Schistosoma mansoni α-N-acetylgalactosaminidase (SmNAGAL) regulates coordinated parasite movement and egg production.

α-galactosidase (α-GAL) and α-N-acetylgalactosaminidase (α-NAGAL) are two glycosyl hydrolases responsible for maintaining cellular homeostasis by regulating glycan substrates on proteins and lipids. Mutations in the human genes encoding either enzyme lead to neurological and neuromuscular impairments seen in both Fabry- and Schindler/Kanzaki- diseases. Here, we investigate whether the parasitic blood fluke Schistosoma mansoni, responsible for the neglected tropical disease schistosomiasis, also contains functionally important α-GAL and α-NAGAL proteins. As infection, parasite maturation and host interactions are all governed by carefully-regulated glycosylation processes, inhibiting S. mansoni's α-GAL and α-NAGAL activities could lead to the development of novel chemotherapeutics. Sequence and phylogenetic analyses of putative α-GAL/α-NAGAL protein types showed Smp_089290 to be the only S. mansoni protein to contain the functional amino acid residues necessary for α-GAL/α-NAGAL substrate cleavage. Both α-GAL and α-NAGAL enzymatic activities were higher in females compared to males (p<0.05; α-NAGAL > α-GAL), which was consistent with smp_089290's female biased expression. Spatial localisation of smp_089290 revealed accumulation in parenchymal cells, neuronal cells, and the vitellaria and mature vitellocytes of the adult schistosome. siRNA-mediated knockdown (>90%) of smp_089290 in adult worms significantly inhibited α-NAGAL activity when compared to control worms (siLuc treated males, p<0.01; siLuc treated females, p<0.05). No significant reductions in α-GAL activities were observed in the same extracts. Despite this, decreases in α-NAGAL activities correlated with a significant inhibition in adult worm motility as well as in egg production. Programmed CRISPR/Cas9 editing of smp_089290 in adult worms confirmed the egg reduction phenotype. Based on these results, Smp_089290 was determined to act predominantly as an α-NAGAL (hereafter termed SmNAGAL) in schistosome parasites where it participates in coordinating movement and oviposition processes. Further characterisation of SmNAGAL and other functionally important glycosyl hydrolases may lead to the development of a novel anthelmintic class of compounds.

'Selection into training will always be an inexact process': A survey of Directors of Physician Education on selection into Basic Physician Training in Australia and New Zealand.

BACKGROUND: Despite being one of the largest medical specialty training programmes in Australasia, there is no standardised method for selection into Basic Physician Training (BPT), and limited data exist regarding current practices. AIMS: To address existing knowledge gaps, we aimed to create a 'snapshot' of current BPT selection practices and explore the perspectives of Directors of Physician Education (DPEs) regarding trainee selection. METHODS: An electronic survey of DPEs from adult and paediatric medicine BPT sites in Australia and New Zealand was undertaken in January-February 2022. A combination of free text, multiple-choice and yes/no answers were analysed using descriptive statistics and qualitative content analysis. RESULTS: A total of 70 responses were received, achieving a response rate of 35% (70/198). Selection practices were found to be heterogenous across BPT sites. Respondents had varying opinions regarding the utility of selection tools and desirable candidate attributes. A heavy reliance upon interviews and the reported use of subjective assessments raise concerns for selection process bias. CONCLUSION: BPT sites should critically evaluate their selection methods, and more research in this field is needed to establish best practice.

International students' perspectives on medical school and internship: 'Oh international? Are you international?'

