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Bioconjugation of polymers to proteins is a method to impart improved stability and pharmacokinetic properties to biologic systems. However, the precise effects of polymer architecture on the resulting bioconjugates are not well understood. Particularly, cyclic polymers are known to possess unique features such as a decreased hydrodynamic radius when compared to their linear counterparts of the same molecular weight, but have not yet been studied. Here, we report the first bioconjugation of a cyclic polymer, poly(ethylene glycol) (PEG), to a model protein, T4 lysozyme, containing a single engineered cysteine residue (V131C). We compare the stability and activity of this conjugate with those of a linear PEG-T4 lysozyme analogue of similar molecular weight. Furthermore, we used molecular dynamics (MD) simulations to determine the behavior of the polymer-protein conjugates in solution. We introduce cyclic polymer-protein conjugates as potential candidates for the improvement of biologic therapeutics.

Through mechanistic work and rational design, we have developed the fastest organometallic abiotic Cys bioconjugation. As a result, the developed organometallic Au(III) bioconjugation reagents enable selective labeling of Cys moieties down to picomolar concentrations and allow for the rapid construction of complex heterostructures from peptides, proteins, and oligonucleotides. This work showcases how organometallic chemistry can be interfaced with biomolecules and lead to a range of reactivities that are largely unmatched by classical organic chemistry tools.

This research investigates the extent to which educational law features and is constructed in the Teaching Council's documentation for Initial Teacher Education (ITE) programmes (2017, 2020) and in the "Code of Professional Conduct for Teachers" (Code) (2016), and analyses teachers' required knowledge of the law across these documents. Document analysis was used to track changes and provide insights. The findings indicate that teachers' knowledge of educational law has a low profile in the criteria used to review and accredit ITE programmes. Despite significant developments in law related to schools and teachers since 2017, including additional statutory requirements for child protection, the 2020 document does not have a commensurate increase in emphasis on law. Contrastingly, the findings indicate a high profile, and a high bar, for teachers' knowledge of the law in the Code. Recommendations include that the Teaching Council analyse graduates' legal knowledge during registration to ensure that they have the requisite skills to adequately perform as a professional; that the emphasis on educational law be increased in the ITE criteria so that it is aligned with the Code, and that programme providers fulfil their duty of care to students by providing them with adequate standalone modules on educational law.

Abstract Mucopolysaccharidosis type IH (MPS IH) is caused by homozygous IDUA gene pathogenic variants. This results in deficiency of the enzyme α-L-iduronidase (IDUA), which is necessary for the degradation of glycosaminoglycans (GAGs). This study outlines the long-term outcomes in adult Irish patients affected with MPS IH, who were followed up for mean 28 years post Haematopoietic Stem Cell Transplantation. Nineteen adult MPS IH patients underwent HSCT in childhood. The participant cohort represents 6 families. Among the 13 patients with Irish Traveller ethnicity, 6 patients were either siblings or first cousins. All these related patients were homozygous for p. Trp402Ter (W402X). Mean age at the first transplantation was 8 months (range 3-21). Five patients had undergone a second transplantation (n=5, 26%) in childhood, due to graft failure. None of the patients had a cardiac valve surgery at the time of the study. 14/19 patients had mild to moderate aortic or mitral valve insufficiency or stenosis. 3/19 patients used non-invasive ventilation at night. Two patients had tracheostomy in situ. Both sensorineural as well as conductive hearing defects. No corneal clouding post corneal transplantation (n=8) was observed. Six patients attended regular secondary school. Multidisciplinary follow-up is needed to address the disease specific complications in adulthood.

Introducing a tri-coordinate boron-based functional group (e.g., boronic ester) into an unactivated C-H bond in the absence of directing groups is an ongoing challenge in synthetic chemistry. Despite previous developments in transition metal-catalyzed and -free approaches, C-H borylation of sterically hindered arenes remains a largely unsolved problem to date. Here, we report a synthetic strategy of a two-step, precious metal-free electrophilic C-H borylation of sterically hindered alkyl- and haloarenes to generate aryl boronic esters. The first step relies on electrophilic aromatic substitution (EAS) induced by cage-opening of Cs2[closo-B10H10], forming a 6-Ar-nido-B10H13 product containing a B-C bond, followed by a cage deconstruction of arylated decaboranes promoted by diols. The combination of these two steps allows for the preparation of aryl boronic esters that are hardly accessible by current direct C-H borylation approaches. This reaction does not require any precious metals, highly-engineered ligands, pre-functionalized boron reagents, or inert conditions. In addition, the unique properties of a non-classical boron cluster electrophile intermediate, B10H13+, afford a regioselectivity with unique steric and electronic control without the undesirable side reactions.

