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Biliary atresia (BA) is a rare pediatric cholangiopathy characterized by fibrosclerosing obliteration of the extrahepatic bile ducts, leading to cholestasis, fibrosis, cirrhosis, and eventual liver failure. The etiology of BA remains unknown, although environmental, inflammatory, infectious, and genetic risk factors have been proposed. We performed a genome-wide association study (GWAS) in a European-American cohort of 343 isolated BA patients and 1716 controls to identify genetic loci associated with BA. A second GWAS was performed in an independent European-American cohort of 156 patients with BA and other extrahepatic anomalies and 212 controls to confirm the identified candidate BA-associated SNPs. Meta-analysis revealed three genome-wide significant BA-associated SNPs on 2p16.1 (rs10865291, rs6761893, and rs727878; P < 5 ×10-8), located within the fifth intron of the EFEMP1 gene, which encodes a secreted extracellular protein implicated in extracellular matrix remodeling, cell proliferation, and organogenesis. RNA expression analysis showed an increase in EFEMP1 transcripts from human liver specimens isolated from patients with either BA or other cholestatic diseases when compared to normal control liver samples. Immunohistochemistry demonstrated that EFEMP1 is expressed in cholangiocytes and vascular smooth muscle cells in liver specimens from patients with BA and other cholestatic diseases, but it is absent from cholangiocytes in normal control liver samples. Efemp1 transcripts had higher expression in cholangiocytes and portal fibroblasts as compared with other cell types in normal rat liver. The identification of a novel BA-associated locus, and implication of EFEMP1 as a new BA candidate susceptibility gene, could provide new insights to understanding the mechanisms underlying this severe pediatric disorder.

Most cancer patients diagnosed with late-stage head and neck squamous cell carcinoma are treated with chemoradiotherapy, which can lead to toxicity. One potential alternative is tumor-limited conversion of a prodrug into its cytotoxic form. We reason this could be achieved by transient and tumor-specific expression of purine nucleoside phosphorylase (PNP), an Escherichia coli enzyme that converts fludarabine into 2-fluoroadenine, a potent cytotoxic drug. To efficiently express bacterial PNP in tumors, we evaluate 44 chemically distinct lipid nanoparticles (LNPs) using species-agnostic DNA barcoding in tumor-bearing mice. Our lead LNP, designated LNP intratumoral (LNP IT ), delivers mRNA that leads to PNP expression in vivo. Additionally, in tumor cells transfected with LNP IT , we observe upregulated pathways related to RNA and protein metabolism, providing insight into the tumor cell response to LNPs in vivo. When mice are treated with LNP IT -PNP, then subsequently given fludarabine phosphate, we observe anti-tumor responses. These data are consistent with an approach in which LNP-mRNA expression of a bacterial enzyme activates a prodrug in solid tumors. Lipid nanoparticles (LNPs) delivering mRNA after intratumoral administration could be a promising cancer treatment strategy. Here this group reports the intratumoral delivery of mRNA with LNPs inducing the expression of purine nucleoside phosphorylase and inhibiting the progression of head and neck squamous cell carcinoma in vivo.

Nitrocellulose (NC) is a conservative material that is used in a variety of applications, such as coating agents, biodegradable plastics, and propellant main charge. Nitrocellulose raw materials are easily obtained from lignocellulose sources, most notably cotton and wood pulp. The egg carton, a recycled paper waste designed for packaging and transporting eggs, is used in this study to make nitrocellulose in pulp form. The effects of different nitration durations (40, 50, and 60 min) from egg carton pulp bleached with various KOH concentrations (0.6 M, 1.0 M, and 1.5 M) on NC properties were evaluated. The accelerant properties of the NC of nitration time in 50 min were studied in a rice husk charcoal briquette. Rice husk charcoal briquettes are made in various ratios with nitrocellulose as an accelerant (97:3, 96:4, and 95:5). The NC was characterized using Fourier transform infrared (IR) spectroscopy and thermogravimetric (TG) analysis. 1.0 M of bleached egg carton pulp has the highest cellulose content (86.94%) with the presence of crystalline structure of cellulose at peak 1430 cm−1 after the bleaching process. Meanwhile, different nitration times revealed that 50 min had the highest nitrogen content (7.97%) with a 1.23 degree of substitution (DS) value. Based on its TG analysis, NC 50 has met the requirements for use as an accelerant for briquettes, with an onset temperature of 91.60 °C and a weight loss of 62.60%. Infrared at peak 1640 cm−1 confirmed the presence of NO2 groups in nitrocellulose successfully formed by nitration. After the addition of nitrocellulose, the calorific value of the briquette increased from 13.54% to 15.47%. Fixed carbon and volatile matter showed the same pattern. The combustion of nitrocellulose-briquette has also been demonstrated by Td10% of degradation, which degraded between 310 and 345 °C.