BACKGROUND: International students account for a significant proportion of medical graduates Australia-wide, and most opting to remain in Australia for their first year of practice (Internship). Hence, understanding this particular demographic's perspectives is crucial for curriculum and workforce planning. Despite this, very few studies have addressed this demographic, and none have explored the impact of the COVID-19 pandemic on international medical students specifically. AIM: A qualitative design was used to explore the perspectives of final-year international medical students at an Australian medical school as they prepared for transition to internship during the COVID-19 pandemic. METHODS: Participants engaged in a semi-structured interview about the pandemic's personal and professional implications. The data were analysed using inductive thematic analysis. RESULTS: Seven out of 34 final-year international medical students at the University of Adelaide participated. The main themes identified were that isolation was magnified, institutional support was lacking and that uncertainty was challenging. The pandemic did not deter participants from pursuing an Australian internship, as Australia was considered a desirable place for internship compared to their home countries. CONCLUSIONS: While the COVID-19 pandemic exacerbated the situation, many of the challenges identified by international students already existed. Issues such as social isolation, racial discrimination, financial hardship and lack of institutional support have been prevalent for decades. Insights from this study reveal a need to improve the medical school experience. Australian Universities have a responsibility to ensure fair treatment of international students by training faculty, implementing support programmes and ensuring an inclusive and culturally safe learning environment.

A scoping review of patient-led teaching of health professions students.

Patients with chronic health conditions may become experts in their own conditions. Thus, utilising patients as teachers, with autonomy over taught content, may better prepare students to deliver patient-centred care. A scoping review following Arksey and O'Malley and Joanna Briggs Institute framework was performed. A total of 2162 articles were identified and 28 unique studies were included. Patient teacher programmes range from single, short 1- to 2-h tutorials to longitudinal community-based programmes. These programmes are mutually beneficial for students, improving awareness of all patient-centred domains, and patients feel empowered by their roles in education.

Key aspects of teaching that affect perceived preparedness of medical students for transition to work: insights from the COVID-19 pandemic.

BACKGROUND: The self-perceived preparedness of medical students to transition into practising junior doctors has implications for patient safety, graduate well-being and development of professional identity. AIMS: To examine the impact of changes to final-year education and placements and determine key elements that contribute to self-perceived preparedness for transition to work. METHODS: An online survey among final-year medical students at one Australian medical school in 2020 (the cohort most affected by the coronarvirus disease 2019 [COVID-19] pandemic), exploring overall self-perceived preparedness and specific competencies, including questions in previous Australian Medical Council/Medical Board of Australia annual national surveys. Quantitative and qualitative content analyses were performed. RESULTS: Thirty-three percent of eligible participants completed the survey. There was a significant decline in overall self-perceived preparedness among participants (mean preparedness, 3.55 ± 0.88) compared with 2019 graduates from the same medical school (mean preparedness, 4.28 ± 0.64, P < 0.001) and the national average (mean preparedness, 3.81 ± 0.93, P = 0.04). There was a decline in self-perceived preparedness for all specific competencies, with complex competencies more greatly affected. Qualitative content analysis of free text responses identified limitations of an online compared with a face-to-face formal education program and specific aspects of placements, which contribute to perceived preparedness. CONCLUSION: The current study highlights key aspects of clinical placements and formal teaching programs that contribute to perceptions of preparedness for transition to clinical practice. Relevant experiential learning in the clinical setting, opportunities for deliberate practice of necessary skills (in simulation and the clinical setting) and reflective opportunities from formal teaching programs contribute to perceived preparedness and are important elements to be included in the final phase of any medical program.

Evaluating an inquiry-based learning program.

