bluuebunny/crossref_metadata_2025 huggingface dataset:
S2.3d Mixed biofilm of Aspergillus fumigatus and Stenotrophomonas maltophilia: Microscopic visualization of galactosaminogalactan and galactomannan polysaccharides in the extracellular matrix
Authors: Valsecchi Isabel , Debourgogne Anne , Fontaine Thierry , Botterel Françoise
Published: September 2022

S2.3 Novel diagnostic tools for invasive mold infection, September 21, 2022, 3:00 PM - 4:30 PM

 

Introduction

Aspergillus fumigatus (Af) and Stenotrophomonas maltophilia (Sm) are commonly co-isolated from the airways of cystic fibrosis patients, especially in mixed biofilms. A mixed Af-Sm biofilm model, developed by our lab, demonstrated that Sm exhibits an antibiosis effect on Af by (1) inhibiting fungal growth, (2) rendering the fungal mycelia highly branched, and (3) increasing the fungal cell wall thickness.1 The presence of three Af cell wall polysaccharides, galactomannan (GM), galactosaminogalactan (GAG), and α-1,3-glucan, have been described in the extracellular matrix (ECM) of Af biofilms.2 GM and GAG are known to be released out from the cell wall of Af.3 GAG contains N-acetylgalactosamines (GalNAc) which undergo partial deacetylation extracellularly, to be converted to GalN, and thus transform this polysaccharide into a polycation with strong surface binding properties.4

Aim of the study

Analyze the structure of fungal cell wall polysaccharides in the formation of Af biofilm alone or mixed with Sm.

Methods

The Af-Sm co-culture was prepared on an 8-chambers Lab-Tek slide as described previously1. Anti-GAG and anti-GM monoclonal antibodies produced at the Aspergillus Unit at Pasteur Institute of Paris, were used to focus on the 3D structure of GAG and GM in the ECM of the biofilm. These polysaccharides were analyzed by fluorescence confocal microscopy at 24 h.

Results and Conclusion

GM was found, as expected, in the hyphal Af cell wall but was very little in the ECM. GAG was also found in the cell wall but mainly formed a beautiful fibrillary network between the hyphae, showing the importance of this polysaccharide in cell-cell interaction and in the structuration of Af biofilm. GAG could be the surface receptor for Sm, which would promote strong adhesion between Sm and Af in the biofilm.

Sources

1. Melloul E et al. Front Microbiol. 2018;

2. Beauvais A et al. Microbiol Spectr. 2015;

3. Fontaine T et al. J Fungi. 2020;

4. Briard B et al. Mycologia 2016.
S3.1a Update in mycetoma control
Authors: Fahal Ahmed Hassan
Published: September 2022

S3.1 Neglected implantation mycoses, September 21, 2022, 4:45 PM - 6:15 PM

Mycetoma is a badly neglected tropical disease, reported globally but endemic in many tropical and subtropical, and Sudan has the highest disease burden. Mycetoma epidemiological features remain uncharacterized. Hence, there is no preventive or control program for mycetoma worldwide. To reduce the disease burden and its socio-economic impacts on patients, families, communities, and the health system in the endemic regions, the Mycetoma Research Center, University of Khartoum, Sudan, WHO Collaborating Center on Mycetoma has adopted a unique holistic approach to management and mycetoma patients, and it gained a great experience on that.

 

In this presentation, we will share the MRC's experience in dealing with the patients at the endemic villages level, supporting the affected communities and collaborating with the local health authorities to improve the life quality of the affected patients.
S3.3c Alveolar macrophage-mediated host resistance against Aspergillus fumigatus
Authors: Obar Joshua
Published: September 2022

S3.3 Innate immune responses to pathogenic fungi, September 21, 2022, 4:45 PM - 6:15 PM

 

 

Alveolar macrophages (AlvMφ) reside on the luminal surface of the airways serving as the primary phagocyte within the airways of the lungs where they act as immune sentinel cells sensing and responding to microbial and environmental exposures. In this role, AlvMφ must be able to respond in a manner that is appropriate to the threat posed which has been hypothesized to occur through sensing microbial vitality and/or patterns of pathogenesis. It is well-established that AlvMφ interact with phagocytose and respond to A. fumigatus, but their role in host resistance against A. fumigatus is currently controversial. Here I will discuss the role of AlvMφ play in orchestrating a robust and effective antifungal innate immune response to mediate A. fumigatus clearance. AlvMφ orchestrate the protective innate immune response against A. fumigatus by sensing live fungal conidia using the cytosolic RNA-sensing MDA5 receptor to initiate the host protective type I and type III interferon response in both mice and humans. The activation of MDA5/MAVS signaling appears to be mediated by both fungal dsRNA-dependent and fungal dsRNA-independent mechanisms. Thus, AlvMφ serve as a central hub for regulating and tuning the antifungal immune response within the respiratory tract.
S3.4b Lactoferrin, a natural source of peptides that potentiate the antifungal activity of amphotericin B
Authors: Fernandes Kenya , Desplazes Evelyne , Kulkarni Sameer , Payne Richard , Carter Dee
Published: September 2022

S3.4 Free oral paper session, September 21, 2022, 4:45 PM - 6:15 PM

 

Objectives

It is notoriously difficult to prevent and treat fungal infections, however, the natural world has come up with remedies that are non-toxic, effective, and evade resistance. Here we investigate lactoferrin, an iron-binding glycoprotein found in milk, tears, and sweat, for its capacity to inhibit fungi and to synergize with commonly used antifungal drugs, with the aim of determining its mode of action.

