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A randomized controlled trial of an oral probiotic to reduce antepartum group B Streptococcus colonization and gastrointestinal symptoms.
Hanson, L, VandeVusse, L, Forgie, M, Malloy, E, Singh, M, Scherer, M, Kleber, D, Dixon, J, Hryckowian, AJ, Safdar, N
American journal of obstetrics & gynecology MFM. 2023;5(1):100748
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Streptococcus agalactiae (or group B Streptococcus [GBS]) is an encapsulated, gram-positive, beta-haemolytic anaerobe that asymptomatically colonizes the genitourinary tract. Vertical transmission of GBS during normal vaginal birth can lead to neonatal colonization and risk for early-onset GBS disease. The aim of this study was to present the findings of a phase II, double-blind, randomised, placebo-controlled trial of an antenatal probiotic intervention to reduce GBS colonization. A secondary aim was to determine if the probiotic intervention reduces gastrointestinal (GI) symptoms of pregnancy. Participants (n=107) were randomly assigned to one of the two groups: probiotic intervention (n=55) or placebo group (n=54). Results show that: - there weren’t any significant differences between the groups in demographic characteristics, perinatal or neonatal outcomes, or intrapartum antibiotic prophylaxis doses. - there wasn’t any significant difference between groups in the presence of the probiotic bacteria on the rectal swabs, whereas the vaginal swabs showed a trend toward greater presence in probiotic group participants. - more probiotic participants took antenatal antibiotics (5/39) compared with controls (1/44). Authors conclude that probiotic bacteria colonisation of the genitourinary tract occurred more in the intervention group than in the control group and significantly reduced GI symptoms of pregnancy.
Abstract
BACKGROUND Probiotics have been suggested as a strategy to reduce antenatal group B Streptococcus colonization. Although probiotics are known to improve gastrointestinal symptoms, this has not been studied during pregnancy. OBJECTIVE This study aimed to evaluate the efficacy of a probiotic to reduce: (1) standard-of-care antenatal group B Streptococcus colonization and colony counts and (2) gastrointestinal symptoms of pregnancy. STUDY DESIGN In a double-blind fashion, 109 healthy adult pregnant people were randomized to Florajen3 probiotic or placebo capsules once daily from 28 weeks' gestation until labor onset. Baseline vaginal and rectal study swabs for group B Streptococcus colony-forming units and microbiome analysis were collected at 28 and 36 weeks' gestation. Standard-of-care vaginal to rectal group B Streptococcus swabs were collected from all participants at 36 weeks' gestation and determined the need for intrapartum antibiotic prophylaxis. Data collection included solicitation of adverse events, demographic information, Antepartum Gastrointestinal Symptom Assessment score, yogurt ingestion, sexual activity, and vaginal cleaning practices. RESULTS A total of 83 participants completed the study to 36 weeks' gestation with no adverse events. Standard-of-care group B Streptococcus colonization was 20.4% in the control group and 15.4% in probiotic group participants (-5%; P=.73). The relative risk for positive standard-of-care vaginal-rectal group B Streptococcus colonization was 1.33 (95% confidence interval, 0.5-3.40) times higher in the control group than in the probiotic group (P=.55). There were no differences in median vaginal (P=.16) or rectal (P=.20) group B streptococcus colony-forming units at baseline or at 36 weeks (vaginal P>.999; rectal P=.56). Antepartum Gastrointestinal Symptom Assessment scores were similar at baseline (P=.19), but significantly decreased in probiotic group participants at 36 weeks (P=.02). No covariates significantly altered group B Streptococcus colonization. Significantly more Florajen3 bacteria components were recovered from the vaginal-rectal samples of probiotic group participants (32%; P=.04) compared with controls. CONCLUSION The findings of this study provided insufficient evidence for the clinical application of the Florajen3 probiotic intervention to reduce standard-of-care vaginal-rectal group B Streptococcus colonization. The prevalence of group B Streptococcus was lower than expected in the study population, and intervention adherence was poor. Probiotic bacteria colonization of the genitourinary tract occurred more in intervention group participants than in controls and significantly reduced gastrointestinal symptoms of pregnancy.
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Constraint and conservation of paired-type homeodomains predicts the clinical outcome of missense variants of uncertain significance.
