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BackgroundThe gut-lung axis is generally recognized, but there are few large studies of the gut microbiome and incident respiratory disease in adults.Objectives3To investigate the associations between gut microbiome and respiratory disease and to construct predictive models from baseline gut microbiome profiles for incident asthma or chronic obstructive pulmonary disease (COPD).MethodsShallow metagenomic sequencing was performed for stool samples from a prospective, population-based cohort (FINRISK02; N=7,115 adults) with linked national administrative health register derived classifications for incident asthma and COPD up to 15 years after baseline. Generalised linear models and Cox regressions were utilised to assess associations of microbial taxa and diversity with disease occurrence. Predictive models were constructed using machine learning with extreme gradient boosting. Models considered taxa abundances individually and in combination with other risk factors, including sex, age, body mass index and smoking status.ResultsA total of 695 and 392 significant microbial associations at different taxonomic levels were found with incident asthma and COPD, respectively. Gradient boosting decision trees of baseline gut microbiome predicted incident asthma and COPD with mean area under the curves of 0.608 and 0.780, respectively. For both incident asthma and COPD, the baseline gut microbiome had C-indices of 0.623 for asthma and 0.817 for COPD, which were more predictive than other conventional risk factors. The integration of gut microbiome and conventional risk factors further improved prediction capacities. Subgroup analyses indicated gut microbiome was significantly associated with incident COPD in both current smokers and non-smokers, as well as in individuals who reported never smoking.ConclusionsThe gut microbiome is a significant risk factor for incident asthma and incident COPD and is largely independent of conventional risk factors.

Background Studies indicate that the nasal microbiome may correlate strongly with the presence or future risk of childhood asthma. Objectives In this study, we tested whether developmental trajectories of the nasopharyngeal microbiome in early life and the composition of the microbiome during illnesses were related to risk of childhood asthma. Methods Children participating in the Childhood Origins of Asthma study (n=285) provided nasopharyngeal mucus samples in the first two years of life, during routine healthy study visits (2, 4, 6, 9, 12, 18 and 24 months of age) and episodes of respiratory illnesses, which were analyzed for respiratory viruses and bacteria. We identified developmental trajectories of early-life microbiome composition, as well as predominant bacteria during respiratory illnesses, and correlated these with presence of asthma at 6, 8, 11, 13 and 18 years of age. Results Of the four microbiome trajectories identified, a Staphylococcus-dominant microbiome in the first 6 months of life was associated with increased risk of recurrent wheezing by age 3 years and asthma that persisted throughout childhood. In addition, this trajectory was associated with the early onset of allergic sensitization. During wheezing illnesses, detection of rhinoviruses and predominance of Moraxella were associated with asthma that persisted throughout later childhood. Conclusion In infancy, the developmental composition of the microbiome during healthy periods and the predominant microbes during acute wheezing illnesses are both associated with the subsequent risk of developing persistent childhood asthma. Clinical Implication Identifying factors that promote early colonization with S. aureus may lead to future interventional studies to prevent childhood asthma., Capsule summary: In a birth cohort study, early colonization of the upper airway with Staphylococcus aureus and detection of rhinoviruses and Moraxella catarrhalis during illnesses were associated with subsequent childhood asthma.

Chronic immune-mediated diseases of adulthood often originate in early childhood. To investigate genetic associations between neonatal immunity and disease, we map expression quantitative trait loci (eQTLs) in resting myeloid cells and CD4+ T cells from cord blood samples, as well as in response to lipopolysaccharide (LPS) or phytohemagglutinin (PHA) stimulation, respectively. Cis-eQTLs are largely specific to cell type or stimulation, and 31% and 52% of genes with cis-eQTLs have response eQTLs (reQTLs) in myeloid cells and T cells, respectively. We identified cis regulatory factors acting as mediators of trans effects. There is extensive colocalisation between condition-specific neonatal cis-eQTLs and variants associated with immune-mediated diseases, in particular CTSH had widespread colocalisation across diseases. Mendelian randomisation shows causal neonatal gene expression effects on disease risk for BTN3A2, HLA-C and others. Our study elucidates the genetics of gene expression in neonatal immune cells, and aetiological origins of autoimmune and allergic diseases., Some immune-mediated diseases may originate in early childhood. The authors mapped eQTLs and response eQTLs to various stimuli in neonatal myeloid cells and T cells, and revealed their potential role in immune-mediated diseases using colocalisation and Mendelian randomisation.