The author investigated the relationship between aspects of student motivation and performance on mathematical tasks varying in cognitive demand relevant to meeting the expectations of the Common Core State Standards for Mathematics (CCSS-M). A sample of 479 primarily Latino middle school students completed established survey measures of motivation and a constructed response assessment of two facets of mathematical competence. The assessment measured students' progress toward performing a procedure and demonstrating understanding by providing a written critique of a peer's work, a more cognitively demanding facet. As predicted, higher interest and efficacy in mathematics, lower performance-avoidance goals, and fewer experiences of negative emotions related to performance levels for both facets, while utility and mastery-approach goals (i.e., focusing on understanding mathematics) related only to the more cognitively demanding facet. Implications of these findings for preparing students to be successful mathematical learners, especially in the many states implementing the CCSS-M, are discussed.

Purpose Detection of all major classes of genomic variants in a single test would decrease cost and increase the efficiency of genomic diagnostics. Genome sequencing (GS) has the potential to provide this level of comprehensive detection. We sought to demonstrate the utility of GS in the molecular diagnosis of 18 patients with clinically defined Alagille syndrome (ALGS), who had a negative or inconclusive result by standard-of-care testing. Methods We performed GS on 16 pathogenic variant-negative probands and two probands with inconclusive results (of 406 ALGS probands) and analyzed the data for sequence, copy-number, and structural variants in JAG1 and NOTCH2 . Results GS identified four novel pathogenic alterations including a copy-neutral inversion, a partial deletion, and a promoter variant in JAG1 , and a partial NOTCH2 deletion, for an additional diagnostic yield of 0.9%. Furthermore, GS resolved two complex rearrangements, resulting in identification of a pathogenic variant in 97.5% ( n  = 396/406) of patients after GS. Conclusion GS provided an increased diagnostic yield for individuals with clinically defined ALGS who had prior negative or incomplete genetic testing by other methods. Our results show that GS can detect all major classes of variants and has potential to become a single first-tier diagnostic test for Mendelian disorders.

IntroductionLow back pain (LBP) is the leading contributor to disability globally. It has a substantial impact on the lives of those who experience it, and places considerable economic burden on healthcare systems. Despite these impacts, and the consistency of guideline recommendations, many individuals do not receive recommended LBP management. Structural barriers to accessing timely, evidence-based care, as well as public uncertainty about where to seek appropriate management, can influence the care individuals receive. Telephone and digitally based helplines assist to overcome many traditional barriers to accessing care and offer a scalable platform to improve the delivery of guideline recommended management for LBP. However, uptake of such services can be limited without targeted promotion and patient-centred design. This project aims to codesign, implement and evaluate an upgraded component of an existing Australian helpline service, tailored for people with back pain and supported by a media awareness campaign. This protocol outlines the codesign process, implementation and planned evaluation of the helpline.Methods and analysesThis protocol uses three complementary frameworks—an iterative codesign process, the Practical Robust Implementation Sustainability Model, and the Reach, Effectiveness, Adoption, Implementation and Maintenance framework—to guide the codesign and development, implementation and evaluation of an upgraded helpline for people with LBP. The codesign process involves key stakeholders, including consumers and clinicians, to inform the development and implementation of both the upgraded helpline service and the media campaign to raise awareness and uptake of the helpline. Data sources will include a pre–post cohort of helpline service users, routinely collected service data (eg, monthly call rate) and health system data to evaluate the broader population level impact (eg, rates of emergency department presentations for LBP in the Australian region targeted by the media campaign). Implementation evaluation will include Reach, Effectiveness, Adoption, Implementation and Maintenance as well as internal and external environmental factors that influence the success of these outcome measures.Ethics and disseminationThe project was approved by the University of Sydney’s Human Research Ethics Committee (HE001081). This project involves collaboration with consumers, clinicians and other stakeholders to interpret, translate and disseminate research findings to relevant audiences.

