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Many 4-year public institutions face significant pedagogical challenges due to the high ratio of students to teaching team members. To address the issue, we developed a workflow using the programming language R as a method to rapidly grade multiple-choice questions, adjust for errors, and grade answer-dependent style multiple-choice questions, thus shifting the teaching teams' time commitment back to student interaction. We provide an example of answer-dependent style multiple-choice questions and demonstrate how the output allows for discrete analysis of questions based on various categories such as Fundamental Statements or Bloom's Taxonomy Levels. Additionally, we show how student demographics can be easily integrated to yield a holistic perspective on student performance in a course. The workflow offers dynamic grading opportunities for multiple-choice questions and versatility through its adaptability to assessment analyses. This approach to multiple-choice questions allows instructors to pinpoint factors affecting student performance and respond to changes to foster a healthy learning environment.

Many 4-year public institutions face significant pedagogical challenges due to the high ratio of students to teaching team members. To address the issue, we developed a workflow using the programming language R as a method to rapidly grade multiple-choice questions, adjust for errors, and grade answer-dependent style multiple-choice questions, thus shifting the teaching teams time commitment back to student interaction. We provide an example of answer-dependent style multiple-choice questions and demonstrate how the output allows for discrete analysis of questions based on various categories such as Fundamental Statements or Blooms Taxonomy Levels. Additionally, we show how student demographics can be easily integrated to yield a holistic perspective on student performance in a course. The workflow offers dynamic grading opportunities for multiple-choice questions and versatility through its adaptability to assessment analyses. This approach to multiple-choice questions allows instructors to pinpoint factors affecting student performance and respond to changes to foster a healthy learning environment.

Abstract Building classification is crucial for population estimation, traffic planning, urban planning, and emergency response applications. Although essential, such data is often not readily available. To alleviate this problem, this work presents a comprehensive dataset by providing residential/non-residential building classification covering the entire United States. We developed a dataset of building types based on building footprints and the available OpenStreetMap information. The dataset is validated using authoritative ground truth data for select counties in the U.S., which shows a high precision for non-residential building classification and a high recall for residential buildings. In addition to the building classifications, this dataset includes detailed information on the OpenStreetMap data used in the classification process. A major result of this work is the resulting dataset of classifying 67,705,475 buildings. We hope that this data is of value to the scientific community, including urban and transportation planners.

Abstract This study examines the supply chain management of micro, small, and medium enterprises (MSMEs) in Africa, aiming to demonstrate the patterns of publication in this field. An extensive examination of bibliometric analysis has been conducted using 338 published works obtained from the Dimensions database over the last 20 years. The study was conducted based on publications, sources, authors, and institutions as the primary units of analysis. The study determined the leading journals, prolific authors, partnering countries, and organizations involved in research on supply chain management specifically focused on micro, small, and medium enterprises (MSMEs) in Africa. Furthermore, it has been uncovered that the investigation of supply chain management in MSMEs in Africa needs to be revised in comparison to that of larger organizations. Moreover, publications in the field are not only insufficiently accessible, but also authored by scholars who are not of African descent. Given the crucial role of MSMEs in the African economy, scholars in this field are encouraged to prioritize research on the supply chain management of MSMEs as a critical issue for the twenty-first century. Furthermore, researchers are recommended to do additional analyses utilizing alternative databases such as Web of Sciences and Scopus.

Asynchronous skeletal muscle degeneration/regeneration is a hallmark feature of Duchenne muscular dystrophy (DMD); however, traditional -omics technologies that lack spatial context make it difficult to study the biological mechanisms of how asynchronous regeneration contributes to disease progression. Here, using the severely dystrophic D2-mdx mouse model, we generated a high-resolution cellular and molecular spatial atlas of dystrophic muscle by integrating spatial transcriptomics and single-cell RNAseq datasets. Unbiased clustering revealed nonuniform distribution of unique cell populations throughout D2-mdx muscle that were associated with multiple regenerative timepoints, demonstrating that this model faithfully recapitulates the asynchronous regeneration observed in human DMD muscle. By probing spatiotemporal gene expression signatures, we found that propagation of inflammatory and fibrotic signals from locally damaged areas contributes to widespread pathology and that querying expression signatures within discrete microenvironments can identify targetable pathways for DMD therapy. Overall, this spatial atlas of dystrophic muscle provides a valuable resource for studying DMD disease biology and therapeutic target discovery.

