Faecal Microbiota Transplantation for the Treatment of Active Ulcerative Colitis

Introduction Ulcerative colitis (UC) is an inflammatory bowel disease that has high rates of persistent or relapsing symptoms despite available therapies. Many of these therapies also have the potential for unacceptable side effects including allergy, intolerance, serious infection and malignancy due to long-term immunosuppression. It is for these reasons that new therapies for UC are required; particularly therapies that target novel pathways and do not suppress the immune system. Faecal microbiota transplantation (FMT) has demonstrated efficacy in the treatment of recurrent and refractory Clostridium difficile infection (CDI) and has been proposed as a novel therapy for UC. Aims The aims of this thesis were to: 1. establish a stool bank of screened donor stool containing viable organisms 2. assess the efficacy and safety of FMT for the induction of remission of UC 3. explore the mechanisms by which FMT may alter the disease process of UC. Methods Methods of stool donor recruitment and screening as well as anaerobic stool processing were developed and optimised. The viability of culturable organisms was validated after 6 months of frozen storage. A double-blind randomised controlled trial of a short duration of FMT using anaerobically prepared stool for the induction of remission of mild to moderate UC was undertaken with clinical and endoscopic remission assessed at 8 weeks and 12 months. Exploratory immunological, microbiological and metabolomic analyses were undertaken. A systematic review and meta-analysis was undertaken to assess the broader evidence for FMT as therapy for the induction of remission of UC. Results A stool bank of anaerobically prepared donor stool was established; 14 (31%) of 44 respondents to donor recruitment questionnaires were eligible. Bacterial viability was similar to baseline at both 2 and 6 months in specimens stored with saline and 10% glycerol and at 2 months in stool stored only in saline, but was reduced by >1 log at 6 months for aerobes, coliforms and lactobacilli in saline alone. In patients undergoing FMT with stool frozen for 2–10 months in 10% glycerol, the cure rate for rCDI was 88% after a single FMT. In mild to moderate active UC, clinical and endoscopic remission was achieved in 12 of the 38 participants (32%) who received pooled donor FMT, compared with 3 of the 35 (9%) who received autologous FMT (odds ratio [OR] 5.0 [95% CI 1.2–20.1]; P = 0.03). A number of bacterial species were associated with the observed donor FMT treatment effect. Neither lamina propria mononuclear cell populations nor short-chain fatty acid levels were associated with the donor FMT treatment effect. Meta-analysis of randomised controlled trials of FMT for UC demonstrated that clinical remission was achieved in 39 of 140 (28%) patients in the donor FMT groups, compared with 13 of 137 (9%) patients in the placebo groups (OR 3.67 [95% CI 1.82– 7.39]; P < 0.01]. Conclusions Establishing a bank of anaerobically prepared frozen donor stool facilitates the delivery of FMT for clinical and clinical trial purposes. Anaerobic stool processing with normal saline and glycerol results in viability of bacteria in frozen storage for 6 months. Donor FMT is an effective therapy for the induction of remission of UC. Further research is required to assess the efficacy and safety of FMT as maintenance therapy for UC and to establish the mechanism of treatment effect.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 201

Larval culture of the calico scallop, Argopecten gibbus

Mature calico scallops, Argopecten gibbus, collected from the grounds off Cape Kennedy, Florida, were induced to spawn in the laboratory. Fertilized eggs were reared to postlarvae in sea water of 23° C ± 2.0° C at a salinity of 35 %o. The external morphology of eggs and developing larval stages are described

False holes as camouflage

Long noted by naturalists, leaf mimicry provides some of the most impressive examples of camouflage through masquerade. Many species of leaf-mimicking Lepidoptera also sport wing markings that closely resemble irregularly shaped holes caused by decay or insect damage. Despite proposals that such markings can either enhance resemblance to damaged leaves or act to disrupt surface appearance through false depth cues, to our knowledge, no attempt has been made to establish exactly how these markings function, or even whether they confer a survival benefit to prey. Here, in two field experiments using artificial butterfly-like targets, we show that false hole markings provide significant survival benefits against avian predation. Furthermore, in a computer-based visual search experiment, we demonstrate that detection of such targets by humans is impeded in a similar fashion. Equally contrasting light marks do not have the same effect; indeed, they lead to increased detection. We conclude that the mechanism is the disruption of the otherwise homogeneous wing surface (surface disruptive camouflage) and that, by resembling the holes sometimes found in real leaves, the disruptive benefits are not offset by conspicuousness costs.Funding provided by: Engineering and Physical Sciences Research CouncilCrossref Funder Registry ID: http://dx.doi.org/10.13039/501100000266Award Number: EP/M006905/