Methods

Lactoferrin (LF) was obtained from a commercial supplier and two dairy companies. LF was tested on suite of pathogenic yeast and mold species for inhibition using CLSI microdilution methods. Synergy was determined with antifungal drugs amphotericin B (AMB), nystatin (NYS), fluconazole (FLC), itraconazole (ITC), voriconazole (VRC), and 5-fluorocytosine (5FC). The effect of LF on fungal cells was analyzed using scanning electron microscopy (SEM). The active peptide/s within LF were then predicted from pepsin and in silico digestion, synthesized, and tested for synergy with amphotericin B (AMB). Tethered synthetic membranes were produced and were loaded with ergosterol or cholesterol to test the nature and specificity of membrane binding by LF and the synthetic peptide.

Results

LF demonstrated antifungal activity against yeast species Cryptococcus, Candida, and Saccharomyces and was much less effective against molds. Good synergy was achieved with AMB but not azole or echinocandin drugs. While the iron-chelating capacity of LF was important for the antifungal activity it was not involved in synergy. SEM revealed cell damage suggesting an interaction between AMB, LF and the fungal membrane or cell wall. A 30-residue peptide from the C lobe of LF was synthesized and tested for activity and synergy. This peptide, dubbed lactofungin (LFG) was inactive alone but was potently synergistic with AMB, indicating a direct role in augmenting AMB activity. Synthetic membranes loaded with ergosterol but not cholesterol were disrupted by AMB + LFG, demonstrating that activity was fungal-specific and was mediated through ergosterol binding.

Conclusion

LF is a complex molecule that causes fungal inhibition via iron binding and when cleaved by pepsin can produce active peptides. As AMB is a highly toxic treatment, the use of LFG as a synergent could help increase activity while lowering the effective dose, thereby reducing undesirable side effects. The action of AMB + LFG appears dependent on ergosterol, suggesting inhibition will be highly fungal-specific.
S3.4c A pipeline toward the identification of novel antifungal compounds derived from the microbial dark matter
Authors: Vanreppelen Giel , Wuyts Jurgen , Holderbusch Alannah , Peys Alexander , Hu Haibo , De Ruysscher Dries , Masschelein Joleen , Luyten Walter , Vandecruys Paul , Van Dijck Patrick
Published: September 2022

S3.4 Free oral paper session, September 21, 2022, 4:45 PM - 6:15 PM

 

Background

The current armamentarium of antifungal drugs and the restricted variety in antifungal drug classes combined with the ever-rising threat of resistant fungal pathogens highlighted the urgent need for novel antifungal compounds. Natural antifungal secondary metabolites have always been the prevalent source for drug development, exemplified by the echinocandin and polyene drug classes. Yet, the golden age discovery platforms were abandoned due to compound rediscovery and its paired economic cost.

Study

In an effort to revive the original success stories, we combined the traditional approach of sampling and screening for active secondary metabolites with present-day advances in sequencing, genome mining, impedance spectroscopy, HPLC, LCMS, and NMR.

Soil bacteria and fungi were isolated through in situ cultivation via the iChip method. After application of the OSMAC approach, 389 broths were identified with activity against Candida albicans. To prioritize active extracts, several criteria were set up; low to absent mammalian host cell toxicity, activity against a broad spectrum of fungal pathogens including wild-type reference strains, and established antifungal drug-resistant variants and species identification of the producing strain. Continuing, Lead hits were purified utilizing bioactivity-based semi-preparative HPLC. The resulting pure fractions were analyzed by tandem LCMS-MS, and proposed structures were later confirmed with NMR. In vitro and in vivo validation of the purified compounds will be performed.

Additionally, aside from discovering a novel antifungal compound, another project goal is to gauge if impedance spectroscopy can provide an early suggestion regarding the mode of action of the present antifungal agent. For this, a POC study was performed which showed that different antifungal drug classes provide distinct signature response profiles by which they can be classified. As such, when active secretion broths show unique impedance profiles, in comparison with the signature profiles of established antifungal drugs, it suggests that they work through a different mode of action.

Results

Several species were identified as producing antifungal secondary metabolites that are currently absent in the literature. Either the compound itself was unknown or literature never described the species as a producer of a known, or variant of a known antimycotic compound. Moreover, several species are novel based on Illumina sequencing. Genera producing our current lead hits include bacteria: Pseudomonas, Tsukamurella, Paraburkholderia, and fungi: Athelia, Penicillium. Within the collection, the Pseudomonas species appear to produce variants of the antimycotic iron-chelating pyoverdine class.
S4.1a Fusariosis: MICs, mono versus combination therapy and fosmanogepix
Authors: Hoenigl Martin
Published: September 2022

S4.1 Treatment of rare mold infections in 2021: the role of new and old antifungals, September 22, 2022, 10:30 AM - 12:00 PM

