Gut microbiota composition and function are symbiotically linked with host health and altered in metabolic, inflammatory and neurodegenerative disorders. Three recognised mechanisms exist by which ...the microbiome influences the gut-brain axis: modification of autonomic/sensorimotor connections, immune activation, and neuroendocrine pathway regulation. We hypothesised interactions between circulating gut-derived microbial metabolites, and the blood-brain barrier (BBB) also contribute to the gut-brain axis. Propionate, produced from dietary substrates by colonic bacteria, stimulates intestinal gluconeogenesis and is associated with reduced stress behaviours, but its potential endocrine role has not been addressed.
After demonstrating expression of the propionate receptor FFAR3 on human brain endothelium, we examined the impact of a physiologically relevant propionate concentration (1 μM) on BBB properties in vitro. Propionate inhibited pathways associated with non-specific microbial infections via a CD14-dependent mechanism, suppressed expression of LRP-1 and protected the BBB from oxidative stress via NRF2 (NFE2L2) signalling.
Together, these results suggest gut-derived microbial metabolites interact with the BBB, representing a fourth facet of the gut-brain axis that warrants further attention.
Within the 21 APEC economies alone, there are an estimated 200 million individuals living with a rare disease. As such, health data on these individuals, and hence patient registries, are vital. ...However, registries can come in many different forms and operating models in different jurisdictions. They possess a varying degree of functionality and are used for a variety of purposes. For instance registries can facilitate service planning as well as underpin public health and clinical research by providing de-identified data to researchers. Furthermore, registries may be used to create and disseminate new knowledge to inform clinical best practice and care, to identify and enrol participants for clinical trials, and to enable seamless integration of patient data for diagnostic testing and cascade screening. Registries that add capability such as capturing patient reported outcomes enable patients, and their carers, to become active partners in their care, rapidly furthering research and ensuring up-to-date practice-based evidence. Typically, a patient registry centres around the notion of health data 'capture', usually for only one or a small subset of the functions outlined above, thereby creating fragmented datasets that, despite the best efforts and intentions, make it difficult to exchange the right data for the right purpose to the right stakeholder under appropriate governance arrangements. Trying to incorporate maximum functionality into a registry is an obvious strategy, but monolithic software solutions are not desirable. As an alternative, we propose that it is important to incorporate analytics as core to a patient registry, rather than just utilising registries as a 'data capture' solution. We contend that embracing an analytics-centric focus makes it reasonable to imagine a future where it will be possible to evaluate the individual outcomes of health interventions in real time. The purposeful and, importantly, the repurposable application of health data will allow stakeholders to extract, create and reuse knowledge to improve health outcomes, assist clinical decision making, and improve health service design and delivery. To realise this vision, we introduce and describe the concept of a Rare Disease Registry and Analytics Platform (RD-RAP); one that we hope will make a meaningful difference to the lives of those living with a rare disease.
Communication between the gut microbiota and the brain is primarily mediated via soluble microbe-derived metabolites, but the details of this pathway remain poorly defined. Methylamines produced by ...microbial metabolism of dietary choline and L-carnitine have received attention due to their proposed association with vascular disease, but their effects upon the cerebrovascular circulation have hitherto not been studied.
Here, we use an integrated in vitro/in vivo approach to show that physiologically relevant concentrations of the dietary methylamine trimethylamine N-oxide (TMAO) enhanced blood-brain barrier (BBB) integrity and protected it from inflammatory insult, acting through the tight junction regulator annexin A1. In contrast, the TMAO precursor trimethylamine (TMA) impaired BBB function and disrupted tight junction integrity. Moreover, we show that long-term exposure to TMAO protects murine cognitive function from inflammatory challenge, acting to limit astrocyte and microglial reactivity in a brain region-specific manner.
Our findings demonstrate the mechanisms through which microbiome-associated methylamines directly interact with the mammalian BBB, with consequences for cerebrovascular and cognitive function. Video abstract.