Abstract T Cell Receptor (TCR) antigen binding underlies a key mechanism of the adaptive immune response yet the vast diversity of TCRs and the complexity of protein interactions limits our ability to build useful low dimensional representations of TCRs. To address the current limitations in TCR analysis we develop a capacity-controlled disentangling variational autoencoder trained using a dataset of approximately 100 million TCR sequences, that we name TCR-VALID. We design TCR-VALID such that the model representations are low-dimensional, continuous, disentangled, and sufficiently informative to provide high-quality TCR sequence de novo generation. We thoroughly quantify these properties of the representations, providing a framework for future protein representation learning in low dimensions. The continuity of TCR-VALID representations allows fast and accurate TCR clustering and is benchmarked against other state-of-the-art TCR clustering tools and pre-trained language models.

Abstract Objective To investigate incorporating a ready‐to‐use 2.5:1 ratio liquid feed into a ketogenic diet (KD) in children and adults with drug‐resistant epilepsy. Methods Following a three‐day baseline, patients (n = 19; age: 19 years [SD 13], range: 8–46 years) followed a KD for 28 days (control period), then incorporated ≥200 mL/day of a ready‐to‐use liquid feed, made with a ratio of 2.5 g of fat to 1 g of protein plus carbohydrate and including medium chain triglycerides ([MCTs]; 25.6% of total fat/100 mL) for 28 days as part of their KD (intervention period). Outcome measures (control vs intervention period) included gastrointestinal (GI) tolerance, adherence to KD and intervention feed, dietary intake, blood ß‐hydroxybutyrate (BHB) concentration, seizure outcomes, health‐related quality of life (HRQoL), acceptability and safety. Results Compared to the control period, during the intervention period, the percentage of patients reporting no GI symptoms increased (+5% [SD 5], p = 0.02); adherence to the KD prescription was similar (p = 0.92) but higher in patients (n = 5) with poor adherence (

Abstract Pathogenic loss-of-function variants in BGN, an X-linked gene encoding biglycan, are associated with Meester-Loeys syndrome (MRLS), a thoracic aortic aneurysm/dissection syndrome. Since the initial publication of five probands in 2017, we have considerably expanded our MRLS cohort to a total of 18 probands (16 males and 2 females). Segregation analyses identified 36 additional BGN variant-harboring family members (9 males and 27 females). The identified BGN variants were shown to lead to loss-of-function by cDNA and Western Blot analyses of skin fibroblasts or were strongly predicted to lead to loss-of-function based on the nature of the variant. No (likely) pathogenic missense variants without additional (predicted) splice effects were identified. Interestingly, a male proband with a deletion spanning the coding sequence of BGN and the 5’ untranslated region of the downstream gene (ATP2B3) presented with a more severe skeletal phenotype. This may possibly be explained by expressional activation of the downstream ATPase ATP2B3 (normally repressed in skin fibroblasts) driven by the remnant BGN promotor. This study highlights that aneurysms and dissections in MRLS extend beyond the thoracic aorta, affecting the entire arterial tree, and cardiovascular symptoms may coincide with non-specific connective tissue features. Furthermore, the clinical presentation is more severe and penetrant in males compared to females. Extensive analysis at RNA, cDNA, and/or protein level is recommended to prove a loss-of-function effect before determining the pathogenicity of identified BGN missense and non-canonical splice variants. In conclusion, distinct mechanisms may underlie the wide phenotypic spectrum of MRLS patients carrying loss-of-function variants in BGN.

Presenting two cases of platelet-rich fibrin (PRF) aided regenerative treatment, performed in immature permanent teeth with large periapical lesions. In contrast to conventional apexification procedures, regenerative procedures can promote root completion and achieve root reinforcement. These case reports evaluated the long-term biological outcome of PRF-aided regeneration in immature permanent teeth with periapical lesions. Three-year and 5-year recalls in these cases revealed functional teeth with complete healing of the large periapical defect. The secondary outcome of regenerative treatment varied in the two reported cases. It was concluded that enhanced repair was achieved by an autologous PRF-aided regenerative procedure, but the secondary outcomes manifest variation.