In asthma, a significant portion of the interaction between genetics and environment occurs through microbiota. The proposed mechanisms behind this interaction are complex and at times contradictory. This review covers recent developments in our understanding of this interaction: the "microbial hypothesis" and the "farm effect"; the role of endotoxin and genetic variation in pattern recognition systems; the interaction with allergen exposure; the additional involvement of host gut and airway microbiota; the role of viral respiratory infections in interaction with the 17q21 and CDHR3 genetic loci; and the importance of in utero and early-life timing of exposures. We propose a unified framework for understanding how all these phenomena interact to drive asthma pathogenesis. Finally, we point out some future challenges for continued research in this field, in particular the need for multiomic integration, as well as the potential utility of asthma endotyping.

Asthma is a common condition caused by immune and respiratory dysfunction, and it is often linked to allergy. A systems perspective may prove helpful in unravelling the complexity of asthma and allergy. Our aim is to give an overview of systems biology approaches used in allergy and asthma research. Specifically, we describe recent “omic”-level findings, and examine how these findings have been systematically integrated to generate further insight.Current research suggests that allergy is driven by genetic and epigenetic factors, in concert with environmental factors such as microbiome and diet, leading to early-life disturbance in immunological development and disruption of balance within key immuno-inflammatory pathways. Variation in inherited susceptibility and exposures causes heterogeneity in manifestations of asthma and other allergic diseases. Machine learning approaches are being used to explore this heterogeneity, and to probe the pathophysiological patterns or “endotypes” that correlate with subphenotypes of asthma and allergy. Mathematical models are being built based on genomic, transcriptomic and proteomic data to predict or discriminate disease phenotypes, and to describe the biomolecular networks behind asthma.The use of systems biology in allergy and asthma research is rapidly growing, and has so far yielded fruitful results. However, the scale and multidisciplinary nature of this research means that it is accompanied by new challenges. Ultimately, it is hoped that systems medicine, with its integration of omics data into clinical practice, can pave the way to more precise, personalised and effective management of asthma.

Cytokines are essential regulatory components of the immune system, and their aberrant levels have been linked to many disease states. Despite increasing evidence that cytokines operate in concert, many of the physiological interactions between cytokines, and the shared genetic architecture that underlies them, remain unknown. Here, we aimed to identify and characterize genetic variants with pleiotropic effects on cytokines. Using three population-based cohorts (n = 9,263), we performed multivariate genome-wide association studies (GWAS) for a correlation network of 11 circulating cytokines, then combined our results in meta-analysis. We identified a total of eight loci significantly associated with the cytokine network, of which two (PDGFRB and ABO) had not been detected previously. In addition, conditional analyses revealed a further four secondary signals at three known cytokine loci. Integration, through the use of Bayesian colocalization analysis, of publicly available GWAS summary statistics with the cytokine network associations revealed shared causal variants between the eight cytokine loci and other traits; in particular, cytokine network variants at the ABO, SERPINE2, and ZFPM2 loci showed pleiotropic effects on the production of immune-related proteins, on metabolic traits such as lipoprotein and lipid levels, on blood-cell-related traits such as platelet count, and on disease traits such as coronary artery disease and type 2 diabetes.

Chronic immune-mediated diseases of adulthood often originate in early childhood. To investigate genetic associations between neonatal immunity and disease, we collected cord blood samples from a birth cohort and mapped expression quantitative trait loci (eQTLs) in resting monocytes and CD4+ T cells as well as in response to lipopolysaccharide (LPS) or phytohemagglutinin (PHA) stimulation, respectively. Cis-eQTLs were largely specific to cell type or stimulation, and response eQTLs were identified for 31% of genes with cis-eQTLs (eGenes) in monocytes and 52% of eGenes in CD4+ T cells. We identified trans-eQTLs and mapped cis regulatory factors which act as mediators of trans effects. There was extensive colocalisation of causal variants for cell type- and stimulation-specific neonatal cis-eQTLs and those of autoimmune and allergic diseases, in particular CTSH (Cathepsin H) which showed widespread colocalisation across diseases. Mendelian randomisation showed causal neonatal gene transcription effects on disease risk for BTN3A2, HLA-C and many other genes. Our study elucidates the genetics of gene expression in neonatal conditions and cell types as well as the aetiological origins of autoimmune and allergic diseases.