Asthma is among the commonest noncommunicable diseases of childhood and often occurs with other atopic comorbidities. A previous case-control study found evidence that compared to children who ...received acellular pertussis (aP) vaccines in early infancy, children who received one or more doses of whole-cell pertussis (wP) vaccine had lower risk of developing IgE-mediated food allergy. We hypothesized that wP vaccination in early infancy might protect against atopic asthma in childhood. Retrospective record-linkage cohort study of children between 5 and < 15 years old and born between January 1997, and December 1999, in the Australian states of Western Australia (WA) and New South Wales (NSW), receiving wP versus aP vaccine as the first pertussis vaccine dose. The main outcome and measures were first and recurrent hospitalizations for asthma; hazard ratios (HRs) and 95% confidence intervals (CIs) were computed by means of Cox and Andersen and Gill models. 274,405 children aged between 5 and < 15 years old (78.4% NSW-born) received a first dose of either wP (67.8%) or aP vaccine before 4 months old. During the follow-up period, there were 5,905 hospitalizations for asthma among 3,955 children. The incidence rate for first hospitalization was 1.5 (95% CI 1.4-1.5) per 1,000 child-years among children receiving wP vaccine as a first dose, and 1.5 (95% CI 1.4-1.6) among those vaccinated with aP vaccine as a first dose. The adjusted HRs for those who received wP vaccine versus aP vaccine as the first dose were 1.02 (95% CI 0.94-1.12) for first hospitalizations and 1.07 (95% CI 0.95-1.2) for recurrent hospitalizations for asthma. We found no convincing evidence of a clinically relevant association between receipt of wP versus aP vaccines in early infancy and hospital presentations for asthma in childhood.
Background In many countries, infant vaccination with acellular pertussis (aP) vaccines has replaced use of more reactogenic whole-cell pertussis (wP) vaccines. Based on immunological and ...epidemiological evidence, we hypothesised that substituting the first aP dose in the routine vaccination schedule with wP vaccine might protect against IgE-mediated food allergy. We aimed to compare reactogenicity, immunogenicity, and IgE-mediated responses of a mixed wP/aP primary schedule versus the standard aP-only schedule. Methods and findings OPTIMUM is a Bayesian, 2-stage, double-blind, randomised trial. In stage one, infants were assigned (1:1) to either a first dose of a pentavalent wP combination vaccine (DTwP-Hib-HepB, Pentabio PT Bio Farma, Indonesia) or a hexavalent aP vaccine (DTaP-Hib-HepB-IPV, Infanrix hexa, GlaxoSmithKline, Australia) at approximately 6 weeks old. Subsequently, all infants received the hexavalent aP vaccine at 4 and 6 months old as well as an aP vaccine at 18 months old (DTaP-IPV, Infanrix-IPV, GlaxoSmithKline, Australia). Stage two is ongoing and follows the above randomisation strategy and vaccination schedule. Ahead of ascertainment of the primary clinical outcome of allergist-confirmed IgE-mediated food allergy by 12 months old, here we present the results of secondary immunogenicity, reactogenicity, tetanus toxoid IgE-mediated immune responses, and parental acceptability endpoints. Serum IgG responses to diphtheria, tetanus, and pertussis antigens were measured using a multiplex fluorescent bead-based immunoassay; total and specific IgE were measured in plasma by means of the ImmunoCAP assay (Thermo Fisher Scientific). The immunogenicity of the mixed schedule was defined as being noninferior to that of the aP-only schedule using a noninferiority margin of 2/3 on the ratio of the geometric mean concentrations (GMR) of pertussis toxin (PT)-IgG 1 month after the 6-month aP. Solicited adverse reactions were summarised by study arm and included all children who received the first dose of either wP or aP. Parental acceptance was assessed using a 5-point Likert scale. The primary analyses were based on intention-to-treat (ITT); secondary per-protocol (PP) analyses were also performed. The trial is registered with ANZCTR (ACTRN12617000065392p). Between March 7, 2018 and January 13, 2020, 150 infants were randomised (75 per arm). PT-IgG responses of the mixed schedule were noninferior to the aP-only schedule at approximately 1 month after the 6-month aP dose GMR = 0·98, 95% credible interval (0·77 to 1·26); probability (GMR > 2/3) > 0·99; ITT analysis. At 7 months old, the posterior median probability of quantitation for tetanus toxoid IgE was 0·22 (95% credible interval 0·12 to 0·34) in both the mixed schedule group and in the aP-only group. Despite exclusions, the results were consistent in the PP analysis. At 6 weeks old, irritability was the most common systemic solicited reaction reported in wP (65 88% of 74) versus aP (59 82% of 72) vaccinees. At the same age, severe systemic reactions were reported among 14 (19%) of 74 infants after wP and 8 (11%) of 72 infants after aP. There were 7 SAEs among 5 participants within the first 6 months of follow-up; on blinded assessment, none were deemed to be related to the study vaccines. Parental acceptance of mixed and aP-only schedules was high (71 97% of 73 versus 69 96% of 72 would agree to have the same schedule again). Conclusions Compared to the aP-only schedule, the mixed schedule evoked noninferior PT-IgG responses, was associated with more severe reactions, but was well accepted by parents. Tetanus toxoid IgE responses did not differ across the study groups. Trial registration Trial registered at the Australian and New Zealand Clinical 207 Trial Registry ( ACTRN12617000065392p ).