Objectives: To determine if early (three months) and late (one year) post-operative continence is improved by performing a novel retropubic vascularised fascial sling (RoboSling) procedure concurrently with robot-assisted radical prostatectomy in men undergoing treatment for localised prostate cancer. To additionally assess surgical outcomes, quality of life and health economic outcomes in patients undergoing the novel RoboSling technique. Methods: This study aims to recruit 120 consecutive patients with clinically localised prostate cancer who have chosen to undergo robot-assisted radical prostatectomy in the Sydney Local Health District, Australia. A prospective assessment of early and late post-operative continence following robot-assisted radical prostatectomy with and without a RoboSling procedure will be performed in a two-group, 1:1, parallel, randomized controlled trial. Four surgeons will take part in the study, all of whom are beyond their learning curve. Patients will be blinded as to whether the RoboSling procedure is performed for them, as will be the research officers collecting the post-operative data on urinary function. Trial Registration: ACTRN12618002058257. Results: The trial is currently underway. Conclusions: The RoboSling technique is unique in that the sling is vascularised and has a broad surface area compared to previously described slings in the literature. If a clinically significant improvement in post-operative continence is established with the RoboSling, then, we can in turn expect improvements in quality of life for men undergoing this technique with radical prostatectomy.

ObjectivesPreterm birth occurs in more than 10% of U.S. births and is the leading cause of U.S. neonatal deaths, with estimated annual costs exceeding $25 billion USD. Using real-world data, we modeled the potential clinical and economic utility of a prematurity-reduction program comprising screening in a racially and ethnically diverse population with a validated proteomic biomarker risk predictor, followed by case management with or without pharmacological treatment.MethodsThe ACCORDANT microsimulation model used individual patient data from a prespecified, randomly selected sub-cohort (N = 847) of a multicenter, observational study of U.S. subjects receiving standard obstetric care with masked risk predictor assessment (TREETOP; NCT02787213). All subjects were included in three arms across 500 simulated trials: standard of care (SoC, control); risk predictor/case management comprising increased outreach, education and specialist care (RP-CM, active); and multimodal management (risk predictor/case management with pharmacological treatment) (RP-MM, active). In the active arms, only subjects stratified as higher risk by the predictor were modeled as receiving the intervention, whereas lower-risk subjects received standard care. Higher-risk subjects' gestational ages at birth were shifted based on published efficacies, and dependent outcomes, calibrated using national datasets, were changed accordingly. Subjects otherwise retained their original TREETOP outcomes. Arms were compared using survival analysis for neonatal and maternal hospital length of stay, bootstrap intervals for neonatal cost, and Fisher's exact test for neonatal morbidity/mortality (significance, p

Objectives Workplace stigmatisation and discrimination are significant barriers to accessing employment opportunities, reintegration and promotion in the workforce for people with mental illnesses in comparison to other disabilities. This paper presents qualitative evidence of anticipated and experienced workplace stigma and discrimination among individuals with major depressive disorder (MDD) in 35 countries, and how these experiences differ across countries based on their Human Development Index (HDI) level.Design Mixed-method cross-sectional survey.Participants, setting and measures The qualitative data were gathered as part of the combined European Union Anti-Stigma Programme European Network and global International Study of Discrimination and Stigma Outcomes for Depression studies examining stigma and discrimination among individuals with MDD across 35 countries. Anticipated and experienced stigma and discrimination were assessed using the Discrimination and Stigma Scale version 12 (DISC-12). This study used responses to the open-ended DISC-12 questions related to employment. Data were analysed using the framework analysis method.Results The framework analysis of qualitative data of 141 participants identified 6 key ‘frames’ exploring (1) participants reported experiences of workplace stigma and discrimination; (2) impact of experienced workplace stigma and discrimination; (3) anticipated workplace stigma and discrimination; (4) ways of coping; (5) positive work experiences and (6) contextualisation of workplace stigma and discrimination. In general, participants from very high HDI countries reported higher levels of anticipated and experienced discrimination than other HDI groups (eg, less understanding and support, being more avoided/shunned, stopping themselves from looking for work because of expectation and fear of discrimination). Furthermore, participants from medium/low HDI countries were more likely to report positive workplace experiences.Conclusions This study makes a significant contribution towards workplace stigma and discrimination among individuals with MDD, still an under-researched mental health diagnosis. These findings illuminate important relationships that may exist between countries/contexts and stigma and discrimination, identifying that individuals from very high HDI countries were more likely to report anticipated and experienced workplace discrimination.

Abstract Background The number of older people in prison is growing. As a result, there will also be more prisoners suffering from dementia. The support and management of this population is likely to present multiple challenges to the prison system. Objectives To examine the published literature on the care and supervision of people living in prison with dementia and on transitioning into the community; to identify good practice and recommendations that might inform the development of prison dementia care pathways. Methods A scoping review methodology was adopted with reporting guided by the PRISMA extension for scoping reviews checklist and explanation. Results Sixty-seven papers were included. Most of these were from high income countries, with the majority from the United Kingdom (n = 34), followed by the United States (n = 15), and Australia (n = 12). One further paper was from India. Discussion The literature indicated that there were difficulties across the prison system for people with dementia along the pathway from reception to release and resettlement. These touched upon all aspects of prison life and its environment, including health and social care. A lack of resources and national and regional policies were identified as important barriers, although a number of solutions were also identified in the literature, including the development of locally tailored policies and increased collaboration with the voluntary sector. Conclusion To our knowledge, this is the most comprehensive and inclusive review of the literature on dementia care pathways in prison to date. It has identified a number of important areas of concern and opportunities for future research across the prison system, and its operations. This will hopefully lead to the identification or adaptation of interventions to be implemented and evaluated, and facilitate the development of dementia care pathways in prisons.

