Germicidal ultraviolet (GUV) light has been used widely to prevent airborne pathogen transmission. Our aim is to investigate the efficacy of GUV technology in reducing the risk of SARS-CoV-2 infection in RACF. METHODS: A multicentre, two-arm double-crossover, randomised controlled trial will be conducted to determine the efficacy of GUV devices to reduce respiratory viral transmission in RACF, as an adjunct to existing infection control measures. The study will be conducted in partnership with three aged care providers in metropolitan and regional South Australia. RACF will be separated into paired within-site zones, then randomised to intervention order (GUV or control). The initial 6-week period will be followed by a 2-week washout before crossover to the second 6-week period. After accounting for estimated within-zone and within-facility correlations of infection, and baseline infection rates (10 per 100 person-days), a sample size of n = 8 zones (n = 40 residents/zone) will provide 89% power to detect a 50% reduction in symptomatic infection rate. The primary outcome will be the incidence rate ratio of combined symptomatic respiratory infections for intervention versus control. Secondary outcomes include incidence rates of hospitalisation for complications associated with respiratory infection; respiratory virus detection in facility air and fomite samples; rates of laboratory confirmed respiratory illnesses and genomic characteristics. DISCUSSION: Measures that can be deployed rapidly into RACF, that avoid the requirement for changes in resident and staff behaviour, and that are effective in reducing the risk of airborne SARS-CoV-2 transmission, would provide considerable benefit in safeguarding a highly vulnerable population. In addition, such measures might substantially reduce rates of other respiratory viruses, which contribute considerably to resident morbidity and mortality. Trial registration Australian and New Zealand Clinical Trials Registry ACTRN12621000567820 (registered on 14th May, 2021).

The influence of early-life microbial exposures on long-term respiratory health.

Host-microbiome interactions exert a profound influence on human physiology and health outcomes. In particular, certain characteristics of commensal microbiota during a critical period in early life are essential for the establishment of immune tone and metabolic control. An increasing body of evidence suggests that early life exposures that disrupt these interactions can substantially influence life-long risks for respiratory disease. Here, we explore how such early life exposures, including antibiotic exposure, maternal diet, preterm birth, mode of delivery, breastfeeding, and environmental variables shape the infant microbiome, and the mechanisms by such changes can in turn impact respiratory health.

The Microbiota-Inflammasome Hypothesis of Major Depression.

We propose the "microbiota-inflammasome" hypothesis of major depressive disorder (MDD, a mental illness affecting the way a person feels and thinks, characterized by long-lasting feelings of sadness). We hypothesize that pathological shifts in gut microbiota composition (dysbiosis) caused by stress and gut conditions result in the upregulation of pro-inflammatory pathways mediated by the Nod-like receptors family pyrin domain containing 3 (NLRP3) inflammasome (an intracellular platform involved in the activation of inflammatory processes). This upregulation exacerbates depressive symptomatology and further compounds gut dysbiosis. In this review we describe MDD/chronic stress-induced changes in: 1) NLRP3 inflammasome; 2) gut microbiota; and 3) metabolic pathways; and how inflammasome signaling may affect depressive-like behavior and gut microbiota composition. The implication is that novel therapeutic strategies could emerge for MDD and co-morbid conditions. A number of testable predictions surface from this microbiota-gut-inflammasome-brain hypothesis of MDD, using approaches that modulate gut microbiota composition via inflammasome modulation, fecal microbiota transplantation, psychobiotics supplementation, or dietary change.

Long-Term Azithromycin Reduces Haemophilus influenzae and Increases Antibiotic Resistance in Severe Asthma.

Rationale: The macrolide antibiotic azithromycin reduces exacerbations in adults with persistent symptomatic asthma. However, owing to the pleotropic properties of macrolides, unintended bacteriological consequences such as augmented pathogen colonization or dissemination of antibiotic-resistant organisms can occur, calling into question the long-term safety of azithromycin maintenance therapy.Objectives: To assess the effects of azithromycin on the airway microbiota, pathogen abundance, and carriage of antibiotic resistance genes.Methods: 16S rRNA sequencing and quantitative PCR were performed to assess the effect of azithromycin on sputum microbiology from participants of the AMAZES (Asthma and Macrolides: The Azithromycin Efficacy and Safety) trial: a 48-week, double-blind, placebo-controlled trial of thrice-weekly 500 mg oral azithromycin in adults with persistent uncontrolled asthma. Pooled-template shotgun metagenomic sequencing, quantitative PCR, and isolate whole-genome sequencing were performed to assess antibiotic resistance.Measurements and Main Results: Paired sputum samples were available from 61 patients (n = 34 placebo, n = 27 azithromycin). Azithromycin did not affect bacterial load (P = 0.37) but did significantly decrease Faith's phylogenetic diversity (P = 0.026) and Haemophilus influenzae load (P < 0.0001). Azithromycin did not significantly affect levels of Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, or Moraxella catarrhalis. Of the 89 antibiotic resistance genes detected, five macrolide resistance genes and two tetracycline resistance genes were increased significantly.Conclusions: In patients with persistent uncontrolled asthma, azithromycin reduced airway H. influenzae load compared with placebo but did not change total bacterial load. Macrolide resistance increased, reflecting previous studies. These results highlight the need for studies assessing the efficacy of nonantibiotic macrolides as a long-term therapy for patients with persistent uncontrolled asthma.