Inquiry-based learning (IBL) is a promising educational framework that is understudied in graduate medical education. To determine participant satisfaction and engagement with phases of an IBL postgraduate education program, a mixed-methods study collected data via survey statements and open-ended responses. The authors included participants attending an intensive care medicine (ICM) IBL program from May to November 2020. Quantitative outcomes included participants' satisfaction with the IBL format and impact of engagement with IBL on the learning experience. Qualitative outcomes explored determinants of engagement with IBL phases and the impact on the learning experience. Of 378 attendees, 167 submitted survey responses (44.2%). There was strong agreement relating to overall satisfaction (93.4%). Responses indicated engagement with "orientation" (94.6%), "conceptualization" (97.3%), "discussion" (91.1%), and "conclusion" (91.0%) but limited engagement with the "investigation" phase (48.1%). Greater engagement with IBL phases had positive impacts, with repeat attenders having clearer learning objectives (79.1% vs. 56.6%, P < 0.05) and enhanced learning through collaborative discussion (65.9% vs. 48.7%, P < 0.05). Qualitative analysis showed that ICM learners value active learning principles, clear objectives, and a safe environment to expand their "knowledge base." Sessions facilitated "clinically relevant learning," with application of theoretical knowledge. Learners transformed and "reframed their understanding," using the input of others' experiences. ICM learners were highly satisfied with the IBL format and reported valuable learning. Participants engaged strongly with all IBL phases except the investigation phase during the sessions. IBL facilitated learners' active construction of meaning, facilitating a constructivist approach to learning.NEW & NOTEWORTHY An inquiry-based learning (IBL) program was launched as part of a novel binational intensive care medicine education program. Postgraduate intensive care medicine practitioners participated in this education intervention, where facilitated group discussions explored core intensive care medicine concepts. Survey responses indicated overall satisfaction, engagement with the IBL format, and a constructivist approach to learning. This study provided new insights into the benefits and challenges of an IBL program in the context of practicing clinicians.

Professionalism and clinical short answer question marking with machine learning.

Machine learning may assist in medical student evaluation. This study involved scoring short answer questions administered at three centres. Bidirectional encoder representations from transformers were particularly effective for professionalism question scoring (accuracy ranging from 41.6% to 92.5%). In the scoring of 3-mark professionalism questions, as compared with clinical questions, machine learning had a lower classification accuracy (P < 0.05). The role of machine learning in medical professionalism evaluation warrants further investigation.

Medical student knowledge and critical appraisal of machine learning: a multicentre international cross-sectional study.

To utilise effectively tools that employ machine learning (ML) in clinical practice medical students and doctors will require a degree of understanding of ML models. To evaluate current levels of understanding, a formative examination and survey was conducted across three centres in Australia, New Zealand and the United States. Of the 245 individuals who participated in the study (response rate = 45.4%), the majority had difficulty with identifying weaknesses in model performance analysis. Further studies examining educational interventions addressing such ML topics are warranted.

Pioneering topological methods for network-based drug-target prediction by exploiting a brain-network self-organization theory.

The bipartite network representation of the drug-target interactions (DTIs) in a biosystem enhances understanding of the drugs' multifaceted action modes, suggests therapeutic switching for approved drugs and unveils possible side effects. As experimental testing of DTIs is costly and time-consuming, computational predictors are of great aid. Here, for the first time, state-of-the-art DTI supervised predictors custom-made in network biology were compared-using standard and innovative validation frameworks-with unsupervised pure topological-based models designed for general-purpose link prediction in bipartite networks. Surprisingly, our results show that the bipartite topology alone, if adequately exploited by means of the recently proposed local-community-paradigm (LCP) theory-initially detected in brain-network topological self-organization and afterwards generalized to any complex network-is able to suggest highly reliable predictions, with comparable performance with the state-of-the-art-supervised methods that exploit additional (non-topological, for instance biochemical) DTI knowledge. Furthermore, a detailed analysis of the novel predictions revealed that each class of methods prioritizes distinct true interactions; hence, combining methodologies based on diverse principles represents a promising strategy to improve drug-target discovery. To conclude, this study promotes the power of bio-inspired computing, demonstrating that simple unsupervised rules inspired by principles of topological self-organization and adaptiveness arising during learning in living intelligent systems (like the brain) can efficiently equal perform complicated algorithms based on advanced, supervised and knowledge-based engineering.

Inpatient iron deficiency detection and management: how do general physicians and gastroenterologists perform in a tertiary care hospital?