Fusarium is one of the most clinically prevalent rare molds causing superficial infections such as keratitis in immunocompetent hosts and severe disseminated infections frequently presenting as fungemia in the immunocompromised. These fungi are ubiquitous in nature and are found in soil and air. Only a few of the ˃ 70 Fusarium spp. are opportunistic pathogens in humans. F. solani and F. oxysporum species complexes are specifically important, causing ˃50% and about 20% of severe fusariosis cases, respectively. Although galactomannan and also beta D glucan may result positive in fusariosis, fungal culture from either blood, BAL, or skin biopsy remains the most frequently utilized test for diagnosing fusariosis. Susceptibility testing of isolates recovered in culture should be used for epidemiologic purposes in defining the range of minimal inhibitory concentrations (MIC) distribution of Fusarium spp., however, studies that prove that susceptibility testing results should be utilized to inform antifungal drug choice are lacking. Although there are no interpretive breakpoints for antifungal agents against Fusarium spp., compounds with MICs that are off-scale, such as >16 μg/ml, at the highest range of concentrations are unlikely to be active in vivo or in patients. Initial combination therapy with a lipid formulation of amphotericin B plus voriconazole, deescalated to monotherapy once MICs come back, is, therefore, a frequently chosen management pathway.

 

A number of drugs in the antifungal pipeline will present additional treatment options for Fusarium, including Fosmanogepix and Olorofim.
S4.5b A randomized, double blind phase II proof-of-concept superiority trial of fosravuconazole 200 mg or 300 mg weekly dose versus itraconazole 400 mg daily, all three arms in combination with surgery, in patients with eumycetoma in Sudan—pharmacokinetic results
Authors: Brüggemann Roger , Nyaoke Borna , Ahmed Eiman Siddig , Siddig Emanwell Edwar , Egondi Thaddaeus , Oyieko Peelen , Bakhiet Sahar Mubarak , Zijlstra Eduard E , Fahal Ahmed H
Published: September 2022

S4.5 Mycetoma Clinical Trial on fosravuconazole treatment in eumycetoma– Top Line Results, September 22, 2022, 10:30 AM - 12:00 PM

 

Objective

To evaluate the pharmacokinetics (PK) of fosravuconazole (measured as ravuconazole) and itraconazole in patients with mild to moderate eumycetoma caused by Madurella mycetomatis using a non-compartmental PK analysis.

Methods

Participants received either 200 mg or 300 mg ravuconazole once weekly or 400 mg itraconazole daily for a total duration of 12 months. Plasma concentrations of ravuconazole and itraconazole were measured on day 1 of week 1, and on weeks 2, 3, 4, and months 2, 3, 6, and 12 (at end of treatment) for analysis of population PK. The exact time of dosing on the days of sample collection, and the exact time of sample collection within the collection time window, were recorded. Plasma concentrations were quantified using Ultraperformance Liquid Chromatography with fluorescence detection (UPLC-UV). Ravuconazole and itraconazole plasma concentration-time data was performed using a standard two stage approach with non-compartmental analysis. Derived exposure parameters of ravuconazole and itraconazole, including, but not limited to, Cmax and AUC at steady state (AUCs), were calculated. The effect of covariates, such as baseline characteristics/demographics, on PK were explored. AUCs were determined when at least three subsequent samples within one dosing interval were available.

Results

A total of 766 samples of ravuconazole in 68 participants and 226 samples of itraconazole in 36 participants were analyzed. The average concentration of ravuconazole (range) was 3.1 mg/l (0.01-12.33 mg/l), and for itraconazole was 1.59 mg/l (0.01-5.53 mg/l).

Detailed Pharmacokinetic results will be communicated and discussed in the oral presentation.
S6.3c Adaptive dynamics in experimental populations of Aspergillus nidulans
Authors: Nandimath Krithi , Auxier Ben , van den Heuvel Joost , Bastiaans Eric , Klatter Mirre , Slakhorst Marijke , Schoustra Sijmen , Debets Alfons J. M. , Nanjundiah Vidyanand , Zwaan Bas J. , Aanen Duur K. , de Visser JAGM
Published: September 2022

S6.3 Fungal adaptation and evolution, September 22, 2022, 4:45 PM - 6:15 PM

 

 

A total of 12 replicate populations initiated with a laboratory strain of the ascomycete fungus Aspergillus nidulans evolved on synthetic minimal glucose agar medium for 1 year, using weekly transfers of 1% of the produced asexual spores to fresh medium. This Aspergillus short-term evolution experiment (ASEX) was designed to understand how filamentous fungi adapt to growth on limited carbon in a spatially structured environment. We observed no systematic improvement in the fitness components tested and neither in the competitive fitness relative to the ancestor. Instead, we observed the repeated evolution of at least two morphotypes, with a fluffy-like (FL) or an ancestor-like (AL) colony morphology, leading to non-transitive fitness interactions among isolates in two selected populations. The genomic analyses of clones from all 12 populations at an early (week 10) and the final time point (week 52), show a clear role of natural selection during ASEX. We also observed a shared genetic basis and different timing of adaptation of AL and FL types. In addition, in most populations, both morphotypes do not form monophyletic groups, but they frequently disappear and re-evolve from ancestral forms of both types. Reduction in asexual spore yield, the most evident parallel phenotypic change found in all our evolved populations, is not due to the direct selection of genes involved in asexual reproduction. Instead, we argue that reduced spore yield is a pleiotropic effect of adaptive changes in metabolism.
S7.4a Vaccine-inducing lung resident CD4 + memory T cells are protective against Cryptococcus gattii infections
Authors: Ueno Keigo , Shimizu Kiminori , Chang Yun , Kwon-Chung June , Miyazaki Yoshitsugu
Published: September 2022