Background Fracture and dislocation of the proximal humerus is common. It is associated with a number of vascular, neurologic, and orthopedic complications; these include brachial plexopathy and avascular necrosis (AVN) of the humeral head. These complications are rare but can potentially cause severe disability to patients; however, they remain poorly described in the literature. To describe vascular, orthopedic, and neurologic outcomes after axillary artery repair, in patients with proximal humeral fractures or dislocations. Methods We conducted a retrospective review of patients admitted to 2 tertiary trauma centers in Victoria, Australia, with fracture or dislocation of the proximal humerus and associated axillary artery injury. Patients were selected according to guidelines for trauma call or alert and the presence of high-risk mechanism of injury. Data on vascular, orthopedic, and neurologic complications were collected. Results Twenty-one patients were identified. Injury to the first part of the axillary artery was noted in 11 patients (52%). Brachial plexus exploration was performed in 17 patients (81%). Four patients (19%) underwent nerve repair. Long-term neurologic recovery was universally poor. Major orthopedic complications included AVN of the humeral head, delayed union, and the need for prosthesis or arthrodesis. Eleven patients (52%) received upper limb fasciotomy. Five patients (24%) underwent delayed secondary upper limb amputation. Conclusions There was an unusually high rate of injuries to the first part of the axillary artery. Close clinical observation is recommended for such patients. AVN of the humeral head and brachial plexopathy remain significant and debilitating complications.

Background: Free fat grafting is popular, but it is still unclear how it works. Although focusing on graft survival seems an obvious direction for improving clinical results, the authors’ research suggests that long-term volume retention is in part attributable to new fat regeneration. Measures to facilitate adipogenesis may therefore be equally important. Methods: To investigate the relative roles of survival and regeneration of fat grafts, the authors measured the fate of human lipoaspirate implanted into the scalps of immunodeficient mice, with and without stromal vascular fraction and a porcine extracellular matrix (Adipogel). Specifically, the authors were interested in volume retention, and the composition of implanted or regenerated tissue at 6 and 12 weeks. Results: Free fat grafts exhibited poor volume retention and survival. Almost all of the injected human adipocytes died, but new mouse fat formed peripheral to the encapsulated fat graft. Adipogel and stromal vascular fraction improved proliferation of murine fat and human vasculature. Human CD34+ stromal cells were present but only in the periphery, and there was no evidence that these cells differentiated into adipocytes. Conclusions: In the authors’ model, most of the implanted tissue died, but unresorbed dead fat accounted substantially for the long-term, reduced volume. A layer of host-derived, regenerated adipose tissue was present at the periphery. This regeneration may be driven by the presence of dying fat, and it was enhanced by addition of the authors’ adipogenic adjuncts. Future research should perhaps focus not only on improving graft survival but also on enhancing the adipogenic environment conducive to fat regeneration.

Introduction Bisphosphonate therapy (BT) is used commonly in the management of osteoporosis. A systematic review was conducted investigating delayed union of lower limb, long bone fractures in patients on BT. We specifically assessed whether BT increases the risk of delayed union or non-union in lower limb, long bone fractures. Methods A literature search was conducted in the PubMed and Embase™ on 4 November 2014. Articles that investigated lower limb fractures, history of BT and fracture union were included in the review. Results A total of 9,809 papers were retrieved and 14 were deemed suitable for this review. The mean time to union in patients on BT was 8.5 months. A longer time to union was reported in a study investigating BT users versus controls (6.5 vs 4.8 months respectively). The mean rate of delayed or non-union for BT associated atypical fractures was 20% per fracture. Specifically in one study, delayed union was more common in the cohort with more than three years of BT (67%) than in the group with less than three years of BT (26%). Surgical fixation was associated with improved outcomes compared with non-operative management. Conclusions BT has been described to be associated with multiple adverse outcomes related to atypical fractures. Current evidence recommends operative management for this patient group. Further investigation is required to evaluate the exact effects of BT on lower limb fractures, in particular typical femoral fractures.

Background The aim of this study was to audit the blood transfusion practice throughout the Epworth Healthcare Hospitals for patients undergoing primary total hip replacement (THR). We determined if blood-saving techniques were having an impact on the risk of allogenic blood transfusion and which patients were at risk of receiving allogenic blood transfusion. Methods This study uses a retrospective audit of 787 patients who had undergone primary THR surgery at three Melbourne hospitals: Epworth Richmond, Epworth Eastern and Epworth Freemasons in 2010. Patient demographics, transfusion requirements and blood-conserving techniques were recorded. Results One hundred and eighty (23%) patients received allogenic blood transfusion and 18 (2.3%) patients received autologous blood transfusion. On multivariate analysis, preoperative anaemia (odds ratio (OR) 4.7, P < 0.0001), female gender (OR 3.1, P < 0.0001) and patient age (OR 1.07 per year of age increase, P < 0.0001) were shown to be significantly associated with higher risk of allogenic blood transfusion. Use of spinal anaesthetic was found to be associated with lower risk of transfusion (OR 0.6, P = 0.0180) compared with general anaesthetic alone. Cell saver, acute normovolaemic haemodilution and re-infusion drain tube usage did not have a significant impact on reducing the risk of allogenic blood transfusion. Conclusion Identification of patients at risk of blood transfusion, correction of preoperative anaemia and a restrictive transfusion policy are important factors to consider in effective perioperative blood management.