Amandeep Virk,1 Patrick-Julien Treacy,2 Ruban Thanigasalam,1– 3 Scott Leslie1– 3 1Department of Uro-Oncology, Chris O’Brien Lifehouse, Sydney, NSW, Australia; 2The Institute of Academic Surgery at Royal Prince Alfred Hospital, Sydney, NSW, Australia; 3Faculty of Medicine and Health, University of Sydney, Sydney, NSW, AustraliaCorrespondence: Amandeep Virk, Chris O’Brien Lifehouse, 119-143 Missenden Road, Camperdown, Sydney, NSW, 2050, Australia, Tel +61421233369, Email amandeep.virk.21@gmail.comPurpose: This study aimed to evaluate what objectives are most important to men undergoing radical prostatectomy to allow treating physicians to personalize perioperative counselling and improve patient quality of life outcomes.Materials and Methods: A predefined search protocol of the Medline and Embase databases was performed from database inception to May 2023. The search was limited to English language and full text. All articles with a specific consideration of patient objectives, preferences or reasons for decision to undergo radical prostatectomy were included for review.Results: Ten articles out of 375 screened met inclusion criteria for review. All 10 articles utilized a qualitative design and originated across 5 countries across the developed world. A common theme of men placing importance on having their tumor physically removed was found. Methodologies allowing free response beyond predefined categories identified a breadth of considerations including personal circumstance, personal belief and current function in the decision-making process. An investigation on radical prostatectomy performed robotically found some men placed preference on the quicker treatment time with surgery compared to radiation therapy, reflective of shorter recovery times with the robotic approach.Conclusion: Variability in results across studies highlights the heterogeneity in patient preferences. Directed investigation of patient objectives with an open-ended questioning approach would personalize the perioperative experience and may improve patient satisfaction and quality of life outcomes.Keywords: prostate cancer, prostatectomy, robotic surgery, objectives, preferences, goals, quality of life

Amandeep Virk,1 Patrick-Julien Treacy,2 Wenjie Zhong,3,4 Norbert Doeuk,1 Celine Doeuk,5 Scott Leslie1– 3 1Department of Uro-Oncology, Chris O’Brien Lifehouse, Camperdown, NSW, Australia; 2The Institute of Academic Surgery at Royal Prince Alfred Hospital, Camperdown, NSW, Australia; 3Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia; 4Faculty of Medicine and Health, The University of New South Wales, Kensington, NSW, Australia; 5Rozelle Medical Centre, Ultimo, NSW, AustraliaCorrespondence: Amandeep Virk, Chris O’Brien Lifehouse, 119-143 Missenden Road, Camperdown, Sydney, NSW, 2050, Australia, Tel +61421233369, Email amandeep.virk.21@gmail.comBackground: Prostate cancer is often considered a disease of older men and this indeed fits with its peak incidence between 65– 79 years of age. Reports of prostate cancer in men younger than 40 years of age and the outcomes of this age group following treatment are few in the literature. Here, we present the case of an unusual diagnosis of high grade prostate cancer in a very young man and outline early outcomes following treatment with robotic-assisted radical prostatectomy.Case Presentation: A 35-year-old male, intermittently taking finasteride for hair loss, was found to have an elevated prostate-specific antigen (PSA) of 12.5ng/mL leading to an incidental diagnosis of high grade prostate cancer. Targeted trans-perineal prostate biopsy found Gleason 4+5=9 acinar adenocarcinoma, without cribriform architecture but with features suspicious for extracapsular extension. Robotic radical prostatectomy with bilateral pelvic lymph node dissection was performed and found Gleason 4+5=9 adenocarcinoma with focal cribriform architecture, extra prostatic extension and clear margins, stage pT3a N0 M0. PSA was undetectable at 12 months, continence was immediate, and the patient reported strong erections soon after surgery. Family history of prostate cancer and genetic testing were both negative.Conclusion: This case highlights that not all clinically significant cancers will be identified by following PSA screening guidelines starting at 50 years of age (or 40 years of age for men with a family history of prostate cancer). While high grade prostate cancer in a man less than 40 years of age is uncommon, the literature suggests the incidence is increasing. Our case alongside series in the literature indicate that these men have better functional outcomes and equal oncological outcomes with early surgical intervention for localized disease when compared to the older population.Keywords: prostate cancer, prostatectomy, robotic surgery, young men, outcomes, case report

Abstract Augmented Reality in education can support students in a wide range of cognitive tasks–fostering understanding, remembering, applying, analysing, evaluating, and creating learning-relevant information more easily. It can help keep up engagement, and it can render learning more fun. Within the framework of a multi-year investigation encompassing primary and secondary schools across Europe, the ARETE project developed several Augmented Reality applications, providing tools for user interaction and data collection in the education sector. The project developed innovative AR learning technology and methodology, validating these in four comprehensive pilot studies, in total involving more than 2,900 students and teachers. Each pilot made use of a different Augmented Reality application covering specific subjects (English literacy skills, Mathematics and Geography, Positive Behaviour, plus, additionally, an Augmented Reality authoring tool applied in a wide range of subjects). In this paper, we introduce the datasets collected during the pilots, describe how the data enabled the validation of the technology, and how the approach chosen could enhance existing augmented reality applications in data exploration and modelling.