Inequitable access to early autism developmental surveillance is evident globally. However, there is limited research examining autism diagnosis, ethnicity, and community profiles when engaging in research for the early identification of autism. We aimed to understand the relationships between child ethnicity, maternal demographics, and autism diagnosis, comparing retrospective data from the 2016 census for eight local government areas (LGAs) in Victoria, Australia. Maternal and child health (MCH) nurses monitored 13,511 children under 42 months for the early signs of autism using the Social Attention Communication Surveillance-Revised (SACS-R) and SACS-R Preschool (SACS-PR) tools during well-child checks. Of these, 340 children with a “high likelihood” of autism attended developmental assessments. Participants’ maternal ethnicity (‘European maternal ethnicity’, EME; ‘non-European maternal ethnicity,’ N-EME; ‘mixed maternal ethnicity,’ MME’), socioeconomic factors, and autism prevalence were compared to their LGA community. Results indicated that study participants were representative of their LGA communities, though bi- and multilingualism was higher in our cohort. Differences in current maternal employment, maternal education, annual family income, and autism prevalence were found between the N-EME, EME, and MME groups. Our study found that research engagement was driven by maternal education, maternal employment, and annual family income, and further research is required to understand these relationships.

Infrastructure systems have direct implications for how health and well-being evolve across urban–rural systems. Scientists, practitioners, and policy-makers use domain-specific methods and tools to characterize sectors of infrastructure, but these approaches do not capture the cascading effects across interrelated infrastructure and governance domains. We argue that the development and management of sustainable urban infrastructure must focus on interactions across urban and rural places to advance equitable health and well-being. We call for a research agenda that focuses on urban–rural infrastructure systems, addressing trade-offs and synergies, decision-making, institutional arrangements, and effective co-production of knowledge across the diverse places connected by infrastructure.

Recent regional research has taken an ‘infrastructure turn’ where scholars have called for examining the transformative ability of different infrastructures in causing systemic inequities beyond the spatial conception of ‘urban and the other’. This research examines the interconnected impact of infrastructure systems on existing spatial inequities through a study in metropolitan Philadelphia, Pennsylvania. This study investigates whether the urban-rural (U-R) gradient concept can enhance understanding of the spatial relationship between socioeconomic indicators and infrastructure systems. Indicators of spatial inequalities were regressed against infrastructure variables and imperviousness, as a proxy for the U-R gradient, using multivariate and spatial regression methods. The models show that imperviousness has a positive correlation with the concentration of racialized minorities and a negative correlation with access to health insurance. The study also shows that the predictive power of multiple infrastructures varies across space and does not adhere to urban boundaries or the U-R gradient. The complex interactions among different infrastructures shape inequities and require further inquiry in urban regions around the world.

Background Commentators believe that the ethical decision-making climate is instrumental in enhancing interprofessional collaboration in intensive care units (ICUs). Our aim was twofold: (1) to determine the perception of the ethical climate, levels of moral distress, and intention to leave one's job among nurses and physicians, and between the different ICU types and (2) determine the association between the ethical climate, moral distress, and intention to leave. Methods We performed a cross-sectional questionnaire study between May 2021 and August 2021 involving 206 nurses and physicians in a large urban academic hospital. We used the validated Ethical Decision-Making Climate Questionnaire (EDMCQ) and the Measure of Moral Distress for Healthcare Professionals (MMD-HP) tools and asked respondents their intention to leave their jobs. We also made comparisons between the different ICU types. We used Pearson's correlation coefficient to identify statistically significant associations between the Ethical Climate, Moral Distress, and Intention to Leave. Results Nurses perceived the ethical climate for decision-making as less favorable than physicians ( p  < 0.05). They also had significantly greater levels of moral distress and higher intention to leave their job rates than physicians. Regarding the ICU types, the Neonatal/Pediatric unit had a significantly higher overall ethical climate score than the Medical and Surgical units (3.54 ± 0.66 vs. 3.43 ± 0.81 vs. 3.30 ± 0.69; respectively; both p  ≤ 0.05) and also demonstrated lower moral distress scores (both p  < 0.05) and lower “intention to leave” scores compared with both the Medical and Surgical units. The ethical climate and moral distress scores were negatively correlated (r = −0.58, p  < 0.001); moral distress and \"intention to leave\" was positively correlated (r = 0.52, p  < 0.001); and ethical climate and “intention to leave” were negatively correlated (r = −0.50, p  < 0.001). Conclusions Significant differences exist in the perception of the ethical climate, levels of moral distress, and intention to leave between nurses and physicians and between the different ICU types. Inspecting the individual factors of the ethical climate and moral distress tools can help hospital leadership target organizational factors that improve interprofessional collaboration, lessening moral distress, decreasing turnover, and improved patient care.