Events in early life contribute to subsequent risk of asthma; however, the causes and trajectories of childhood wheeze are heterogeneous and do not always result in asthma. Similarly, not all atopic individuals develop wheeze, and vice versa. The reasons for these differences are unclear. Using unsupervised model-based cluster analysis, we identified latent clusters within a prospective birth cohort with deep immunological and respiratory phenotyping. We characterised each cluster in terms of immunological profile and disease risk, and replicated our results in external cohorts from the UK and USA. We discovered three distinct trajectories, one of which is a high-risk “atopic” cluster with increased propensity for allergic diseases throughout childhood. Atopy contributes varyingly to later wheeze depending on cluster membership. Our findings demonstrate the utility of unsupervised analysis in elucidating heterogeneity in asthma pathogenesis and provide a foundation for improving management and prevention of childhood asthma.

Repeated cycles of infection-associated lower airway inflammation drives the pathogenesis of persistent wheezing disease in children. Tracking these events across a birth cohort during their first five years, we demonstrate that >80% of infectious events indeed involve viral pathogens, but are accompanied by a shift in the nasopharyngeal microbiome (NPM) towards dominance by a small range of pathogenic bacterial genera. Unexpectedly, this change in NPM frequently precedes the appearance of viral pathogens and acute symptoms. In non-sensitized children these events are associated only with “transient wheeze” that resolves after age three. In contrast, in children developing early allergic sensitization, they are associated with ensuing development of persistent wheeze, which is the hallmark of the asthma phenotype. This suggests underlying pathogenic interactions between allergic sensitization and antibacterial mechanisms.

Repeated cycles of infection-associated lower airway inflammation drive the pathogenesis of persistent wheezing disease in children. In this study, the occurrence of acute respiratory tract illnesses (ARIs) and the nasopharyngeal microbiome (NPM) were characterized in 244 infants through their first five years of life. Through this analysis, we demonstrate that >80% of infectious events involve viral pathogens, but are accompanied by a shift in the NPM toward dominance by a small range of pathogenic bacterial genera. Unexpectedly, this change frequently precedes the detection of viral pathogens and acute symptoms. Colonization of illness-associated bacteria coupled with early allergic sensitization is associated with persistent wheeze in school-aged children, which is the hallmark of the asthma phenotype. In contrast, these bacterial genera are associated with "transient wheeze" that resolves after age 3 years in non-sensitized children. Thus, to complement early allergic sensitization, monitoring NPM composition may enable early detection and intervention in high-risk children.

OBJECTIVES: The incidence of animal bite injuries in Australia is high. There is currently no established method for reliably predicting whether a patient with a bite injury will require admission to hospital or surgery. DESIGN: A retrospective audit of mammalian bite injuries at seven major hospitals in Melbourne, Victoria, over a 2-year period. The associations between each predictor and outcome of interest were analysed with univariate and multiple regression analyses. SETTING: Seven major hospitals in Melbourne, Victoria: the Alfred Hospital, Austin Hospital, Frankston Hospital, Monash Medical Centre, Royal Melbourne Hospital, St Vincent's Hospital and Western Hospital. PARTICIPANTS: Patients presenting to emergency departments with mammalian bite injuries. MAIN OUTCOME MEASURES: Hospital admission, intravenous antibiotic therapy, surgery, reoperation, readmission. RESULTS: We identified 717 mammalian bite injuries. The mean age of the patients was 36.5 years (median, 34 years; range, 0-88 years), with an equal number of males and females. The overall rate of hospital admission was 50.8%, and the mean length of stay was 2.7 days. Intravenous antibiotics were administered in 46% of cases; surgery was undertaken in 43.1% of cases. The re-operation rate was 4.5%, the re-admission rate was 3%. CONCLUSIONS: Our study provides a detailed epidemiological analysis of animal bite injuries at seven major hospitals in Victoria. Risk factors for hospitalisation and surgery may assist in identifying patients who require admission and surgical intervention. Language: en