Low-temperature combustion (LTC) concepts, such as homogeneous charge compression ignition (HCCI) and partially premixed combustion (PPC), aim to reduce in-cylinder temperatures in internal combustion engines, thereby lowering emissions of nitrogen oxides (NOx) and soot. These LTC concepts are particularly attractive for decarbonizing conventional diesel engines using renewable fuels such as methanol. This paper uses numerical simulations and a finite-rate chemistry model to investigate the combustion and emission processes in LTC engines operating with pure methanol. The aim is to gain a deeper understanding of the physical and chemical processes in the engine and to identify optimal engine operation in terms of efficiency and emissions. The simulations replicated the experimentally observed trends for CO, unburned hydrocarbons (UHCs), and NOx emissions, the required intake temperature to achieve consistent combustion phasing at different injection timings, and the distinctively different combustion heat release processes at various injection timings. It was found that the HCCI mode of engine operation required a higher intake temperature than PPC operation due to methanol’s low ignition temperature in fuel-richer mixtures. In the HCCI mode, the engine exhibited ultra-low NOx emissions but higher emissions of UHC and CO, along with lower combustion efficiency compared to the PPC mode. This was attributed to poor combustion efficiency in the near-wall regions and engine crevices. Low emissions and high combustion efficiency are achievable in PPC modes with a start of injection around a crank angle of 30° before the top dead center. The fundamental mechanism behind the engine performance is analyzed.

Central to criticisms of teacher professional development is an insufficient focus on its impact including minimal evidence of changes to practice coupled with inadequate emphasis on student outcomes. This year-long study of one case study school investigates the impact of a seven-month professional development initiative designed to support teachers in implementing a reform approach to mathematics teaching. Data sources include teacher interviews, lesson observations, student focus group interviews, and document reviews. Findings suggest initially impoverished mathematics experiences that later begin to show signs of enrichment. Students' insights into changing practice indicate that students want to be challenged more in mathematics and experience this challenge in inclusive learning environments where all students are valued and supported. A key finding is the effectiveness of student insights in increasing teachers' engagement with the professional development initiative and in motivating teachers' engagement in, and commitment to, the reform process. These findings highlight the complexity of the teacher change process, in particular, how cognitive dissonance plays a key role in changing practice. Central to creating this cognitive dissonance were students' insightful perspectives about learning mathematics. This research contends that student voice can provide unique context-specific insights yet is under-utilised in professional development theory and practice.

There is a body of research which highlights the importance of students studying mathematics at an advanced level, hence policy-makers worldwide look for ways to increase the uptake of advanced mathematics. In Ireland, the Government announced the introduction of a Bonus Points Initiative which came into effect in 2012, in an attempt to increase the number of Senior Cycle students opting to study higher-level mathematics and to improve Irish students' mathematical capabilities. Despite a rise in the number of students studying higher-level mathematics, very little research has been conducted to determine if it was the Bonus Points initiative, a reformed mathematics curriculum, or other factors that led to the surge in uptake. To address this gap in the research, this study investigates Irish students' reasons for participating in higher-level mathematics and seeks to determine if such reasons differ across gender, school type, or prior attainment levels. The findings suggest that the points system used by Ireland's Central Applications Office for entry to post-secondary education (CAO, n.d.), in particular the provision of Bonus Points for higher-level mathematics in Ireland, is the main driving factor behind students' participation in higher-level mathematics, with parents also being influential in decision-making. Significant differences in the reasons offered by males and females were found, while prior attainment seemed to have the biggest influence on students' reasoning regardless of gender.

Undergraduate research initiatives such as mentoring programs, conferences, and journals typically focus on the later stages of undergraduate studies. It is not unusual for a student to reach the final year of their program without developing their awareness of research within their discipline or their institution. SUREbyts is a project that provides first- and second-year undergraduate students with access to research through video recordings of professional researchers and research students discussing their own research, with each video structured around a research question with a set of possible solutions. This article presents the successes and challenges faced by the project's initial implementation in six higher education institutions in Ireland and offers advice to institutions globally that are considering engaging their students with research in this way.