This paper develops a conceptual framework to understand the relationship between perceived employer branding, employee engagement, and desirable attitudinal and behavioural outcomes. This conceptual framework proposes employee engagement as a mediator between perceived employer branding and different attitudes and behaviours such as job satisfaction, organisational commitment, turnover intention, task performance, and organisational citizenship behaviour in accordance with social exchange theory and the job-demand resources model. The paper expanded the research on employer branding by presenting a comprehensive framework incorporating engagement as a mediator between perceived employer branding and several new outcome variables, namely, job satisfaction, turnover intention, and task performance. With this comprehensive conceptual framework, a foundation has been laid for future researchers to verify the relationship between these constructs empirically. Further, implications have been suggested for organisations in designing their human resource policies and practices.

This article explores the ways in which female teachers negotiate their developing teacher identities and educational reform. It provides interesting data from the case of India that reflects female teacher identity and agency in the context of educational reform. Few studies specifically reference gendered responses to education reform; fewer still focus on how female teachers respond and act upon these reforms. It is argued that educational reform efforts in India should take into account female teachers' lives and development. This small qualitative study explores through semi-structured interviews the emerging identities of eight female teachers who work in five different higher secondary schools in Chennai, Tamil Nadu. Their responses were analysed using the voice-centred relational approach. The findings point to the importance of understanding the different ways female teachers negotiate their developing teacher identities in response to the changing structural and cultural contexts in which they find themselves.

This article examines the historical backdrop to the involvement of teaching Sisters in convent schooling for girls in India and the Islamic Republic of Pakistan, since the late nineteenth century. It then explores how, as a consequence of a range of social changes, leadership in convent schools has changed in both countries, across the twentieth century. The Irish Sisters who founded and established these schools commenced "passing the baton" of convent school leadership to Indian and Pakistani women. The article draws on interviews to examine ways in which successive generations of women in the study refer to the legacy of the past, and the issue of women in education leadership.

Gait is impaired in musculoskeletal conditions, such as knee arthropathy. Gait analysis is used in clinical practice to inform diagnosis and monitor disease progression or intervention response. However, clinical gait analysis relies on subjective visual observation of walking as objective gait analysis has not been possible within clinical settings due to the expensive equipment, large-scale facilities, and highly trained staff required. Relatively low-cost wearable digital insoles may offer a solution to these challenges. In this work, we demonstrate how a digital insole measuring osteoarthritis-specific gait signatures yields similar results to the clinical gait-lab standard. To achieve this, we constructed a machine learning model, trained on force plate data collected in participants with knee arthropathy and controls. This model was highly predictive of force plate data from a validation set (area under the receiver operating characteristics curve [auROC] = 0.86; area under the precision-recall curve [auPR] = 0.90) and of a separate, independent digital insole dataset containing control and knee osteoarthritis subjects (auROC = 0.83; auPR = 0.86). After showing that digital insole-derived gait characteristics are comparable to traditional gait measurements, we next showed that a single stride of raw sensor time-series data could be accurately assigned to each subject, highlighting that individuals using digital insoles can be identified by their gait characteristics. This work provides a framework for a promising alternative to traditional clinical gait analysis methods, adds to the growing body of knowledge regarding wearable technology analytical pipelines, and supports clinical development of at-home gait assessments, with the potential to improve the ease, frequency, and depth of patient monitoring.

Abstract Introduction Black and Minoritised Ethnicity (BME) occupational therapists face lower career progression opportunities and mentoring is one possible intervention that may offer support. BME persons may have different expectations and experiences from their mentor, and research exploring their perceptions of mentoring is important. In Occupational Therapy there is a growing awareness of the need to be true to the values of social justice. The aim of this research is to learn about BME occupational therapists’ experiences and perceptions of mentoring for career progression. Methods Four online focus groups involving 19 participants from the UK were held, discussions were facilitated by researchers using a topic guide. Participants responses were analysed, and codes were brought together to create Themes including career progression and role models, mentoring relationship, similarity with the mentor and outcomes from mentoring. Results The study highlighted that trust is integral to effective mentoring relationships and BME occupational therapists want mentors who they can trust with their experiences and stories. Compatibility between mentors and mentees in terms of personality, values, and working styles is crucial for effective mentoring relationships. Providing opportunities for networking, acknowledging good work and giving permission were all seen as outcomes from good mentoring. The absence of BME role models and ingroup bias were also reported as issues to be addressed. Conclusion This study explores the perception of mentorship as a mechanism for career advancement in occupational therapists from BME backgrounds, with these results transferable to other health and care professional groups. We recommend the creation of a mentoring charter for BME healthcare workers in the United Kingdom to ensure that those from BME backgrounds feel supported, mentored, and provided with equitable access to resources, including adequate mentoring and networking opportunities.