Summary Objective Originally derived from a Wistar rat strain, a proportion of which displayed spontaneous absence-type seizures, Genetic Absence Epilepsy Rats from Strasbourg (GAERS) represent the most widely utilized animal model of genetic generalized epilepsy. Here we compare the seizure, behavioral, and brain morphometric characteristics of four main GAERS colonies that are being actively studied internationally: two from Melbourne (MELB and STRAS-MELB), one from Grenoble (GREN), and one from Istanbul (ISTAN). Methods Electroencephalography (EEG) recordings, behavioral examinations, and structural magnetic resonance imaging (MRI) studies were conducted on GAERS and Non-Epileptic Control (NEC) rats to assess and compare the following: (1) characteristics of spike-and-wave discharges, (2) anxiety-like and depressive-like behaviors, and (3) MRI brain morphology of regions of interest. Results Seizure characteristics varied between the colonies, with MELB GAERS exhibiting the least severe epilepsy phenotype with respect to seizure frequency, and GREN GAERS exhibiting four times more seizures than MELB. MELB and STRAS-MELB colonies both displayed consistent anxiety and depressive-like behaviors relative to NEC. MELB and GREN GAERS showed similar changes in brain morphology, including increased whole brain volume and increased somatosensory cortical width. A previously identified mutation in the Cacna1h gene controlling the CaV3.2 T-type calcium channel (R1584P) was present in all four GAERS colonies, but absent in all NEC rats. Significance This study demonstrates differences in epilepsy severity between GAERS colonies that were derived from the same original colony in Strasbourg. This multi-institute study highlights the potential impact of environmental conditions and/or genetic drift on the severity of epileptic and behavioral phenotypes in rodent models of epilepsy.

Background: The best strategy for stent exchange in malignant biliary obstruction is not known. Some experts advocate routine prophylactic stent exchange every 3-4 months, a strategy which might lead to many unnecessary procedures. Aim: A prospective randomized study comparing 2 commonly practiced strategies: scheduled vs. as required stent exchanges. Methods: Pts. requiring biliary stenting for malignant obstruction were randomized to either (i) scheduled exchanges every 4 months or earlier if stents occluded (SCH) or (ii) exchanges only when stents occluded (PRN). End points were either metal stenting, surgery, death or resolution of stricture not needing stenting. LFTs were monitored monthly in both gps. Occlusion was defined as a doubling of nadir alkaline phosphatase or bilirubin. Results: Of the 69 pts. recruited 5 were excluded (4- benign; 1-immediate surgery). 30 pts. (9 M) were randomized to SCH and 34 pts. (15 M) to the PRN arm. The 2 gps. were comparable in all respects (SCH : PRN) mean ages (69:72); diagnoses (%) pancreatic Ca (73 : 76), cholangioCa (10 : 14), metastases (13 : 9) and ampullary Ca (1 : 0); mean comorbidity indices (0.83 : 0.97); & stent diameters (≥10 Fr). Number of ERCPs per pt. in the 2 gps. was not different, 2.1(SCH) vs 2(PRN). Number of stents per patient [(SCH : PRN): 1 stent (15:15); 2 stents (4:10); 3 stents (5:5); 4 stents (3:2); 5 stents (3:2)] and end points [death (22:26); metal stenting (6:7); surgery (1:0); misc (1:1)] were similar. Indications for metal stenting (SCH:PRN) duodenal stenosis (3:7) and rapid reocclusion (3:1) were similar. 43% pts. (SCH) and 47% pts. (PRN) died with patent stents. The mean stent survival was 90 d (SCH) vs 97 d (PRN), (p=NS). There was no difference in the survival time of each serial stent between the two gps. There was 1 episode of stent related cholangitis leading to death in the PRN arm on day 108 (T=3.82; p>0.05). There was no difference in the number of episodes of cholangitis; 10 in SCH vs 15 in PRN (T=1.29763; p>0.25). Time to death or other endpoints was not different in the two gps. (p=0.99). Conclusion: (1) There is no difference in measured outcomes when plastic stent exchanges are performed electively every 4 months or on an as required basis for biochemical occlusion in malignant biliary obstruction. (2) Using biochemical occlusion rather than clinical occlusion may result in a lower stent related mortality than previously reported. (3) Other factors (e.g. physical proximity, personal preference) should be used when selecting a strategy.