IntroductionResearch points to a relationship between owner personality and strength of attachment to one’s pet, with implications for psychological health. So far, studies in this area, albeit sparse, have focused on the ‘Big Five’ traits of owner personality. The ‘Dark Triad’ is a cluster of traits that has also been linked to emotional deficits, but has been overlooked in relation to pet attachment. This study therefore examined the association between owner personality and pet attachment, focusing on both the ‘Big Five’ and ‘Dark Triad’ traits of personality.MethodsA cross-sectional design was employed to collect quantitative data from dog and cat owners across the globe between May-June 2023. A purpose-designed online survey collected sociodemographic details, along with information on pet ownership, strength of the pet-owner bond and participant personality, assessed using the Big Five personality scale and the Short Dark Triad scale. The survey was fully completed by 759 dog and 179 cat owners.ResultsAnalysis revealed significant correlations between many of the participants’ personality traits, both within and between scales. Strength of pet attachment was positively correlated with neuroticism and conscientiousness, and, more weakly, to Machiavellianism. Regression analysis revealed that females, dog owners, people over the age of 50 and individuals who had children under 18 years to care for were more strongly attached to their pets than others. Both neuroticism and conscientiousness were found to be significant predictors of participants’ pet attachment scores. None of the Dark Triad traits significantly predicted the criterion.DiscussionThis study points to a relationship between strength of attachment to one’s pet and owner personality, at least as measured using the Big Five approach to personality assessment. There was little to support an association between the Dark Triad traits and strength of attachment to one’s pet, although the link between these characteristics and attachment styles is still unknown. The investigation lends support for the idea that high attachment levels are associated with personality traits aligned to psychological ill-health. Further work is recommended in this area, with a greater focus on both strength and quality (e.g., attachment style) of the pet-owner bond.

Classic galactosemia (CG, OMIM #230400, ORPHA: 79,239) is a hereditary disorder of galactose metabolism that, despite treatment with galactose restriction, affects brain function in 85% of the patients. Problems with cognitive function, neuropsychological/social emotional difficulties, neurological symptoms, and abnormalities in neuroimaging and electrophysiological assessments are frequently reported in this group of patients, with an enormous individual variability. In this review, we describe the role of impaired galactose metabolism on brain dysfunction based on state of the art knowledge. Several proposed disease mechanisms are discussed, as well as the time of damage and potential treatment options. Furthermore, we combine data from longitudinal, cross-sectional and retrospective studies with the observations of specialist teams treating this disease to depict the brain disease course over time. Based on current data and insights, the majority of patients do not exhibit cognitive decline. A subset of patients, often with early onset cerebral and cerebellar volume loss, can nevertheless experience neurological worsening. While a large number of patients with CG suffer from anxiety and depression, the increased complaints about memory loss, anxiety and depression at an older age are likely multifactorial in origin.

We report the measurement and analysis of sulfonium-π, thioether-π, and ammonium-π interactions in a β-hairpin peptide model system, coupled with computational investigation and PDB analysis. These studies indicated that the sulfonium-π interaction is the strongest and that polarizability contributes to the stronger interaction with sulfonium relative to ammonium. Computational studies demonstrate that differences in solvation of the trimethylsulfonium versus the trimethylammonium group also contribute to the stronger sulfonium-π interaction. In comparing sulfonium-π versus sulfur-π interactions in proteins, analysis of SAM- and SAH-bound enzymes in the PDB suggests that aromatic residues are enriched in close proximity to the sulfur of both SAM and SAH, but the populations of aromatic interactions of the two cofactors are not significantly different, with the exception of the Me-π interactions in SAM, which are the most prevalent interaction in SAM but are not possible for SAH. This suggests that the weaker interaction energies due to loss of the cation-π interaction in going from SAM to SAH may contribute to turnover of the cofactor.

Development of inhibitors for histone methyllysine reader proteins is an active area of research due to the importance of reader protein-methyllysine interactions in transcriptional regulation and disease. Optimized peptide-based chemical probes targeting methyllysine readers favor larger alkyllysine residues in place of methyllysine. However, the mechanism by which these larger substituents drive tighter binding is not well understood. This study describes the development of a two-pronged approach combining genetic code expansion (GCE) and structure-activity relationships (SAR) through systematic variation of both the aromatic binding pocket in the protein and the alkyllysine residues in the peptide to probe inhibitor recognition in the CBX5 chromodomain. We demonstrate a novel change in driving force for larger alkyllysines, which weaken cation-π interactions but increases dispersion forces, resulting in tighter binding. This GCE-SAR approach establishes discrete energetic contributions to binding from both ligand and protein, providing a powerful tool to gain mechanistic understanding of SAR trends.

Background There is increasing heterogeneity in the clinical phenotype of patients admitted to the intensive care unit (ICU) with coronavirus disease 2019 (COVID-19,) and reasons for mechanical ventilation are not limited to COVID pneumonia. We aimed to compare the characteristics and outcomes of intubated patients admitted to the ICU with the primary diagnosis of acute hypoxemic respiratory failure (AHRF) from COVID-19 pneumonia to those patients admitted for an alternative diagnosis. Methods Retrospective cohort study of adults with confirmed SARS-CoV-2 infection admitted to nine ICUs between March 18, 2020, and April 30, 2021, at an urban university institution. We compared characteristics between the two groups using appropriate statistics. We performed logistic regression to identify risk factors for death in the mechanically ventilated COVID-19 population. Results After exclusions, the final sample consisted of 319 patients with respiratory failure secondary to COVID pneumonia and 150 patients intubated for alternative diagnoses. The former group had higher ICU and hospital mortality rates (57.7% vs. 36.7%, P