BACKGROUND: Iron deficiency (ID) is often an indicator of underlying pathology. Early detection and treatment avoids long-term morbidity and allows for prompt iron repletion, avoiding ID anaemia (IDA) and the need for blood transfusion. AIM: To evaluate the management of ID in two internal medicine units (general medical (GM) and gastroenterology (GE)) in a large metropolitan hospital and compare it to international guidelines. METHODS: All consecutive inpatient admissions in the GM and GE units were retrospectively reviewed until 40 patients in each service were identified with anaemia and/or microcytic hypochromic blood counts. Patient records and electronic discharge summaries were then reviewed to assess the recognition, investigation and management of these abnormalities. RESULTS: Overall, only 60% (48/80) of the cases of microcytic hypochromic picture and/or anaemia were recognised. Cases were more likely to be detected under the GE unit, 77.5% (31/40) versus 42% (17/40) in GM (P < 0.002). Of the 31 recognised GE cases, 28 (90%) were investigated further with iron studies and/or endoscopic procedures. ID was confirmed in nearly half (5/11) of those tested; however, only 2 of 5 received iron replacement. Among GM patients, only 11 of the 17 recognised cases (64%) were investigated further. Iron studies were performed in all 11, confirming IDA in 4 (36%), all of whom received intravenous iron. A faecal human haemoglobin test was performed in two GM patients and one GE patient. CONCLUSION: There remains significant room for improvement in the recognition, investigation and management of ID in hospital practice in Australia.

Intensive care utilisation after elective surgery in Australia and New Zealand: A point prevalence study.

Objective: We aimed to describe the characteristics, outcomes and resource utilisation of patients being cared for in an ICU after undergoing elective surgery in Australia and New Zealand (ANZ). Methods: This was a point prevalence study involving 51 adult ICUs in ANZ in June 2021. Patients met inclusion criteria if they were being treated in a participating ICU on he study dates. Patients were categorised according to whether they had undergone elective surgery, admitted directly from theatre or unplanned from the ward. Descriptive and comparative analysis was performed according to the source of ICU admission. Resource utilisation was measured by Length of stay, organ support and occupied bed days. Results: 712 patients met inclusion criteria, with 172 (24%) have undergone elective surgery. Of these, 136 (19%) were admitted directly to the ICU and 36 (5.1%) were an unplanned admission from the ward. Elective surgical patients occupied 15.8% of the total ICU patient bed days, of which 44.3% were following unplanned admissions. Elective surgical patients who were an unplanned admission from the ward, compared to those admitted directly from theatre, had a higher severity of illness (AP2 17 vs 13, p<0.01), require respiratory or vasopressor support (75% vs 44%, p<0.01) and hospital mortality (16.7% vs 2.2%, p < 0.01). Conclusions: ICU resource utilisation of patients who have undergone elective surgery is substantial. Those patients admitted directly from theatre have good outcomes and low resource utilisation. Patient admitted unplanned from the ward, although fewer, were sicker, more resource intensive and had significantly worse outcomes.

Perceived and actual value of Student-led Objective Structured Clinical Examinations.

INTRODUCTION: Student-led Objective Structured Clinical Examinations (OSCEs) provide formative learning opportunities prior to Faculty-led OSCEs. It is important to undertake quality assurance measurements of peer-led assessments because, if they are found to be unreliable and invalid, they may have detrimental impacts. The objectives of this study were to explore and evaluate Student-led OSCEs hosted by fifth-year medical students. METHODS: Student-led OSCE results were analysed to examine reliability (Cronbach's alpha). The relationship between Student-led and Faculty-led OSCEs was evaluated using linear regression. Qualitative data were acquired by survey and semi-structured interviews and were analysed using an inductive content analysis approach. RESULTS: In total, 85 (94%) of 91 eligible students consented to study participation. Student-led OSCEs had a low-moderate reliability [Cronbach alpha = 0.47 (primary care) and 0.61 (human reproduction/paediatrics) (HRH)]. A statistically significant, positive relationship between Student-led and Faculty-led OSCE results was observed. Faculty-led OSCE grades increased by 0.49 (95% CI: 0.18, 0.80) to 1.09 (95% CI: 0.67, 1.52), for each percentage increase in Student-led OSCE result. Student-led OSCE participants highly valued the authentic peer-assessed experience. Reported benefits included a reduction of perceived stress and anxiety prior to Faculty-led OSCEs, recognition of learning gaps, contribution to overall clinical competency and facilitation of collaboration between peers. DISCUSSION: Student-led OSCEs are moderately reliable and can predict Faculty-led OSCE performance. This form of near-peer assessment encourages the metacognitive process of reflective practice and can be effectively implemented to direct further study. Faculties should collaborate with their student bodies to facilitate Student-led OSCEs and offer assistance to improve the quality, and benefits, of these endeavours.