Thai, MHN, Gardner, A, Redpath, L, Mattiske, T, Dearsley, O, Shaw, M, Vulto-van Silfhout, AT, Pfundt, R, Dixon, J, McGaughran, J, et al
Human mutation. 2020;(8):1407-1424
Abstract
The need to interpret the pathogenicity of novel missense variants of unknown significance identified in the homeodomain of X-chromosome aristaless-related homeobox (ARX) gene prompted us to assess the utility of conservation and constraint across these domains in multiple genes compared to conventional in vitro functional analysis. Pathogenic missense variants clustered in the homeodomain of ARX contribute to intellectual disability (ID) and epilepsy, with and without brain malformation in affected males. Here we report novel c.1112G>A, p.Arg371Gln and c.1150C>T, p.Arg384Cys variants in male patients with ID and severe seizures. The third case of a male patient with a c.1109C>T, p.Ala370Val variant is perhaps the first example of ID and autism spectrum disorder (ASD), without seizures or brain malformation. We compiled data sets of pathogenic variants from ClinVar and presumed benign variation from gnomAD and demonstrated that the high levels of sequence conservation and constraint of benign variation within the homeodomain impacts upon the ability of publicly available in silico prediction tools to accurately discern likely benign from likely pathogenic variants in these data sets. Despite this, considering the inheritance patterns of the genes and disease variants with the conservation and constraint of disease variants affecting the homeodomain in conjunction with current clinical assessments may assist in predicting the pathogenicity of missense variants, particularly for genes with autosomal recessive and X-linked patterns of disease inheritance, such as ARX. In vitro functional analysis demonstrates that the transcriptional activity of all three variants was diminished compared to ARX-Wt. We review the associated phenotypes of the published cases of patients with ARX homeodomain variants and propose expansion of the ARX-related phenotype to include severe ID and ASD without brain malformations or seizures. We propose that the use of the constraint and conservation data in conjunction with consideration of the patient phenotype and inheritance pattern may negate the need for the experimental functional validation currently required to achieve a diagnosis.
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Reduction of body iron in HFE-related haemochromatosis and moderate iron overload (Mi-Iron): a multicentre, participant-blinded, randomised controlled trial.
Ong, SY, Gurrin, LC, Dolling, L, Dixon, J, Nicoll, AJ, Wolthuizen, M, Wood, EM, Anderson, GJ, Ramm, GA, Allen, KJ, et al
The Lancet. Haematology. 2017;(12):e607-e614
Abstract
BACKGROUND The iron overload disorder hereditary haemochromatosis is most commonly caused by HFE p.Cys282Tyr homozygosity. In the absence of results from any randomised trials, current evidence is insufficient to determine whether individuals with hereditary haemochromatosis and moderately elevated serum ferritin, should undergo iron reduction treatment. This trial aimed to establish whether serum ferritin normalisation in this population improved symptoms and surrogate biomarkers. METHODS This study was a multicentre, participant-blinded, randomised controlled trial done at three centres in Australia. We enrolled people who were homozygous for HFE p.Cys282Tyr, aged between 18 and 70 years, with moderately elevated serum ferritin, defined as 300-1000 μg/L, and raised transferrin saturation. Participants were randomly assigned, via a computer-generated random number, to undergo either iron reduction by erythrocytapheresis (treatment group) or sham treatment by plasmapheresis (control group). Randomisation was stratified by baseline serum ferritin (<600 μg/L or ≥600 μg/L), sex, and study site. Erythrocytapheresis and plasmapheresis were done every 3 weeks, the number of procedures and volume of red cells or plasma removed determined on the basis of each patient's haemoglobin, haematocrit, and serum ferritin concentration, as well their height and weight. In the erythrocytapheresis group, the target was to reduce serum ferritin to less than 300 μg/L. The number of procedures for the control group was based on the initial serum ferritin and prediction of decrease in serum ferritin of approximately 120 μg/L per treatment. The primary outcome was patient-reported Modified Fatigue Impact Scale (MFIS) score, measured at baseline and before unblinding. Analyses were by intention to treat, including the safety analysis. The trial is registered with ClinicalTrials.gov, number NCT01631708, and has been completed. FINDINGS Between Aug 15, 2012, and June 9, 2016, 104 participants were randomly assigned to the treatment (n=54) and control (n=50) groups, of whom 94 completed the study (50 in the treatment group and 44 in the control group). Improvement in MFIS score was greater in the treatment group than in the control group (mean difference -6·3, 95% CI -11·1 to -1·4, p=0·013). There was a significant difference in the cognitive subcomponent (-3·6, -5·9 to -1·3, p=0·0030), but not in the physical (-1·90 -4·5 to 0·63, p=0·14) and psychosocial (-0·54, -1·2 to 0·11, p=0·10) subcomponents. No serious adverse events occurred in either group. One participant in the control group had a vasovagal event and 17 participants (14 in the treatment group and three in the control group) had transient symptoms assessed as related to hypovolaemia. Mild citrate reactions were more common in the treatment group (32 events [25%] in 129 procedures) compared with the control group (one event [1%] in 93 procedures). INTERPRETATION To our knowledge, this study is the first to objectively assess the consequences of iron removal in individuals with hereditary haemochromatosis and moderately elevated serum ferritin. Our results suggest that serum ferritin normalisation by iron depletion could be of benefit for all individuals with hereditary haemochromatosis and elevated serum ferritin levels. FUNDING National Health and Medical Research Council (Australia).