The 4-anilino-6,7-ethylenedioxy-5-fluoroquinazoline scaffold is presented as a novel model system for the characterization of the weak NH⋅⋅⋅F hydrogen bonding (HB) interaction. In this scaffold, the aniline NH proton is forced into close proximity with the nearby fluorine (dH,F ∼2.0 Å, ∠∼138°), and a through-space interaction is observed by NMR spectroscopy with couplings (1h JNH,F ) of 19±1 Hz. A combination of experimental (NMR spectroscopy and X-ray crystallography) and theoretical methods (DFT calculations) were used for the characterization of this weak interaction. In particular, the effects of conformational rigidity and steric compression on coupling were investigated. This scaffold was used for the direct comparison of fluoride with methoxy as HB acceptors, and the susceptibility of the NH⋅⋅⋅F interaction to changes in electron distribution and resonance was probed by preparing a series of molecules with different electron-donating or -withdrawing groups in the positions para to the NH and F. The results support the idea that fluorine can act as a weak HB acceptor, and the HB strength can be modulated through additive and linear electronic substituent effects.

The clinical management of pregnancy and spontaneous preterm birth (sPTB) relies on estimates of gestational age (GA). Our objective was to evaluate the effect of GA dating uncertainty on the observed performance of a validated proteomic biomarker risk predictor, and then to test the generalizability of that effect in a broader range of GA at blood draw. In a secondary analysis of a prospective clinical trial (PAPR; NCT01371019), we compared two GA dating categories: both ultrasound and dating by last menstrual period (LMP) (all subjects) and excluding dating by LMP (excluding LMP). The risk predictor's performance was observed at the validated risk predictor threshold both in weeks 191/7-206/7 and extended to weeks 180/7-206/7. Strict blinding and independent statistical analyses were employed. The validated biomarker risk predictor showed greater observed sensitivity of 88% at 75% specificity (increases of 17% and 1%) in more reliably dated (excluding-LMP) subjects, relative to all subjects. Excluding dating by LMP significantly improved the sensitivity in weeks 191/7-206/7. In the broader blood draw window, the previously validated risk predictor threshold significantly stratified higher and lower risk of sPTB, and the risk predictor again showed significantly greater observed sensitivity in excluding-LMP subjects. These findings have implications for testing the performance of models aimed at predicting PTB.

BackgroundEffective healthcare disparities curricula seek to train physicians who are well equipped to address the health needs of an increasingly diverse society. Current literature on healthcare disparities curricula and implementation focuses on courses created independent of existing educational materials. Our aim was to develop and implement a novel resource-conserving healthcare disparities curriculum to enhance existing medical school lectures without the need for additional lectures.MethodsThis non-randomized intervention was conducted at the University of California Los Angeles. The curriculum was offered to all first-year medical students in the class of 2021 (n=188). With institutional approval, a new healthcare disparities curriculum was created based on the Society of General Internal Medicine's core learning objectives for effective healthcare disparities curricula (J General Internal Med 25:S160-163, 2010). Implementation of the curriculum made use of "teachable moments" within existing medical school lectures. Teachable moments were broad lecture topics identified by the research team as suitable for introducing relevant healthcare disparities content. The new lecture-enhancing healthcare disparities curriculum was delivered with the related lecture via integrated PDF documents uploaded to an online learning management system. Students were encouraged to complete pre- and post- course assessments to examine changes in disparities knowledge and self-rated confidence in addressing disparities. Matched χ2 tests were used for statistical analysis.ResultsParticipating students (n=92) completed both pre- and post-course assessments and were retrospectively stratified, based on self-reported use of the new lecture enhancing curriculum, into the "high utilizer" group (use of materials "sometimes" or "very often," n=52) and the comparison "low utilizer" group (use of the materials "rarely" or "very rarely," n=40). Students who self-identified as underrepresented racial and ethnic minorities in medicine were more likely to utilize the material (41% of the high utilizers vs. 17% of the low utilizer group, p

This article presents a synthesis of findings from a large-scale research project, the Global Visions Through Mobilizing Networks--Co-developing Intercultural Music Teacher Education in Finland, Israel and Nepal (https://sites.uniarts.fi/web/globalvisions/home), and conveys its theoretical and practical explorations and insights. By envisioning 21st-century music teacher education from the perspective of interculturality and through transnational collaboration, Global Visions has engaged with international societal changes and struggles related to the rising tides of xenophobia, populism, and social disharmony, by focusing on what happens at the boundaries, in dialogue, and in conflict when difference is encountered, experienced, and reflected upon. While the dominant culturalist view presents music as neutral and diversity as tied mainly to ethnicity, Global Visions has recognized, analyzed, exemplified, and increased understanding of the complex politics of diversity. Resulting in envisioned music teacher education programs as innovative game changers, the project has enhanced professional reflexivity through considering the responsibility and moral aspects of music teacher education. Six main focus areas of the project are presented with recommendations for future research and practice in music teacher education: (a) research education and research as intervention; (b) reflexivity and professional learning in intercultural encounters; (c) the capacity to aspire in music teacher education; (d) the development of intersectional praxis; (e) intercultural music education as a political engagement; and (f) transcultural professional development and international professionalization.