Abstract All other parts of the entrepreneurial ecosystem in any country are commonly governed by the political and legal aspects of the entrepreneurial ecosystem. This is a novel approach that examines the integrated effect of the entrepreneurial ecosystem's political–legal subsystem on the performance of MSEs based on system theory and the mediating role of entrepreneurial competence taking a resource-based view in to account. There has been no detailed examination of the entrepreneurial ecosystem of MSEs in Africa in general, and Ethiopia in particular. A total sample of 499 MSE operators engaged in the three priority sectors: manufacturing, construction and urban agriculture was selected from the population of 4086 operators in three metropolitan cities of Amhara National Regional State, Ethiopia, using a proportional stratified sampling. Though the political–legal aspects of the entrepreneurial ecosystem have a major impact on both entrepreneurial competency and MSE’s performance, the relationship between entrepreneurial competencies and MSE performance was found to be insignificant. The role of entrepreneurial competency in mediating the relationships between policy and business performance and other business environments and business performance was shown to be insignificant. It is suggested by the study that the policies that the government designs concerning MSEs should be workable and attractive including the provision of different incentives. Lastly, other researchers in the area are suggested to further clarify the contradictions in the findings regarding the relationship between entrepreneurial competencies and the performance of SMEs.

Anita Atwal,1 Vimal Sriram,2,3 Elizabeth A McKay4 1London South Banking University, School of Allied and Community Health, London, UK; 2University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK; 3Collaborative Learning and Capacity Building Theme, NIHR Applied Research Collaboration in Northwest London, London, UK; 4Edinburgh Napier University, School of Health and Social Care, Edinburgh, UKCorrespondence: Anita Atwal, Tel +44 20 7974403011, Email atwala@lsbu.ac.ukIntroduction: Diversity, equality and belonging are important aspects within Allied Health Professional (AHP) groups. Mentoring is considered as a solution to improve career progression. To date, there is no consensus on what good mentoring looks like and whether current models are fit for purpose for Black and Minoritised Ethnicity AHPs.Methods: Scoping review to understand mentoring among Black and Minoritised Ethnicity (BME) AHPs through searches in four electronic databases using pre-defined criteria.Results: From 1440 studies screened, 2 studies were included in this review that researched mentoring for BME AHPs in a health and/or social care setting. Themes that emerged from the literature were related to access and amount of mentoring for BME AHPs, psychosocial mentoring may influence cross-race mentorship outcomes and organisational issues related to workforce pressures and management support. There is uncertainty around the importance of same race relationships in mentoring but there is some evidence that within cross-race mentoring this could influence outcomes.Conclusion: It is unknown if mentoring enables career success in BME AHPs. There is emerging evidence on the importance of psychosocial mentoring within cross-race relationships. Careful reflection and further research is needed on how current mentoring models work and ensure fair access to mentorship and support for BME AHPs.Keywords: mentoring, ethnic minority, career progression, allied health, psychosocial

Abstract Background As a result of aging, skeletal muscle undergoes atrophy and a decrease in function. This age-related skeletal muscle weakness is known as “sarcopenia”. Sarcopenia is part of the frailty observed in humans. In order to discover treatments for sarcopenia, it is necessary to determine appropriate preclinical models and the genes and signaling pathways that change with age in these models. Methods and results To understand the changes in gene expression that occur as a result of aging in skeletal muscles, we generated a multi-time-point gene expression signature throughout the lifespan of mice and rats, as these are the most commonly used species in preclinical research and intervention testing. Gastrocnemius, tibialis anterior, soleus, and diaphragm muscles from male and female C57Bl/6J mice and male Sprague Dawley rats were analyzed at ages 6, 12, 18, 21, 24, and 27 months, plus an additional 9-month group was used for rats. More age-related genes were identified in rat skeletal muscles compared with mice; this was consistent with the finding that rat muscles undergo more robust age-related decline in mass. In both species, pathways associated with innate immunity and inflammation linearly increased with age. Pathways linked with extracellular matrix remodeling were also universally downregulated. Interestingly, late downregulated pathways were exclusively found in the rat limb muscles and these were linked to metabolism and mitochondrial respiration; this was not seen in the mouse. Conclusions This extensive, side-by-side transcriptomic profiling shows that the skeletal muscle in rats is impacted more by aging compared with mice, and the pattern of decline in the rat may be more representative of the human. The observed changes point to potential therapeutic interventions to avoid age-related decline in skeletal muscle function.