Background In Australian remote communities, First Nations children with otitis media (OM)-related hearing loss are disproportionately at risk of developmental delay and poor school performance, ...compared to those with normal hearing. Our objective was to compare OM-related hearing loss in children randomised to one of 2 pneumococcal conjugate vaccine (PCV) formulations. Methods and findings In 2 sequential parallel, open-label, randomised controlled trials (the PREVIX trials), eligible infants were first allocated 1:1:1 at age 28 to 38 days to standard or mixed PCV schedules, then at age 12 months to PCV13 (13-valent pneumococcal conjugate vaccine, +P) or PHiD-CV10 (10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine, +S) (1:1). Here, we report prevalence and level of hearing loss outcomes in the +P and +S groups at 6-monthly scheduled assessments from age 12 to 36 months. From March 2013 to September 2018, 261 infants were enrolled and 461 hearing assessments were performed. Prevalence of hearing loss was 78% (25/32) in the +P group and 71% (20/28) in the +S group at baseline, declining to 52% (28/54) in the +P groups and 56% (33/59) in the +S group at age 36 months. At primary endpoint age 18 months, prevalence of moderate (disabling) hearing loss was 21% (9/42) in the +P group and 41% (20/49) in the +S group (difference −19%; (95% confidence interval (CI) −38, −1, p = 0.07) and prevalence of no hearing loss was 36% (15/42) in the +P group and 16% (8/49) in the +S group (difference 19%; (95% CI 2, 37, p = 0.05). At subsequent time points, prevalence of moderate hearing loss remained lower in the +P group: differences −3%; (95% CI −23, 18, p = 1.00 at age 24 months), −12%; (95% CI −30, 6, p = 0.29 at age 30 months), and −9%; (95% CI −23, 5, p = 0.25 at age 36 months). A major limitation was the small sample size, hence low power to reach statistical significance, thereby reducing confidence in the effect size. Conclusions In this study, we observed a high prevalence and persistence of moderate (disabling) hearing loss throughout early childhood. We found a lower prevalence of moderate hearing loss and correspondingly higher prevalence of no hearing loss in the +P group, which may have substantial benefits for high-risk children, their families, and society, but warrant further investigation. Trial registration ClinicalTrials.gov NCT01735084 and NCT01174849
Population-level studies of severe pertussis extending beyond infancy are sparse, and none in the context of antenatal vaccination. We compared hospitalized pertussis cases from birth to 15 years of ...age before and after introduction of antenatal immunization.
Active surveillance of laboratory-confirmed pertussis hospitalizations in a national network of pediatric hospitals in Australia January 2012 to June 2019. Impact of maternal vaccination was assessed by vaccine effectiveness (VE) in cases and test-negative controls with <2 months of age and by before-after comparison of age distribution of cases. Among cases eligible for one or more vaccine doses, we examined proportions age-appropriately immunized and with comorbidities by age group.