AbstractObjectivesPreterm birth occurs in more than 10% of U.S. births and is the leading cause of U.S. neonatal deaths, with estimated annual costs exceeding $25 billion USD. Using real-world data, we modeled the potential clinical and economic utility of a prematurity-reduction program comprising screening in a racially and ethnically diverse population with a validated proteomic biomarker risk predictor, followed by case management with or without pharmacological treatment.MethodsThe ACCORDANT microsimulation model used individual patient data from a prespecified, randomly selected sub-cohort (N=847) of a multicenter, observational study of U.S. subjects receiving standard obstetric care with masked risk predictor assessment (TREETOP; NCT02787213). All subjects were included in three arms across 500 simulated trials: standard of care (SoC, control); risk predictor/case management comprising increased outreach, education and specialist care (RP-CM, active); and risk predictor/case management with pharmacological treatment (RP-MM, active). In the active arms, only subjects stratified as higher-risk by the predictor were modeled as receiving the intervention, whereas lower-risk subjects received standard care. Higher-risk subjects’ gestational ages at birth were shifted based on published efficacies, and dependent outcomes, calibrated using national datasets, were changed accordingly. Subjects otherwise retained their original TREETOP outcomes. Arms were compared using survival analysis for neonatal and maternal hospital length of stay, bootstrap intervals for neonatal cost, and Fisher’s exact test for neonatal morbidity/mortality (significance, p

In this paper, we provide general information about college student mental health, including common mental health issues, contributing factors, and barriers to help-seeking. We then suggest research-based practices college campuses at large, and specifically higher education faculty, may take to address student mental health concerns.

Abstract The unpredictability of artificial intelligence (AI) services and products pose major ethical concerns for multinational companies as evidenced by the prevalence of unfair, biased, and discriminate AI systems. Examples including Amazon’s recruiting tool, Facebook’s biased ads, and racially biased healthcare risk algorithms have raised fundamental questions about what these systems should be used for, the inherent risks they possess, and how they can be mitigated. Unfortunately, these failures not only serve to highlight the lack of regulation in AI development, but it also reveals how organisations are struggling to alleviate the dangers associated with this technology. We argue that to successfully implement ethical AI applications, developers need a deeper understanding of not only the implications of misuse, but also a grounded approach in their conception. Judgement studies were therefore conducted with experts from data science backgrounds who identified six performance areas, resulting in a theoretical framework for the development of ethically aligned AI systems. This framework also reveals that these performance areas require specific mechanisms which must be acted upon to ensure that an AI system implements and meets ethical requirements throughout its lifecycle. The findings also outline several constraints which present challenges in the manifestation of these elements. By implementing this framework, organisations can contribute to an elevated trust between technology and people resulting in significant implications for both IS research and practice. This framework will further allow organisations to take a positive and proactive approach in ensuring they are best prepared for the ethical implications associated with the development, deployment and use of AI systems.

BackgroundHyaluronidase (Hyal) can reverse complications of hyaluronic acid (HA) fillers, which has contributed substantially to the popularity of such procedures. Still, there are differing opinions regarding Hyal treatment, including dosage recommendations in filler complication management. ObjectiveWe aimed to address unanswered questions regarding Hyal treatment for HA filler complications, including timing and dosage, skin pretesting, properties of various Hyals and interactions with HA gels, and pitfalls of the treatment. MethodsPubMed and Google Scholar databases were searched from inception for articles on Hyal therapy for filler complications. Articles were evaluated regarding their contribution to the field. The extensive literature review includes international leaders’ suggestions and expert panels’ recommendations. ResultsThere are limited controlled data but increasing clinical experience with Hyal treatment. The currently used Hyals provide good results and have an acceptable safety profile. Nonemergent complications such as the Tyndall effect, noninflamed nodules, and allergic or hypersensitivity reactions should be treated with low or moderate Hyal doses. Hyal should be considered with prior or simultaneous oral antibiotic treatment in managing inflammatory nodules. Hyal may be tried for granulomas that have not responded to intralesional steroids. Emergent complications such as vascular occlusion and blindness require immediate, high-dose Hyal treatment. Regarding blindness, the injection technique, retrobulbar versus supraorbital, remains controversial. Ultrasound guidance can increase the efficacy of the above interventions. ConclusionsHyal is essential in aesthetic practice because it can safely treat most HA filler complications. Immediate Hyal treatment is required for emergent complications. Aesthetic practitioners should be versed in using Hyal and effective dosage protocols.