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Background: The assessment of erythema in patients with atopic dermatitis (AD) is based on clinical examination. The difficulty of perceiving erythema in Black patients with AD has led to underestimation of AD severity in these patients. Objective: In this study, we analyzed the concentration of skin tape soluble protein of AD lesions against common AD clinical signs. Method: A total of 50 children with AD were included. Skin tape total soluble protein was extracted from AD lesions and analyzed against validated AD clinical signs, including erythema, excoriation, edema, oozing, and lichenification. Results: Concentration of skin tape soluble protein is positively correlated with acute signs of AD, especially erythema. Conclusion: Determination of concentration of skin tape protein is a potential tool for grading erythema of AD lesions, and it may have an application in improving the health disparity of assessment of eczema severity in Black patients with AD.

Background Cancer–testis (CT) genes are targets for tumor antigen-specific immunotherapy given that their expression is normally restricted to the immune-privileged testis in healthy individuals with aberrant expression in tumor tissues. While they represent targetable germ tissue antigens and play important functional roles in tumorigenesis, there is currently no standardized approach for identifying clinically relevant CT genes. Optimized algorithms and validated methods for accurate prediction of reliable CT antigens (CTAs) with high immunogenicity are also lacking.Methods Sequencing data from the Genotype-Tissue Expression (GTEx) and The Genomic Data Commons (GDC) databases was used for the development of a bioinformatic pipeline to identify CT exclusive genes. A CT germness score was calculated based on the number of CT genes expressed within a tumor type and their degree of expression. The impact of tumor germness on clinical outcome was evaluated using healthy GTEx and GDC tumor samples. We then used a triple-negative breast cancer mouse model to develop and test an algorithm that predicts epitope immunogenicity based on the identification of germline sequences with strong major histocompatibility complex class I (MHCI) and MHCII binding affinities. Germline sequences for CT genes were synthesized as long synthetic peptide vaccines and tested in the 4T1 triple-negative model of invasive breast cancer with Poly(I:C) adjuvant. Vaccine immunogenicity was determined by flow cytometric analysis of in vitro and in vivo T-cell responses. Primary tumor growth and lung metastasis was evaluated by histopathology, flow cytometry and colony formation assay.Results We developed a new bioinformatic pipeline to reliably identify CT exclusive genes as immunogenic targets for immunotherapy. We identified CT genes that are exclusively expressed within the testis, lack detectable thymic expression, and are significantly expressed in multiple tumor types. High tumor germness correlated with tumor progression but not with tumor mutation burden, supporting CTAs as appealing targets in low mutation burden tumors. Importantly, tumor germness also correlated with markers of antitumor immunity. Vaccination of 4T1 tumor-bearing mice with Siglece and Lin28a antigens resulted in increased T-cell antitumor immunity and reduced primary tumor growth and lung metastases.Conclusion Our results present a novel strategy for the identification of highly immunogenic CTAs for the development of targeted vaccines that induce antitumor immunity and inhibit metastasis.

AbstractThe entrepreneurial ecosystem’s policy dimensions contribute to the performance improvement of Micro and Small Enterprises (MSEs). The social feminist theory argues that females fundamentally differ from males in their entrepreneurial attitude and business performance. Studies in the area are coming up with contradictory results in this regard. Investigations that addressed the moderating effect of gender on the relationship between the policy component of the entrepreneurial ecosystem and the performance of MSEs are not adequately available. Based on a sample of 498 MSEs in the metropolitan cities of Amhara Region, Ethiopia, the result suggests that the entrepreneurial ecosystem’s policy component is less conducive to MSEs. We also found that gender does not moderate the relationship between policy and MSEs’ performance. There exists no difference in the entrepreneurial ecosystem among the metropolitan cities and the sectors that MSEs are engaged. The study contributes to a greater understanding of the policy component of the Entrepreneurial Ecosystems, its significance for women entrepreneurs in MSEs and gender differences attributed to policy direction.

