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During pulmonary mucormycosis, inhaled sporangiospores adhere to, germinate, and invade airway epithelial cells to establish infection. We provide evidence that HIF1α plays dual roles in airway epithelial cells during Mucorales infection. We observed an increase in HIF1α protein accumulation and increased expression of many known HIF1α-responsive genes during in vitro infection, indicating that HIF1α signaling is activated by Mucorales infection. Inhibition of HIF1α signaling led to a substantial decrease in the ability of R. delemar to invade cultured airway epithelial cells. Transcriptome analysis revealed that R. delemar infection induces the expression of many pro-inflammatory genes whose expression was significantly reduced by HIF1α inhibition. Importantly, pharmacological inhibition of HIF1α increased survival in a mouse model of pulmonary mucormycosis without reducing fungal burden. These results suggest that HIF1α plays two opposing roles during mucormycosis: one that facilitates the ability of Mucorales to invade the host cells and one that facilitates the ability of the host to mount an innate immune response.

BACKGROUND: Sargramostim (yeast-derived, glycosylated recombinant human granulocyte-macrophage colony-stimulating factor [rhu GM-CSF]) augments innate and adaptive immune responses and accelerates hematopoietic recovery of chemotherapy-induced neutropenia. However, considerably less is known about its efficacy as adjunctive immunotherapy against invasive fungal diseases (IFDs). METHODS: The clinical courses of 15 patients with pediatric malignancies and IFDs treated adjunctively with sargramostim at a single institution were analyzed in a retrospective cohort review. Further, a systematic review of published reports of rhu GM-CSF for IFDs was also conducted. RESULTS: Among 65 cases, 15 were newly described pediatric patients and 50 were previously published cases of IFDs treated with rhu GM-CSF. Among the newly reported pediatric patients, IFDs were caused by Candida spp., Trichosporon sp., and molds (Aspergillus spp., Rhizopus sp., Lichtheimia sp., and Scedosporium sp). Twelve (80%) were neutropenic at baseline, and 12 (80%) were refractory to antifungal therapy. Among 12 evaluable patients, the overall response rate was 92% (8 [67%] complete responses, 3 [25%] partial responses, and 1 [8%] stable). Treatment is ongoing in the remaining 3 patients. Among 50 published cases (15 Candida spp., 13 Mucorales, 11 Aspergillus spp., 11 other organisms), 20 (40%) had baseline neutropenia and 36 (72%) were refractory to standard therapy before rhu GM-CSF administration. Consistent with responses in the newly reported patients, the overall response rate in the literature review was 82% (40 [80%] complete responses, 1 [2%] partial response, and 9 [18%] no response). CONCLUSIONS: Sargramostim may be a potential adjunctive immunomodulator for selected patients with hematological malignancies and refractory IFDs.

Following a period of close to a century when the Irish language was placed at the margins of the education system under British rule, there was a radical change in curriculum provision following political independence in Ireland in the 1920s. The importance of the Irish language in defining sovereignty, national identity, and nationhood in the Irish Free State was central to these curricular changes. Within months of the achievement of political independence, curriculum policy was revised to include provision for the teaching of the Irish language to all pupils in primary schools as well as the use of Irish as the medium of instruction in infant classes (the first two years of primary school). The education system became the linchpin in the political and cultural campaign to restore the Irish language as the vernacular. This paper critically examines how nationalist thinking in Ireland, which had its origins in nineteenth-century European discourses, impacted on curriculum decisions pertaining to the Irish language in the early 1900s. Focusing on the interrelationship between nationalism, language, and education, it traces the process and provisions of curriculum development in Ireland in the 1920s. Overall the paper argues that the influence of nationalism as understood in the wider European context of the time shifted emphasis in Ireland away from bilingualism (Irish and English languages) to the revival of the Irish language in the 1920s, primarily through the education system, to add political legitimacy to the new Irish Free State.

Molds are ubiquitous in the environment, and immunocompromised patients are at substantial risk of morbidity and mortality due to their underlying disease and the resistance of pathogenic molds to currently recommended antifungal therapies. This combination of weakened-host defense, with limited antifungal treatment options, and the opportunism of environmental molds renders patients at risk and especially vulnerable to invasive mold infections such as Aspergillus and members of the Order Mucorales. Currently, available antifungal drugs such as azoles and echinocandins, as well as combinations of the same, offer some degree of efficacy in the prevention and treatment of invasive mold infections, but their use is often limited by drug resistance mechanisms, toxicity, drug-drug interactions, and the relative paucity of oral treatment options. Clearly, there is a need for agents that are of a new class that provides adequate tissue penetration, can be administered orally, and have broad-spectrum efficacy against fungal infections, including those caused by invasive mold organisms. Ibrexafungerp, an orally bioavailable glucan synthase inhibitor, is the first in a new class of triterpenoid antifungals and shares a similar target to the well-established echinocandins. Ibrexafungerp has a very favorable pharmacokinetic profile for the treatment of fungal infections with excellent tissue penetration in organs targeted by molds, such as the lungs, liver, and skin. Ibrexafungerp has demonstrated in vitro activity against Aspergillus spp. as well as efficacy in animal models of invasive aspergillosis and mucormycosis. Furthermore, ibrexafungerp is approved for use in the USA for the treatment of women with vulvovaginal candidiasis. Ibrexafungerp is currently being evaluated in clinical trials as monotherapy or in combination with other antifungals for treating invasive fungal infections caused by yeasts and molds. Thus, ibrexafungerp offers promise as a new addition to the clinician's armamentarium against these difficult-to-treat infections.