S7.4 Pathogenesis and host defense, September 23, 2022, 10:30 AM - 12:00 PM

Cryptococccus gattii is a highly virulent fungal pathogen that can cause cryptococcosis in previously healthy individuals. It is not fully understood how innate and acquired immune responses cooperatively suppress C. gattii infection. Hitherto, we have reported the following findings, (1) Specific environment for exposure of dectin-1 and dectin-2 ligands in cryptococcal cells (PLOS ONE 2019, PMID 31398236), (2) CD11b-mediated immune recognition for C. gattii and capsule dependent immune evasion from CD11b recognition (Eur J Immunol 2021, PMID 33728652), (3) Dendritic cells (DCs)-based vaccine induced lung resident memory Th17 cells and ameliorates C. gattii infection (Mucosal Immunol 2018, PMID 30279512), and (4) Neutrophil and opsonization can mediate fungicidal activity for cryptococcal cells (Med Mycol 2019, PMID 30668754). Based on these findings, we have inferred that induction of lung resident memory T cells (lung TRM) and TRM-driven myeloid cells including granulocytes is necessary for controlling this infection. Currently, we are developing new intranasal (IN) vaccines using highly immunogenic whole cell antigens and characterizing protective lung TRM induced by the vaccines. Just as with component vaccines, whole cell vaccines are also featured for cryptococcal infection because these are highly cross-reactive and protective against each serotype (Biol Pharm Bull 2020, PMID 32009111).

 

We developed two IN vaccines using whole cell antigen and adjuvant. Both vaccines induced IL-5-producing lung TRM and significantly reduced fungal burden in lungs and improved survival rates of mice following C. gattii infection, while not protective against C. neoformans infection. Although immune suppressive agent FTY720 can eliminate most circulating T cells and sustain tissue-resident subset, IN vaccines induced Th2-related immune response including eosinophils and IFN-γ independent granuloma, and reduced the fungal burden in lungs after the infection in the presence of FTY720. Vaccine-mediated protection was completely lost in the Rag-1 knockout mice deficient in T- and B-cells, while the fungal burden was reduced in the Rag-1 knockout mice after receiving the immunized CD4 + T cells in the adoptive transfer experiments. These results suggest that Th2-related lung TRM induced by IN vaccines are also protective against C. gattii infection as well as Th17-related counterparts induced by DC vaccine.
Prompt cusp formation from the gravitational collapse of peaks in the initial cosmological density field
Authors: White Simon D M
Published: September 2022

I present an analytic model for the early post-collapse evolution of a spherical density peak on the coherence scale of the initial fluctuations in a universe filled with collisionless and pressure-free ‘dust’. On a time-scale which is short compared to the peak’s collapse time t0, its inner regions settle into an equilibrium cusp with a power-law density profile, ρ ∝ r−12/7. Within this cusp, the circular orbit period P at each radius is related to the enclosed mass M by P = t0(M/Mc)2/3 where Mc is a suitably defined characteristic mass for the initial peak. The relaxation mechanism which produces this cusp gives insight into those which are active in high-resolution simulations of first halo formation in cold or warm dark matter universes, and, indeed, a simple argument suggests that the same power-law index γ = −12/7 should describe the prompt cusps formed during the collapse of generic peaks, independent of any symmetry assumption. Further work is needed to investigate the additional factors required to explain the slightly flatter exponent, γ ≈ −1.5, found in high-resolution numerical simulations of peak collapse.
Protestant Theology
Authors: Sauter Gerhard
Published: September 2022

The doctrine of the last things concerns both the ultimate destiny of the human race and the end of the world of which humans are a part. It points to the coherence of God's mysteries and to the right way of perceiving salvation, to God's redemption of humanity through its calling into the community of faithful people, and finally to God's last judgment and radical renewal of the world. This concept attempts to offer comprehensive answers to a number of questions: What are the last things? Why are they the end? And where will we finally be? As a compilation of the subjects of hope, eschatology takes on the question: What may we hope—in the face of death? Yet the discussion of this question is embedded in the perception of God's acting from the beginning of world and time, which culminates in Jesus Christ's incarnation, death, and resurrection. This article deals with the theology of Protestants, eschatology and the destination of history, radical eschatology, and the views of Friedrich Schleiermacher and Karl Barth.
Early Onset Neonatal Sepsis in Canada: 2011-2012
Authors: Sgro M , Kobylianskii *A , Sankaran K , Tran D , Yudin M , Campbell D
Published: September 2022

BACKGROUND: Canadian and US studies suggest that the organisms responsible for early-onset neonatal sepsis (EONS) are changing, with an increase in Escherichia coli (EC) as well as antibiotic-resistant organisms. Current Canadian guidelines for prevention and treatment of EONS are based on Group B streptococcus (GBS) as the likely organism. Population-level data may inform updates to these national strategies.

OBJECTIVES: To determine the incidence, types of organisms and corresponding resistance patterns involved in EONS in Canada. To identify how the organisms are affected by maternal antibiotic prophylaxis and other factors.

DESIGN/METHODS: Cases of EONS (defined as positive blood and/or cerebrospinal fluid (CSF) culture at <7 days of age) between January 2011 and December 2012 were identified through the Canadian Paediatric Surveillance Program (CPSP). Neonates were excluded if they were asymptomatic with a positive culture likely to be a contaminant, or if the CSF culture was positive as a result of an intracranial procedure.