ABSTRACT We aimed to determine the epidemiology and clinical management of patients presenting to an Australian tertiary emergency department (ED) with a suspected snake bite. Nepean Hospital covers a geographical area known to harbour venomous elapid snake species. A Retrospective chart review of all patients presenting to Nepean ED from 2011 to 2020 was performed. We searched the electronic medical records (eMR) for triage presentations including search terms of “snakebite”, “bite” “envenomation”, or “bite-snake” and a discharge or independent diagnosis of “snakebite” or “envenomation”. Our review identified 110 patients presenting with snakebite, of whom nine had signs or symptoms indicating envenomation. The most common envenomation syndrome was venom-induced consumption coagulopathy (VICC) and the most commonly suspected culprit snake was the Eastern Brown Snake. Our data broadly agreed with national data on epidemiology and demographics. We noted a satisfactory rate of compliance with local snake bite protocols with evidence of early diagnosis and antivenom administration. We had no cases of anaphylaxis and one case of serum sickness. Our study of a tertiary hospital experience in the management of snake bite demonstrated an appropriate adherence to national guidelines and early clinician recognition of envenomation syndromes. It also demonstrated appropriate antivenom use without obvious time delay.

While tumor infiltration by CD8+ T cells is now widely accepted to predict outcomes, the clinical significance of intratumoral B cells is less clear. We hypothesized that spatial distribution rather than density of B cells within tumors may provide prognostic significance. We developed statistical techniques (fractal dimension differences and a box-counting method 'occupancy') to analyze the spatial distribution of tumor-infiltrating lymphocytes (TILs) in human triple-negative breast cancer (TNBC). Our results indicate that B cells in good outcome tumors (no recurrence within 5 years) are spatially dispersed, while B cells in poor outcome tumors (recurrence within 3 years) are more confined. While most TILs are located within the stroma, increased numbers of spatially dispersed lymphocytes within cancer cell islands are associated with a good prognosis. B cells and T cells often form lymphocyte clusters (LCs) identified via density-based clustering. LCs consist either of T cells only or heterotypic mixtures of B and T cells. Pure B cell LCs were negligible in number. Compared to tertiary lymphoid structures (TLS), LCs have fewer lymphocytes at lower densities. Both types of LCs are more abundant and more spatially dispersed in good outcomes compared to poor outcome tumors. Heterotypic LCs in good outcome tumors are smaller and more numerous compared to poor outcome. Heterotypic LCs are also closer to cancer islands in a good outcome, with LC size decreasing as they get closer to cancer cell islands. These results illuminate the significance of the spatial distribution of B cells and LCs within tumors.

BackgroundWith the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.MethodsWe tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk.ResultsWe report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs.ConclusionsOverall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.

The goal of immunotherapy is to mobilize the immune system to kill cancer cells. Immunotherapy is more effective and, in general, the prognosis is better, when more immune cells infiltrate the tumor. We explore the question of whether the spatial distribution rather than just the density of immune cells in the tumor is important in forecasting whether cancer recurs. After reviewing previous work on this issue, we introduce a novel application of maximum entropy to quantify the spatial distribution of discrete point-like objects. We apply our approach to B and T cells in images of tumor tissue taken from triple negative breast cancer patients. We find that the immune cells are more spatially dispersed in good clinical outcome (no recurrence of cancer within at least 5 years of diagnosis) compared to poor clinical outcome (recurrence within 3 years of diagnosis). Our results highlight the importance of spatial distribution of immune cells within tumors with regard to clinical outcome, and raise new questions on their role in cancer recurrence.