Among 419 eligible cases, the proportion <2 months of age significantly decreased from 33.1% in 2012 to 2014 compared with 19.6% in 2016 to 2019 when mothers of only 4 of 17 (23.5%) cases <2 months of age had received antenatal vaccination. VE was estimated to be 84.3% (95% CI, 26.1-96.7). Across all years (2012-2019), of 55 cases 4-11 months of age, 21 (38%) had ≥2 vaccine doses, whereas among 155 cases ≥12 months of age, 122 (85.2%) had ≥3 vaccine doses. Prevalence of comorbidities (primarily cardiorespiratory) increased from 5 (2.1%) <6 months of age to 36 (24.2%) ≥12 months of age (P < 0.001), with 6/16 (38%) cases ≥12 months of age who required intensive care having comorbidities.
Below the age of 12 months, prevention of severe pertussis will be maximized by high maternal antenatal vaccine uptake and timeliness of infant vaccine doses. Despite full immunization, we found children ≥12 months of age accounted for 27% of hospitalizations <15 years, with 24% having comorbities, suggesting new vaccine strategies, such as additional doses or more immunogenic vaccines, require evaluation.
Cystic fibrosis (CF) is a rare, inherited, life-limiting condition predominantly affecting the lungs, for which there is no cure. The disease is characterized by recurrent pulmonary exacerbations ...(PEx), which are thought to drive progressive lung damage. Management of these episodes is complex and generally involves multiple interventions targeting different aspects of disease. The emergence of innovative trials and use of Bayesian statistical methods has created renewed opportunities for studying heterogeneous populations in rare diseases. Here, we present the protocol for the BEAT CF PEx cohort, a prospective, multi-site, perpetual, platform enrolling adults and children with CF. The BEAT CF PEx cohort will be used to evaluate the comparative effectiveness of interventions for the treatment of PEx requiring intensive therapy (PERITs), with a primary focus on short-term improvements in lung function. This will be achieved through the conduct of cohort-nested studies, including adaptive clinical trials, within the BEAT CF PEx cohort. This protocol will outline key features of the BEAT CF PEx cohort, including the design, implementation, data collection and management, governance and analysis, and dissemination of results.
This platform will be conducted across multiple sites, commencing with CF treatment centers in Australia. People of all ages with a clinical diagnosis of CF will be eligible to participate, except those who have previously received a lung transplant. Data including demographic and clinical information, treatment details, and outcomes (including safety, microbiology, and patient-reported outcome measures including quality of life scores) will be systematically collected and securely stored via a digital centralized trial management system (CTMS). The primary endpoint is the absolute change in the percentage predicted forced expiratory volume in 1 s (ppFEV
) from the commencement of intensive therapy to 7 to 10 days afterwards.
The BEAT CF PEx cohort will report clinical, treatment, and outcome data for PEx among people with CF and is intended to serve as a core (master) protocol for future nested, interventional trials evaluating treatment(s) for these episodes. The protocols for nested sub-studies are beyond the scope of this document and will be reported separately.
ANZCTR BEAT CF Platform - ACTRN12621000638831. Registration date: Sept. 26, 2022.
Aim
To examine rates and predictors of 7‐day readmission in infants hospitalised before 3 months of age with infectious and non‐infectious conditions.
Methods
Retrospective population‐based ...data‐linkage study of 121 854 infants from a 5‐year metropolitan birth cohort (2008–2012). Cox proportional hazard models were used to examine associations between infant and maternal factors with 7‐day readmission.
Results
A total of 11 669 (9.6%) infants were hospitalised at least once by 3 months of age (median 23 days old, 56% male) with 12 602 total index hospitalisations. Infection‐related conditions accounted for 29.4% (n = 3705). Readmission within 7 days occurred after 4.8% of all index hospitalisations and 5.4% of infection‐related hospitalisations. Age ≤21 days was the strongest readmission risk factor (hazard ratio 7.7 (95% confidence interval 4.7–12.7) compared to infants 61–90 days old). Other risk factors included shorter index hospitalisations, younger maternal age and multi‐gravidity.
Conclusion
Hospitalisations and readmissions occur for many young infants. Risk factors for readmission should inform risk‐based management guidelines.
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