Item response theory and validity of the NEO-FFI in adolescents

The present study applied item response theory (IRT) to the NEO five factor inventory (NEO-FFI) completed by a community based sample of adolescents. The results revealed that many of these personality items may not be discriminating well, with some traits demonstrating greater reliability than others. Furthermore, the threshold values highlighted that the majority of the items had skewed responses, suggesting a limited utility of some response categories. Generally, removing poorly discriminating items does not harm external validity, suggesting IRT reduces measurement error and increases reliability without compromising validity

Hospitalized Children with 2009 Pandemic Influenza A (H1N1): Comparison to Seasonal Influenza and Risk Factors for Admission to the ICU

BACKGROUND: Limited data are available describing the clinical presentation and risk factors for admission to the intensive care unit for children with 2009 H1N1 infection. METHODS: We conducted a retrospective chart review of all hospitalized children with 2009 influenza A (H1N1) and 2008-09 seasonal influenza at The Children's Hospital, Denver, Colorado. RESULTS: Of the 307 children identified with 2009 H1N1 infections, the median age was 6 years, 61% were male, and 66% had underlying medical conditions. Eighty children (26%) were admitted to the ICU. Thirty-two (40%) of the ICU patients required intubation and 17 (53%) of the intubated patients developed acute respiratory distress syndrome (ARDS). Four patients required extracorporeal membrane oxygenation. Eight (3%) of the hospitalized children died. Admission to the ICU was significantly associated with older age and underlying neurological condition. Compared to the 90 children admitted during the 2008-09 season, children admitted with 2009 H1N1 influenza were significantly older, had a shorter length of hospitalization, more use of antivirals, and a higher incidence of ARDS. CONCLUSIONS: Compared to the 2008-09 season, hospitalized children with 2009 H1N1 influenza were much older and had more severe respiratory disease. Among children hospitalized with 2009 H1N1 influenza, risk factors for admission to the ICU included older age and having an underlying neurological condition. Children under the age of 2 hospitalized with 2009 H1N1 influenza were significantly less likely to require ICU care compared to older hospitalized children

3D printing is a transformative technology in congenital heart disease

Survival in congenital heart disease has steadily improved since 1938, when Dr. Robert Gross successfully ligated for the first time a patent ductus arteriosus in a 7-year-old child. To continue the gains made over the past 80 years, transformative changes with broad impact are needed in management of congenital heart disease. Three-dimensional printing is an emerging technology that is fundamentally affecting patient care, research, trainee education, and interactions among medical teams, patients, and caregivers. This paper first reviews key clinical cases where the technology has affected patient care. It then discusses 3-dimensional printing in trainee education. Thereafter, the role of this technology in communication with multidisciplinary teams, patients, and caregivers is described. Finally, the paper reviews translational technologies on the horizon that promise to take this nascent field even further

Deficient resident memory T-cell and Cd8 T-cell response to commensals in inflammatory bowel disease

Background Aims: The intestinal microbiota is closely associated with resident memory lymphocytes in mucosal tissue. We sought to understand how acquired cellular and humoral immunity to the microbiota differ in health versus inflammatory bowel disease (IBD). Methods Resident memory T-cells (Trm) in colonic biopsies and local antibody responses to intraepithelial microbes were analyzed. Systemic antigen-specific immune T- and B-cell memory to a panel of commensal microbes was assessed. Results Systemically, healthy blood showed CD4 and occasional CD8 memory T-cell responses to selected intestinal bacteria but few memory B-cell responses. In IBD, CD8 memory T-cell responses decreased although B-cell responses and circulating plasmablasts increased. Possibly secondary to loss of systemic CD8 T-cell responses in IBD, dramatically reduced numbers of mucosal CD8+ Trm and γδ T-cells were observed. IgA responses to intraepithelial bacteria were increased. Colonic Trm expressed CD39 and CD73 ectonucleotidases, characteristic of regulatory T-cells. Cytokines/factors required for Trm differentiation were identified, and in vitro-generated Trm expressed regulatory T-cell function via CD39. Cognate interaction between T-cells and dendritic cells induced T-bet expression in dendritic cells, a key mechanism in regulating cell-mediated mucosal responses. Conclusions A previously unrecognized imbalance exists between cellular and humoral immunity to the microbiota in IBD, with loss of mucosal T-cell-mediated barrier immunity and uncontrolled antibody responses. Regulatory function of Trm may explain their association with intestinal health. Promoting Trm and their interaction with dendritic cells rather than immunosuppression may reinforce tissue immunity, improve barrier function and prevent B-cell dysfunction in microbiota-associated disease and IBD etiology