BackgroundINAD is an autosomal recessive neurogenetic disorder caused by biallelic pathogenic variants in PLA2G6. The downstream enzyme, iPLA2, plays a critical role in cell membrane homeostasis by helping to regulate levels of phospholipids. The clinical presentation occurs between 6 months and 3 years with global developmental regression, hypotonia, and progressive spastic tetraparesis. Progression is often rapid, resulting in severe spasticity, visual impairment, and cognitive decline, with many children not surviving past the first decade of life. To date, no accepted tool for assessing the severity of INAD exists; other commonly used scales (e.g. CHOP-INTEND, Modified Ashworth, Hammersmith Functional Motor Scale) do not accurately gauge the current severity of INAD, nor are they sensitive/specific enough to monitor disease progression. Finally, these other scales are not appropriate, because they do not address the combination of CNS, peripheral nerve, and visual pathology that occurs in children with INAD.MethodsWe have developed and validated a structured neurological examination for INAD (scored out of 80). The examination includes six main categories of pediatric developmental evaluation: 1) gross motor-and-truncal-stability skills, 2) fine motor skills, 3) bulbar function, 4) ocular function, 5) temporo-frontal function, and, 6) Functional evaluation of the autonomic nervous system. A cohort of patients diagnosed with INAD were followed prospectively to validate the score against disease severity and disease progression.ResultsWe show significant correlation between the total neurological assessment score and months since symptom onset with a statistically significant (p = 6.7 × 10- 07) correlation between assessment score and disease onset. As hypothesized, the coefficient of months-since-symptom-onset is strongly negative, indicating a negative correlation between total score and months since symptom onset.ConclusionWe have developed and validated a novel neurological assessment score in INAD that demonstrates strong correlation with disease severity and disease progression.

Urban Norway rats (Rattus norvegicus) can carry various human pathogens, and may be involved in pathogen propagation and transmission to humans. From January 31-August 14, 2021, a community outbreak of Shigella flexneri serotype 2a occurred among unhoused or poorly housed people in the Downtown Eastside neighborhood of Vancouver, British Columbia, Canada. The source could not be identified; however, patients reported contact with rats, and previous studies indicated transmission of rat-associated zoonotic pathogens among the unhoused or poorly housed residents of this neighborhood. The study objective was to determine if rats trapped in the outbreak area were carriers of Shigella spp. and other zoonotic enteric pathogens. From March 23-April 9, 2021, 22 rats were lethally trapped within the outbreak area. Colonic content was analyzed using the BioFire FilmArray Gastrointestinal (multiplex PCR) panel for human enteropathogens, which detected: Campylobacter spp. (9/22), Clostridioides difficile (3/22), Yersinia enterocolitica (5/22), Cryptosporidium spp. (8/22), Giardia duodenalis (5/22), Rotavirus A (1/22), enteroaggressive Escherichia coli (2/22), enteropathogenic E. coli (10/22), and Shigella spp. or enteroinvasive E. coli (EIEC) (3/22). An ipaH PCR assay was used for targeted detection of Shigella spp./EIEC, with five rats positive. Two samples contained insertion sites unique to S. flexneri isolated from the human outbreak. This study highlights the potential for rats to carry a broad range of human pathogens, and their possible role in pathogen maintenance and/or transmission.

Objective To determine current UK medical students’ career intentions after graduation and on completing the Foundation Programme (FP), and to ascertain the motivations behind these intentions.Design Cross-sectional, mixed-methods survey of UK medical students, using a non-random sampling method.Setting All 44 UK medical schools recognised by the General Medical Council.Participants All UK medical students were eligible to participate. The study sample consisted of 10 486 participants, approximately 25.50% of the medical student population.Outcome measures Career intentions of medical students postgraduation and post-FP, motivations behind these career intentions, characterising the medical student population and correlating demographic factors and propensity to leave the National Health Service (NHS).Results The majority of participating students (8806/10 486, 83.98%) planned to complete both years of the FP after graduation, with under half of these students (4294/8806, 48.76%) intending to pursue specialty training thereafter. A subanalysis of career intentions after the FP by year of study revealed a significant decrease in students’ intentions to enter specialty training as they advanced through medical school. Approximately a third of surveyed students (3392/10 486, 32.35%) intended to emigrate to practise medicine, with 42.57% (n=1444) of those students not planning to return. In total, 2.89% of students intended to leave medicine altogether (n=303). Remuneration, work-life balance and working conditions were identified as important factors in decision-making regarding emigration and leaving the profession. Subgroup analyses based on gender, type of schooling, fee type and educational background were performed. Only 17.26% of surveyed students were satisfied or very satisfied with the overall prospect of working in the NHS.Conclusions The Ascertaining the career Intentions of UK Medical Students study highlights UK students’ views and career intentions, revealing a concerning proportion of those surveyed considering alternative careers or emigration. Addressing factors such as remuneration, work-life balance and working conditions may increase retention of doctors and improve workforce planning efforts.