Weisfeiler-Lehman goes dynamic: An analysis of the expressive power of Graph Neural Networks for attributed and dynamic graphs.

Graph Neural Networks (GNNs) are a large class of relational models for graph processing. Recent theoretical studies on the expressive power of GNNs have focused on two issues. On the one hand, it has been proven that GNNs are as powerful as the Weisfeiler-Lehman test (1-WL) in their ability to distinguish graphs. Moreover, it has been shown that the equivalence enforced by 1-WL equals unfolding equivalence. On the other hand, GNNs turned out to be universal approximators on graphs modulo the constraints enforced by 1-WL/unfolding equivalence. However, these results only apply to Static Attributed Undirected Homogeneous Graphs (SAUHG) with node attributes. In contrast, real-life applications often involve a much larger variety of graph types. In this paper, we conduct a theoretical analysis of the expressive power of GNNs for two other graph domains that are particularly interesting in practical applications, namely dynamic graphs and SAUGHs with edge attributes. Dynamic graphs are widely used in modern applications; hence, the study of the expressive capability of GNNs in this domain is essential for practical reasons and, in addition, it requires a new analyzing approach due to the difference in the architecture of dynamic GNNs compared to static ones. On the other hand, the examination of SAUHGs is of particular relevance since they act as a standard form for all graph types: it has been shown that all graph types can be transformed without loss of information to SAUHGs with both attributes on nodes and edges. This paper considers generic GNN models and appropriate 1-WL tests for those domains. Then, the known results on the expressive power of GNNs are extended to the mentioned domains: it is proven that GNNs have the same capability as the 1-WL test, the 1-WL equivalence equals unfolding equivalence and that GNNs are universal approximators modulo 1-WL/unfolding equivalence. Moreover, the proof of the approximation capability is mostly constructive and allows us to deduce hints on the architecture of GNNs that can achieve the desired approximation.

Hepatocellular carcinoma metastasis to sphenoid wing.

We present a case report where hepatocellular carcinoma metastasis to the sphenoid wing was the initial presentation of an occult primary.

Intensive care utilisation after elective surgery in Australia and New Zealand: getting the balance right.

Of the total intensive care unit (ICU) admissions in Australia and New Zealand, 36.6% occur following an elective surgical procedure. How best to use ICU services in this setting is not clear, despite this being an expensive and resource-intensive method of care delivery. The literature relating to this area has not demonstrated a clear association between improved outcomes and routine ICU utilisation. It has, however, demonstrated that methods of care delivery in this setting vary at the local, national and international level. There is now an increased interest in how we can offer safe, efficient care to patients who need ICU-level support after elective surgery, as well as where and when that care can be offered. We had previously performed a literature review relating to ICU utilisation in the elective surgical post-operative setting. This perspective piece arises from this literature review as well as extensive clinical experience from the authors. We discuss the need for a move towards an evidence-based indication for ICU admission and how this may be achieved. We then move on to the various alternative models of care that could be offered, briefly discussing their positives and potential drawbacks. We finish by outlining the research priorities and how these might be implemented in clinical practice. Getting the balance right between ICU admission and higher acuity ward-level care for post-operative elective surgical patients is difficult. However, this is an important challenge that we as a healthcare community must be working to answer.

Intracerebral Administration of a Novel Self-Assembling Peptide Hydrogel Is Safe and Supports Cell Proliferation in Experimental Intracerebral Haemorrhage.