RESULTS: Over the 2-year period, 127 cases meeting our criteria were identified, and there were 754,849 total Canadian live births. The incidence for EONS was 0.17/1000 live births. 79.5% of cases presented within the first 24 hours of life, while 15% presented between 72 h-7 days. GBS accounted for 41.7% of cases, while EC accounted for 35.4%. Resistance was noted in 33.9% of cases overall. 55.6% of EC were resistant, with ampicillin resistance being the most common. The species of infecting organism was significantly associated with gestational age, very low birth weight, age at presentation, the mother having received GBS prophylaxis, and rupture of membranes lasting more than 18 h. GBS was most common in term and EC in preterm neonates. The overall EONS case fatality rate was 11%, with most of these being deaths from EC.

CONCLUSION: Our study suggests a lower rate of EONS than historically suggested, with differing dominant organisms based on gestational ages of the neonates. Later ages at presentation and high rates of resistance especially among EC cases further complicate the picture. We recommend a review of the Canadian prevention and treatment guidelines based on our findings.
Changes in Pulmonary Function After A Caffeine Loading Dose and Extubation Outcome in Preterm Infants with Respiratory Distress Syndrome
Authors: Yusuf K , Elsharkawy A , Alshaikh B , Petan L , Vine M
Published: September 2022

BACKGROUND: Prolonged endotracheal intubation in preterm infants leads to adverse outcomes including bronchopulmonary dysplasia, pneumonia and sepsis. Extubating preterm infants early can lead to apneas, respiratory distress and hypoxemia with reintubation, a destabilizing and traumatic event. Identifying readiness for extubation would avoid these harmful events. Current clinical criteria perform poorly in predicting extu-bation outcome in preterm infants. Caffeine is used to facilitate extubation and also affects pulmonary function.

OBJECTIVES: To determine pulmonary functions before and after a caffeine loading dose in preterm infants < 31 weeks gestation with respiratory distress syndrome (RDS) undergoing their first trial of extubation and use them to predict extubation outcome.

DESIGN/METHODS: We determined dynamic compliance (Cdyn), tidal volume (TV), minute ventilation (MV), and dynamic airway resistance (Rdyn) before and after a loading dose of 10 mg/kg of caffeine base in preterm infants <31 weeks gestation with RDS prior to extubation. These measurements were taken as an average of ten non-distorted breaths with < 10% endotracheal air leak. Infants were ventilated with the EvitaXl Neo (Draeger, Germany). Pulmonary function readings were downloaded from the ventilator. Extubation failure was defined as the need for reintubation within 72 h after extubation. Exclusion criteria included grade 3-4 intra-ventricular hemorrhage, sedation, pneumothorax, medications affecting pulmonary function, chromosomal and congenital malformations. Mann Whitney test was used for continuous variables and the χ2 or Fisher’s exact test for dichotomous data. A p value <0.05 was considered significant.

RESULTS: Blood gas values and ventilator parameters were similar between the groups before extubation.There was significant improvement in pulmonary function after a loading dose caffeine. Amongst pulmonary functions, ratio of Cdyn before and after caffeine performed best in predicting extubation outcome with an area under the curve of 0.85 (95% CI 0.79-0.94).

CONCLUSION: Caffeine improves pulmonary function in preterm infants. A ratio of dynamic compliance before and after caffeine best predicted extu-bation outcome. Our results need validation in a prospective study.
Can We Predict Post-Hemorrhagic Ventricular Dilatation in Preterm Infants with Severe Intraventricular Hemorrhage?
Authors: Afifi J , Vincer M , Shah V , Ye XY , Shah P S , Barrington K , Kelly E , Piedboeuf B , El-Naggar W
Published: September 2022

BACKGROUND: The incidence of post-hemorrhagic ventricular dilatation (PHVD) remains high in preterm infants. Little is known about the risk factors for PHVD in infants with severe intraventricular hemorrhage (IVH).

OBJECTIVES: To determine the predictors of PHVD among preterm infants with severe IVH.

DESIGN/METHODS: We conducted a retrospective review of all pre-term infants (22+0 - 32+6 weeks) who were admitted to NICUs participating in the Canadian Neonatal Network between 2010 and 2014. Infants with severe IVH (IVH with ventricular dilatation or parenchymal bleeding) who survived ≥ 72 hours were included. Perinatal and neonatal risk factors were compared between infants with and without PHVD (lateral ventricles >10 mm).

RESULTS: Of 16600 eligible infants, 1964 (11.8%) developed severe IVH. Of 1815 infants with severe IVH who survived ≥72 hours, 616 (34%) developed PHVD. Factors associated with occurrence of PHVD include: lower gestational age, small for gestational age, low 5 minute Apgar score, SNAPII score>20, surfactant therapy, high frequency oscillatory ventilation (HFOV), inotropes and occurrence of pneumothorax. [table 1]. There were no differences between both groups in relation to antenatal steroids, multiple pregnancy, mode of delivery, birth weight, gender or the proportion received prophylactic indomethacin. Multivariate analysis showed low five-minute Apgar score and HFOV to be independent predictors of PHVD while maternal magnesium sulfate and small for gestation (SGA) to be protective against PHVD.[table 2].