Herein we disclose an iron-catalyzed method to access skeletal rearrangement reactions akin to the Dowd-Beckwith ring expansion from unactivated C(sp3)-H bonds. Photoinduced ligand-to-metal charge transfer at the iron center generates a chlorine radical, which abstracts electron-rich C(sp3)-H bonds. The resulting unstable alkyl radicals can undergo rearrangement in the presence of suitable functionality. Addition to an electron deficient olefin, recombination with a photoreduced iron complex, and subsequent protodemetallation allows for redox-neutral alkylation of the resulting radical. Simple adjustments to the reaction conditions enable the selective synthesis of the directly alkylated or the rearranged-alkylated products. As a radical clock, these rearrangements also enable the measurement of rate constants of addition into various electron deficient olefins in the Giese reaction.

The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.

Abstract Background People with mobility limitations can benefit from rehabilitation programs incorporating intensive, repetitive, and task-specific exercises using digital devices such as virtual reality gaming systems, tablet and smartphone applications, and wearable devices. The Activity and MObility UsiNg Technology (AMOUNT) rehabilitation trial (n = 300) showed improvements in mobility in people using these types of digital devices in addition to their usual rehabilitation care when the intervention was provided by an additional study-funded physiotherapist. However, it is not clear if this intervention can be implemented by hospital physiotherapists with a usual clinical load. The AMOUNT Implementation trial aims to explore the feasibility of conducting a large-scale implementation trial. Methods A pragmatic, assessor blinded, feasibility hybrid type II randomized controlled trial will be undertaken at a public hospital in Australia. There will be two phases. Phase I (Implementation phase) will involve implementing the digital devices into physiotherapy practice. Physiotherapists from the rehabilitation ward will receive a multifaceted implementation strategy guided by the Capabilities, Opportunities, Motivation-Behaviour (COM-B) theoretical model. The implementation strategy includes identifying and training a clinical champion; providing digital devices and education and training; facilitating use of the devices through clinical reasoning sessions and journal clubs; and audit and feedback of exercise dosage documentation. Phase II (Trial phase) will involve randomising 30 eligible inpatients from the same ward into either usual care or usual care plus an additional 30 min or more of exercises using digital devices. This intervention will be provided by the physiotherapists who took part in the implementation phase. We will collect data on feasibility, implementation, and patient-level clinical outcomes. The three primary outcome measures are the extent to which physiotherapists document the dosage of exercises provided to participants (feasibility criteria: exercise practice sheets complete for ≥85% of all participants); ability to recruit participants; and fidelity to the protocol of using digital devices to prescribe exercises (feasibility criteria: average of ≥ 30mins per day for > 50% intervention participants). Discussion This feasibility study will provide important information to guide the planning and conduct of a future large-scale implementation trial. Trial registration Australian and New Zealand Clinical Trial Registry; ACTRN12621000938808; registered 19/07/2021. Trial sponsor: Prince of Wales Hospital. 320–346 Barker Street, Randwick, NSW, 2031, Australia. Protocol version: 6.2 7th April 2021.

Electrophilic borylation of sterically hindered arenes is a challenging transformation. Here, authors report a metal-free electrophilic C–H borylation of hindered arenes using a boron cluster reagent producing valuable aryl boronic esters.

Human induced pluripotent stem cell (hiPSC)-derived kidney organoids have prospective applications ranging from basic disease modelling to personalised medicine. However, there remains a necessity to refine the biophysical and biochemical parameters that govern kidney organoid formation. Differentiation within fully-controllable and physiologically relevant 3D growth environments will be critical to improving organoid reproducibility and maturation. Here, we matured hiPSC-derived kidney organoids within fully synthetic self-assembling peptide hydrogels (SAPHs) of variable stiffness (storage modulus, G′). The resulting organoids contained complex structures comparable to those differentiated within the animal-derived matrix, Matrigel. Single-cell RNA sequencing (scRNA-seq) was then used to compare organoids matured within SAPHs to those grown within Matrigel or at the air-liquid interface. A total of 13,179 cells were analysed, revealing 14 distinct clusters. Organoid compositional analysis revealed a larger proportion of nephron cell types within Transwell-derived organoids, while SAPH-derived organoids were enriched for stromal-associated cell populations. Notably, differentiation within a higher G’ SAPH generated podocytes with more mature gene expression profiles. Additionally, maturation within a 3D microenvironment significantly reduced the derivation of off-target cell types, which are a known limitation of current kidney organoid protocols. This work demonstrates the utility of synthetic peptide-based hydrogels with a defined stiffness, as a minimally complex microenvironment for the selected differentiation of kidney organoids.

Zinc is an essential cofactor for bacterial metabolism, and many Enterobacteriaceae express the zinc transporters ZnuABC and ZupT to acquire this metal in the host. However, the probiotic bacterium Escherichia coli Nissle 1917 (or "Nissle") exhibits appreciable growth in zinc-limited media even when these transporters are deleted. Here, we show that Nissle utilizes the siderophore yersiniabactin as a zincophore, enabling Nissle to grow in zinc-limited media, to tolerate calprotectin-mediated zinc sequestration, and to thrive in the inflamed gut. We also show that yersiniabactin's affinity for iron or zinc changes in a pH-dependent manner, with increased relative zinc binding as the pH increases. Thus, our results indicate that siderophore metal affinity can be influenced by the local environment and reveal a mechanism of zinc acquisition available to commensal and pathogenic Enterobacteriaceae.