Intracerebral haemorrhage (ICH) is the deadliest form of stroke, but current treatment options are limited, meaning ICH survivors are often left with life-changing disabilities. The significant unmet clinical need and socioeconomic burden of ICH mean novel regenerative medicine approaches are gaining interest. To facilitate the regeneration of the ICH lesion, injectable biomimetic hydrogels are proposed as both scaffolds for endogenous repair and delivery platforms for pro-regenerative therapies. In this paper, the objective was to explore whether injection of a novel self-assembling peptide hydrogel (SAPH) Alpha2 was feasible, safe and could stimulate brain tissue regeneration, in a collagenase-induced ICH model in rats. Alpha2 was administered intracerebrally at 7 days post ICH and functional outcome measures, histological markers of damage and repair and RNA-sequencing were investigated for up to 8 weeks. The hydrogel Alpha2 was safe, well-tolerated and was retained in the lesion for several weeks, where it allowed infiltration of host cells. The hydrogel had a largely neutral effect on functional outcomes and expression of angiogenic and neurogenic markers but led to increased numbers of proliferating cells. RNAseq and pathway analysis showed that ICH altered genes related to inflammatory and phagocytic pathways, and these changes were also observed after administration of hydrogel. Overall, the results show that the novel hydrogel was safe when injected intracerebrally and had no negative effects on functional outcomes but increased cell proliferation. To elicit a regenerative effect, future studies could use a functionalised hydrogel or combine it with an adjunct therapy.

Using ChEMBL to Complement Schistosome Drug Discovery.

Schistosomiasis is one of the most important neglected tropical diseases. Until an effective vaccine is registered for use, the cornerstone of schistosomiasis control remains chemotherapy with praziquantel. The sustainability of this strategy is at substantial risk due to the possibility of praziquantel insensitive/resistant schistosomes developing. Considerable time and effort could be saved in the schistosome drug discovery pipeline if available functional genomics, bioinformatics, cheminformatics and phenotypic resources are systematically leveraged. Our approach, described here, outlines how schistosome-specific resources/methodologies, coupled to the open-access drug discovery database ChEMBL, can be cooperatively used to accelerate early-stage, schistosome drug discovery efforts. Our process identified seven compounds (fimepinostat, trichostatin A, NVP-BEP800, luminespib, epoxomicin, CGP60474 and staurosporine) with ex vivo anti-schistosomula potencies in the sub-micromolar range. Three of those compounds (epoxomicin, CGP60474 and staurosporine) also demonstrated potent and fast-acting ex vivo effects on adult schistosomes and completely inhibited egg production. ChEMBL toxicity data were also leveraged to provide further support for progressing CGP60474 (as well as luminespib and TAE684) as a novel anti-schistosomal compound. As very few compounds are currently at the advanced stages of the anti-schistosomal pipeline, our approaches highlight a strategy by which new chemical matter can be identified and quickly progressed through preclinical development.

Small Molecule Ligands of the BET-like Bromodomain, SmBRD3, Affect Schistosoma mansoni Survival, Oviposition, and Development.

Schistosomiasis is a disease affecting >200 million people worldwide, but its treatment relies on a single agent, praziquantel. To investigate new avenues for schistosomiasis control, we have conducted the first systematic analysis of bromodomain-containing proteins (BCPs) in a causative species, Schistosoma mansoni. Having identified 29 putative bromodomains (BRDs) in 22 S. mansoni proteins, we selected SmBRD3, a tandem BRD-containing BCP that shows high similarity to the human bromodomain and extra terminal domain (BET) family, for further studies. Screening 697 small molecules identified the human BET BRD inhibitor I-BET726 as a ligand for SmBRD3. An X-ray crystal structure of I-BET726 bound to the second BRD of SmBRD3 [SmBRD3(2)] enabled rational design of a quinoline-based ligand (15) with an ITC Kd = 364 ± 26.3 nM for SmBRD3(2). The ethyl ester pro-drug of compound 15 (compound 22) shows substantial effects on sexually immature larval schistosomula, sexually mature adult worms, and snail-infective miracidia in ex vivo assays.