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Bariatric surgery in class I obesity : a Position Statement from the International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO).
Busetto, L, Dixon, J, De Luca, M, Shikora, S, Pories, W, Angrisani, L
Obesity surgery. 2014;(4):487-519
Abstract
Class I obesity conveys an increased risk of comorbidities, impairs physical and mental health-related quality of life, and it is associated to an increased psychosocial burden, particularly in women. The need for effective and safe therapies for class I obesity is great and not yet met by nonsurgical approaches. Eligibility to bariatric surgery has been largely based on body mass index (BMI) cut points and limited to patients with more severe obesity levels. However, obese patients belonging to the same BMI class may have very different levels of health, risk, and impact of obesity on quality of life. Individual patients in class I obesity may have a comorbidity burden similar to, or greater than, patients with more severe obesity. Therefore, the denial of bariatric surgery to a patient with class I obesity suffering from a significant obesity-related health burden and not achieving weight control with nonsurgical therapy simply on the basis of the BMI level does not appear to be clinically justified. A clinical decision should be based on a more comprehensive evaluation of the patient's current global health and on a more reliable prediction of future morbidity and mortality. After a careful review of available data about safety and efficacy of bariatric surgery in patients with class I obesity, this panel reached a consensus on ten clinical recommendations.
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Beyond obesity and lifestyle: a review of 21st century chronic disease determinants.
Egger, G, Dixon, J
BioMed research international. 2014;:731685
Abstract
The obesity epidemic and associated chronic diseases are often attributed to modern lifestyles. The term "lifestyle" however, ignores broader social, economic, and environmental determinants while inadvertently "blaming the victim." Seen more eclectically, lifestyle encompasses distal, medial, and proximal determinants. Hence any analysis of causality should include all these levels. The term "anthropogens," or "…man-made environments, their by-products and/or lifestyles encouraged by these, some of which may be detrimental to human health" provides a monocausal focus for chronic diseases similar to that which the germ theory afforded infectious diseases. Anthropogens have in common an ability to induce a form of chronic, low-level systemic inflammation ("metaflammation"). A review of anthropogens, based on inducers with a metaflammatory association, is conducted here, together with the evidence for each in connection with a number of chronic diseases. This suggests a broader view of lifestyle and a focus on determinants, rather than obesity and lifestyle per se as the specific causes of modern chronic disease. Under such an analysis, obesity is seen more as "a canary in a mineshaft" signaling problems in the broader environment, suggesting that population obesity management should be focused more upstream if chronic diseases are to be better managed.
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Non-nutrient causes of low-grade, systemic inflammation: support for a 'canary in the mineshaft' view of obesity in chronic disease.
Egger, G, Dixon, J
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2011;(5):339-45
Abstract
A form of low-grade, systemic inflammation ('metaflammation') is linked to many types of chronic disease. Initially, this was thought to be causally related to weight gain and obesity and a possible explanation of the link between obesity and disease. However, several lifestyle-related inducers of such inflammation, some of which are associated with obesity, but some of which are not, have now been identified. The most common of these have been nutritive related, suggesting that there could still be a relationship, either directly or indirectly, with obesity. Here we provide evidence for non-nutritive inflammatory inducers, providing further support for an earlier suggestion that while obesity, beyond a point, may have a direct link with disease, this may be neither necessary nor sufficient to explain the current epidemic of chronic disease. A more ubiquitous cause encompassing all inflammatory inducers is the modern, post-industrial environment and lifestyles emanating from this. Obesity may thus be more of 'a canary in the mineshaft', warning of bigger global problems, than just a single pathway to modern environmentally driven disease.