CONCLUSION: Our study identified factors involved in the prediction of PHVD in a national cohort of preterm infants. The mechanisms by which these factors may impact PHVD need further investigation.
Increasing Incidence of Optic Nerve Hypoplasia/ Septo-Optic Dysplasia Spectrum: Geographic Clustering in Northern Canada
Authors: Rodd C , Khaper T , Bunge M , Clark I , Rafay M , Mhanni A , Kirouac N , Sharma A , Wicklow B
Published: September 2022

BACKGROUND: Since optic nerves and pituitary gland are embryologi-cally related, optic nerve hypoplasia (ONH) and septo-optic dysplasia (SOD) represent a clinical spectrum associated with visual impairment, pituitary deficiencies, and severe CNS structural malformations(SODplus). ONH is a leading cause of pediatric blindness in North America; genetic mutations are rarely observed. We recently perceived an increase in the number of children with SOD in our clinic. Similarly, several studies have reported a rise in the incidence of ONH/SOD in other jurisdictions.

OBJECTIVES: Our primary objectives were to examine trends in annual incidence in Manitoba and geographical clustering in our catchment area ofManitoba, NW Ontario and Nunavut.

DESIGN/METHODS: This was a retrospective 1996-2015 chart review from all medical services (Neurology, Ophthalmology, Endocrinology, Genetics) caring for these children to extract information pertaining to anthropometric measures, radiologic findings, parental characteristics, endocrinopathies, and neurologic symptoms. Postal codes were used to assign map co-ordinates and census-based material and social deprivation indices. Numbers of children from Manitoba only were used to calculate annual incidence. From 2010-2014, a Quality Assurance (QA) sub-study identified all pediatric radiology reports containing the words 'optic nerve'; the additional cases of ONH/SOD children not identified by chart review were used to better define the true incidence in Manitoba.

RESULTS: Ninety-three children were identified in our catchment area by chart review; Poisson regression confirmed a striking 1.11-fold annual increase (95%CI=1.07-1.16) or ~800% over two decades. The annual incidence (averaged 2010-2014) reached 53.3 per 100,000 affecting 1 in 1875 live births (chartdata). Including children identified by QA sub-study, the incidence rose to 113.3 per 100,000 live births in Manitoba. These are much higher than previously reported. Most children (~60%) had SODplus. Common presenting or follow-upfeatures were hypoglyce-mia, nystagmus, seizures, and developmental delay (50%); 40% had hormone deficiencies; 80% (75/93) had reduced visual acuity, typically bilateral. Many childrenwere born prematurelywith young (mean 21y: IQR 19-26y), primiparous mothers. Unhealthy maternal lifestyles and severe material deprivation were noted. There wasdisproportionate clustering in Northern Manitoba (3 times the average provincial rate) and in Nunavut.

CONCLUSION: We noted a dramatic rise in the annual incidence of ONH/SOD in Manitoba, NW Ontario and Nunavut, which is much higher than previous reports. This disorderwas strongly associated with poverty in northern communities. The temporal picture was consistent with environmental, nutritional, or toxic etiologies. About half of the children were severely affected with increased morbidity and health care burdens.
A Retrospective Evaluation of A Paediatric Consult Clinic Serving Uninsured Children in Canada
Authors: Suleman S , Humphreys J , Singer A , Markin R , Razik F , Au H
Published: September 2022

BACKGROUND: Children new to Canada may not have health insurance which limits access to health care and increases their vulnerability to poorer health outcomes. As part of a resident advocacy initiative, a monthly pediatric consult clinic was created within a community health clinic to serve uninsured children living in a suburb of a major Canadian city. At the time of its inception in 2009, 35% of patients seen in the health clinic did not have provincial health insurance and an additional 35-40% did not receive Interim Federal Health (IFH) that they were otherwise entitled to (Denburg et al., 2010).

OBJECTIVES: To describe the demographics and health issues of uninsured immigrant children referred to a pediatric consult clinic.

DESIGN/METHODS: This study is a retrospective chart review characterizing the patients seen from 2009 – 2013. We collected demographic information, presenting symptoms, diagnoses and clinical outcomes. After REB approval, 180 patients were identified and 159 charts were found. Data was extracted from each chart and coded into a database. Of these files, 38 were removed because of duplicate entries or if they were not seen in the clinic. A total of 121 charts were included in the final analysis. An audit was performed by a blinded reviewer to identify any discrepancies in transcription prior to descriptive analysis.

RESULTS: Over half (52.1%) of patients seen in our clinic were landed immigrants or Canadians, while 19.8% had refugee status. 49.3% of patients were in a 3-month waiting period for provincial health insurance, while 12.6% had IFH, 11.6% had OHIP and 21.5% had no insurance at all. Only 34% spoke English as their primary language. The top three presenting complaints were developmental, dermatologic and respiratory. The most common final diagnoses were psychiatric and behavioural, dermato-logic and nutritional. The majority of patients required counselling (67%), with 14% prescribed a short medication course and 20% requiring ongoing medication.