This research critically examines the efforts of the British State and the various churches to re-vision the character and status of elementary school teachers in Ireland between the 1830s and the 1920s. In a climate of regular political revolution and denominational hostility, the Westminster government and all churches were anxious to promote civility, loyalty and religious allegiance among the Irish populace through education. To advance these aims, strict criteria for the selection, training, recruitment and management of teachers were developed and introduced by the State and churches. The aim here is to explore and analyse the interface between, and impact of, national and local oversight on the professional standing and identity of teachers. Collectively, the concerted efforts of the State and churches led to a re-vision of the position and a change in the status of teachers that has had a lasting impact on their professional identity.

Team teaching as a concept and approach has long been advocated at a policy level both internationally and in Ireland. However, there is very little focussed research on the use of team teaching as an approach in post-primary schools in Ireland or on its potential as a medium of teacher professional development. This article presents the findings of a two-year collaboration between the Department of Education, Maynooth University and the Professional Development Service for Teachers (PDST) to support student teachers and qualified teachers to engage in team teaching. It reports on the context for the collaboration and the educational policy landscape relating to team teaching in Ireland. The main focus of this paper is to report the perceptions of experienced teachers about the potentialities of team teaching as a form of professional development. The findings highlight the fragmented and tenuous way in which team teaching exists in many schools, with one teacher asserting that it is 'promoted widely but not valued'. Despite challenges, the data affirm a very strong appetite among post-primary teachers in Ireland for increased support to use team teaching as an approach that they report to be a valuable medium of professional development.

BackgroundInvasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential.MethodsTo achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups' findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved.ResultsThere is no change in the classifications of "proven," "probable," and "possible" IFD, although the definition of "probable" has been expanded and the scope of the category "possible" has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses.ConclusionsThese updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.

In recent years, the global public health community has increasingly recognized the importance of antimicrobial stewardship (AMS) in the fight to improve outcomes, decrease costs, and curb increases in antimicrobial resistance around the world. However, the subject of antifungal stewardship (AFS) has received less attention. While the principles of AMS guidelines likely apply to stewarding of antifungal agents, there are additional considerations unique to AFS and the complex field of fungal infections that require specific recommendations. In this article, we review the literature on AMS best practices and discuss AFS through the lens of the global core elements of AMS. We offer recommendations for best practices in AFS based on a synthesis of this evidence by an interdisciplinary expert panel of members of the Mycoses Study Group Education and Research Consortium. We also discuss research directions in this rapidly evolving field. AFS is an emerging and important component of AMS, yet requires special considerations in certain areas such as expertise, education, interventions to optimize utilization, therapeutic drug monitoring, and data analysis and reporting.

Mucormycosis is a difficult to diagnose rare disease with high morbidity and mortality. Diagnosis is often delayed, and disease tends to progress rapidly. Urgent surgical and medical intervention is lifesaving. Guidance on the complex multidisciplinary management has potential to improve prognosis, but approaches differ between health-care settings. From January, 2018, authors from 33 countries in all United Nations regions analysed the published evidence on mucormycosis management and provided consensus recommendations addressing differences between the regions of the world as part of the "One World One Guideline" initiative of the European Confederation of Medical Mycology (ECMM). Diagnostic management does not differ greatly between world regions. Upon suspicion of mucormycosis appropriate imaging is strongly recommended to document extent of disease and is followed by strongly recommended surgical intervention. First-line treatment with high-dose liposomal amphotericin B is strongly recommended, while intravenous isavuconazole and intravenous or delayed release tablet posaconazole are recommended with moderate strength. Both triazoles are strongly recommended salvage treatments. Amphotericin B deoxycholate is recommended against, because of substantial toxicity, but may be the only option in resource limited settings. Management of mucormycosis depends on recognising disease patterns and on early diagnosis. Limited availability of contemporary treatments burdens patients in low and middle income settings. Areas of uncertainty were identified and future research directions specified.

Conceptualisations and constructs of children and childhood are temporally and contextually grounded. Historical documents are rich sources of insight and understanding regarding how children were understood, valued and treated at various times by particular societies. This article explores the conceptualisation of children and childhood in the 26-county Irish Free State (South) and the 6-county Northern Ireland (North) in the 1920s following the partition of Ireland, through the lens of educational documentation, primarily national primary school curricula. The focus on both jurisdictions is interesting in the context of partition, exploring the sometimes divergent and often convergent ways in which children were conceptualised across borders and boundaries. This article reveals, using Sorin and Galloway's framework as a conceptual and analytical tool, that conceptualisations of children were broadly similar in the North and South but differed in their focus and enactment in both fledgling states. These disparities are largely attributable to the very different political, social and religious orientations of both jurisdictions and the use of education as a vehicle for nation-building, as well as identity and gender formation. The article also explores alternative conceptualisations of children in education policy in the North and South by presenting case study 'outliers' of educational provision. A century since partition, conclusions and implications are noted that resonate with contemporary elements of convergence and divergence on educational policy and the conceptualisation of children across the island of Ireland.

BACKGROUND:Posaconazole (POS) is a potent triazole antifungal agent approved in adults for treatment and prophylaxis of invasive fungal infections (IFIs). The objectives of this study were to evaluate the pharmacokinetics (PK), safety, and tolerability of POS oral suspension in pediatric subjects with neutropenia. METHODS:This was a prospective, multicenter, sequential dose-escalation study. Enrolled subjects were divided into 3 age groups: AG1, 7 to