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European Society of Hypertension Working Group on Obesity Antihypertensive effects of weight loss: myth or reality?
Straznicky, N, Grassi, G, Esler, M, Lambert, G, Dixon, J, Lambert, E, Jordan, J, Schlaich, M, , , ,
Journal of hypertension. 2010;(4):637-43
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Inflammatory effects of nutritional stimuli: further support for the need for a big picture approach to tackling obesity and chronic disease.
Egger, G, Dixon, J
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2010;(2):137-49
Abstract
The discovery of a form of low-grade systemic inflammation (called 'metaflammation'), and the close evolutionary link between the immune and metabolic systems, poses questions about the supposed antigens (inducers) of such an immune reaction. Initially, this was thought to be mediated through obesity. However, we have identified a number of lifestyle or environmentally related inducers that may cause metaflammation, even in the absence of obesity. In this paper, the third of a series linking obesity with broad environmental and evolutionary factors, we identify nutritional stimuli with evidence of an involvement in metaflammation. From this we propose that components of certain foods and beverages with which humans have not evolved, are more often the inducers of an inflammatory effect in the body than those with which humans have become more familiar, and to which a neutral, or anti-inflammatory response may be expected to have developed. The implications of such a finding are considered in relation to broader aspects of the environment, economic growth, policy change and current global financial issues.
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Obesity and chronic disease: always offender or often just accomplice?
Egger, G, Dixon, J
The British journal of nutrition. 2009;(8):1238-42
Abstract
Over a decade ago, the finding of a form of low-grade systemic inflammation ('metaflammation') associated with obesity, insulin resistance and chronic disease proffered a causal explanation for the latter. However, recent work has shown that metaflammation is also associated with several modern lifestyle-related and environmental inducers, with or without obesity. Here, we present accumulating data to show a link between metaflammation and a number of non-microbial environmental and lifestyle stimulants, both with and without obesity. This implies that obesity may often be an accomplice to, as much as an offender in, major metabolic disease. The real (albeit distal) cause of such a disease appears to lie in aspects of the modern techno-industrial environment driving unhealthy lifestyle behaviours. If true, this suggests that while individual weight loss may be a component of chronic disease management, it may be neither 'necessary' nor 'sufficient' to reduce the problem at a population level. Greater multidisciplinary and policy input is needed to modify the economic and political drivers of the modern, obesogenic environment.
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Adiposopathy and bariatric surgery: is 'sick fat' a surgical disease?
Bays, HE, Laferrère, B, Dixon, J, Aronne, L, González-Campoy, JM, Apovian, C, Wolfe, BM, ,
International journal of clinical practice. 2009;(9):1285-300
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Abstract
OBJECTIVE To review how bariatric surgery in obese patients may effectively treat adiposopathy (pathogenic adipose tissue or 'sick fat'), and to provide clinicians a rationale as to why bariatric surgery is a potential treatment option for overweight patients with type 2 diabetes, hypertension, and dyslipidaemia. METHODS A group of clinicians, researchers, and surgeons, all with a background in treating obesity and the adverse metabolic consequences of excessive body fat, reviewed the medical literature regarding the improvement in metabolic disease with bariatric surgery. RESULTS Bariatric surgery improves metabolic disease through multiple, likely interrelated mechanisms including: (i) initial acute fasting and diminished caloric intake inherent with many gastrointestinal surgical procedures; (ii) favourable alterations in gastrointestinal endocrine and immune responses, especially with bariatric surgeries that reroute nutrient gastrointestinal delivery such as gastric bypass procedures; and (iii) a decrease in adipose tissue mass. Regarding adipose tissue mass, during positive caloric balance, impaired adipogenesis (resulting in limitations in adipocyte number or size) and visceral adiposity are anatomic manifestations of pathogenic adipose tissue (adiposopathy). This may cause adverse adipose tissue endocrine and immune responses that lead to metabolic disease. A decrease in adipocyte size and decrease in visceral adiposity, as often occurs with bariatric surgery, may effectively improve adiposopathy, and thus effectively treat metabolic disease. It is the relationship between bariatric surgery and its effects upon pathogenic adipose tissue that is the focus of this discussion. CONCLUSIONS In selective obese patients with metabolic disease who are refractory to medical management, adiposopathy is a surgical disease.