CONCLUSION: Almost 70% of patients seen had no insurance at the time of their visit, with most in the mandatory 3-month wait for provincial health coverage. Our study suggests that children still need access to health care during this period. The most common diagnoses related to mental health and development suggesting a high prevalence in immigrants and supporting the need to screen for these issues when caring for children new to Canada.
Audit of Pulse Oximetry Screening for Critical Congenital Heart Disease (Cchd) in Newborns
Authors: Lightfoot M , Hough P , Hudak A , Gordon M , Barker S , Meeder R , Colpitts M , Roberts J , Smith WG
Published: September 2022

BACKGROUND: UK data suggests that 25% of infants with CCHD are not diagnosed with heart disease until after discharge from the nursery (0.6 per 1000). In general SpO2 ≤ to 95% or a difference of upper and lower SpO2 of more than 3% in a newborn greater than 24 hours of age is considered significant. In March 2014 the Maternal Child Newborn Screening Committee of the Provincial Council for Maternal Child Health (PCMCH) recommended screening for critical congenital heart disease in Ontario.

OBJECTIVES: To assess the efficacy and cost related parameters of a new screening protocol for CCHD.

DESIGN/METHODS: An audit of consecutive healthy normal newborn patients over a one-year period was undertaken.

RESULTS: The cost of screening estimated for our center was approximately $7.20 per patient. The median age of screening was 25 hours (6-80 hours). Four patients were screened positive and were seen by a paediatrician in consultation. No Echocardiograms were ordered. No child in this screening survey had CCHD (specificity 99.4%). The screening compliance was 94.7%. One patient from our regional catchment area was delivered at an alternate secondary level center where there is no CCHD protocol in effect. The infant was discharged home and returned to the primary level center two days later in shock. The ultimate diagnosis was Hypoplastic Left Heart Syndrome. The estimated cost of the resuscitation was $1000. The emergency transport (direct) cost for this unstable newborn by helicopter is estimated to be $5000.00.

Conclusion: Cost analysis: The total direct costs of the CCHD screening program for a year is approximately $5200. The costs for the four patients who were falsely identified as having CCHD is estimated at $200. The total direct cost to the system of the one patient in our region who was not screened and was subsequently identified as having CCHD was estimated to be $6000. Assessment issues: In contrast to the US references, none of the false positive cases had an echocardiogram ordered. The cases were dealt with by utilizing a consultation with a paediatrician. Compliance with routine newborn orders: The screening compliance rate of 94.7%.

CONCLUSIONS: A simple screening test for Critical Congenital Heart Disease was successfully undertaken in a secondary level center over a one-year period. The test was cost effective, with high specificity (99.4%) and good compliance (94.7%).
Developing Skills for Developmental Disabilities: Assessing Efficacy in An Innovative Preclinical Elective
Authors: Peters L , Penner S , Kanji R , Andrews D
Published: September 2022

BACKGROUND: Many medical students feel they are not trained with adequate skills and knowledge regarding cognitive and physical disability. Because of this, students may have poor clinical skills in assessing developmental delays and discomfort when interacting with these patients. “Developing Skills for Developmental Disabilities (DSDD)” is a 12-hour preclinical (years 1 and 2) elective developed collaboratively by a group of medical students and developmental pedi-atric faculty. This elective provides training in disability, behaviour, family challenges, and available interventions via faculty presentations, peer teaching, simulation sessions, and observation of a clinical developmental intervention program.

OBJECTIVES: Our objective is to assess the efficacy of this new elective-which aims to assist students in correctly and comfortably identifying pediatric patients with, or at risk for, developmental delays and ininterac-tions withfamily members.

DESIGN/METHODS: Participating students completed a 10-question survey (responses administered on a 5 point Likert scale) at the start and end of the elective, whereby they self-assessed confidence and knowledge when engagingchildren with developmental disabilities. This questionnaire was adapted from confidence surveys used for other curriculum assessments.

RESULTS: 22 preclinical students enrolled in DSDD. Of these, 20 completed the elective and both surveys. Out ofthe 20 participants, 8 (40%) had previous work experience with disability, and 11 (55%) had personal experience (family or friend related). A significant (p0.001, CI 95%) increase in self-reported confidence was seen in 8 of10 survey questions.

CONCLUSION: Overall, DSSD increased preclinical students' self-reported confidence and knowledge regarding pediatric patients with developmental disabilities. Future plans include arepeatsurveycomparing students who opt to take the elective with a control group, randomly selected from the remainder of the class. This willaddress any potential self-selection bias. Because this brief form of intervention was significant in increasing student confidence and skill, aspects of this approach may be adapted into teaching tools for office practice (e.g. assessing development and/ordiscussing care with parents) when medical students are working alongside general pediatricians seeing children with chronic developmental disabilities.
The Generalizability of the Paediatric Developmental Passport: A Multi-Site Randomized Controlled Trial
Authors: Young E , Aiyadurai R , Cellupica U , Jegathesan T , Dillon K , Friedman G , Huber J , Merchant S , Minhas R , Maguire J
Published: September 2022

BACKGROUND: The Pediatric Developmental Passport (passport) is an innovative tracking tool for families of children with autism spectrum disorder (ASD). It provides a mechanism for clearly communicating appropriate regional developmental services, an opportunity track progress in accessing these developmental services and a valuable summary of the developmental care received by that child for pediatrician. A qualitative study with parents and health professionals (developmental pediatricians, developmental nurses, pediatricians) lead to the design and iterative review of the passport.

OBJECTIVES: The objective of this study was to determine the general-izability and effectiveness of the passport compared to placebo in a multi-site pragmatic randomized control trial.

DESIGN/METHODS: A pragmatic multi-site randomized controlled trial was conducted with families of children between 0-6 years of age diagnosed with ASD. Families from two different models of developmental care were enrolled into the study. One site was a sub-urban developmental consultation clinic and the second site was a shared-care model between developmental pediatricians and general pediatricians in an urban resource restricted area. All families included in the study were randomized to receive the passport or placebo (blank card). Agencies providing Autism specific behaviour therapy (ABA) within each site were contacted directly to obtain accurate contact and access status of recommended developmental services. To determine passport effectivenes a pearson’s chi square test was conducted using a significant p value of <0.05.

RESULTS: Forty children with ASD were included and followed in this study. The passport proved to be significantly more effective in aiding families to contact developmental services than the placebo (blank card). A significantly larger portion of families (90.5%) with the passport contacted agencies for ABA (applied behaviour analysis) therapy compared to families with the placebo (61.9%, (p value significant at <0.05). More families with the passport tended to contact ABA in less than 2 months (48%) than the placebo group (35%), but this was not statistically significant.

CONCLUSION: The pediatric developmental passport enables families of children newly diagnosed with Autism to contact necessary behavioural services more often than those who did not receive the passport after diagnosis.
Learning Problems Among Children of Refugee Background: A Systematic Scoping Review
Authors: Graham H , Minhas R
Published: September 2022

BACKGROUND: Learning problems are common, affecting up to one in ten children, occurring within the dynamic, multidimensional context of family, school, community and broader sociocultural environment. Refugee children have, by definition, experienced forced migration, and multiple transitions, and ongoing socioeconomic and cultural challenges that may have cumulative risk factors for learning problems and educational disadvantage.

OBJECTIVES: To review the prevalence and major determinants of learning problems in resettled refugee children and available evidence on their educational outcomes.

DESIGN/METHODS: A scoping review using Arksey and O'Malley’s framework for scoping studies was employed (a systematic search, selection, extraction, analysis and reporting strategy) to identify the prevalence, major determinants of learning problems and educational achievement in resettled refuge children. Relevant studies were identified from searches of MEDLINE, EMBASE, PubMed, CINAHL PsycInfo, and ERIC. Inclusion criteria were peer-reviewed articles in English addressing the prevalence and/or determinants of learning problems in refugee children. Two independent authors conducted abstract and full text article review. The data was extracted systematically and analysed using Arksey and O'Malley’s descriptive analytical method for scoping studies.

RESULTS: A total of 2002 studies were identified and 28 studies met the inclusion criteria to be included in the review. No information was available on the prevalence of specific learning issues, language disorders, or autism spectrum disorders. Included studies found refugee children to possess significant ‘resource’ factors that promote learning success and had similar academic outcomes compared to their native-born peers. Prevalence data were limited, with single studies informing most of the reported estimates. Eight studies examined the impact of trauma on learning identifying mental health issues, personal risk behaviours and lower school performance as key risk factors. Key resource factors were strong family ties, absence of racial discrimination, and school safety.

CONCLUSION: This review provides prevalence estimates for learning problems in refugee children, and highlights key ‘risk’ and ‘resource’ factors. This review provides paediatricians recommendations on how best to identify learning strengths and challenges in refugee children, to better advocate for support in achieving academic success. This review advocates for a larger experimental based research measuring educational outcomes in refugee children. Further research is needed to better define the prevalence of learning problems among children of refugee background and to map out the learning progress longitudinally.
Paediatric Visits to Community Emergency Departments: Outcomes from Referrals and Unscheduled Return Visits to a Paediatric Centre
Authors: Reiner E , Grafstein E , Doan Q
Published: September 2022

BACKGROUND: Approximately 85% of children in Canada who seek emergency care do so in a general emergency department (ED), yet also have access to a dedicated pediatric ED (PED) within reasonable range. Existing pediatric literature describing return visits to the ED for the same medical complaint – an important quality indicator of ED performance – has yet to report on patient flow patterns from general EDs to a PED.

OBJECTIVES: We sought to measure the proportion of children seen at general EDs who subsequently present to a PED for further care. We also sought to elucidate the reasons behind this pattern of revisits, and to describe the clinical management provided at the subsequent visit.

DESIGN/METHODS: A retrospective cohort study was conducted combining linked administrative databases and health records review. We reviewed all pediatric visits (<17 years of age) at 5 general EDs in Vancouver, linking visits between general EDs and the PED based on clincally compatible presentations. Our primary outcome measure was the proportion of general ED visits with a subsequent visit to a PED (within 7 days) during the 2012-13 fiscal year. Secondary outcomes included reasons for PED consultation, the clinical services accessed, and disposition at the PED.

RESULTS: During the study period, 582/17,824 (3.3%) children seen at GEDs subsequently presented to the PED within 7 days. The top 3 diagnoses among these were: fracture, viral infection, and musculoskeletal complaints. Of the 582 children with a visit to the PED, 167 (28.7%) were referred to the PED for a consultation, while the rest were family-initiated. Referred visits were more frequently associated with pediatric subspecialist consultation than family-initiated visits (41.3% versus 21.7%, p<0.01). The referred group more frequently resulted in a surgical procedure (12.0% versus 3.6%, p<0.01) or hospital admission (48.5% versus 11.6%, p<0.01).

CONCLUSION: Knowing the proportion, management, and outcomes of children that are treated in a general ED and subsequently at a PED may provide an important quality measure and opportunities to improve the management of common pediatric emergencies in the community.