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OBJECTIVES: To identify models for senior mentor programs (SMPs), critical factors in program development, achievement of goals and objectives, effect on medical school environment, and future of programs. DESIGN: Ten SMPs were systematically selected to represent a variety of medical schools, geographic regions, and program types. The National Senior Mentor Program Evaluation relied upon archived data within the programs and new data collected during site visits. Archived data included internally conducted program evaluations, student course evaluations, and survey and focus group results. Site visit data were collected from key informant interviews with program staff and faculty, medical school leadership and students, and older adults serving as mentors. SETTING: Ten U.S. medical schools with SMPs. PARTICIPANTS: Evaluation participants at each site included program faculty, key medical school administrators, participating students, and mentors. MEASUREMENTS: Program evaluation. RESULTS: All 10 programs demonstrated a positive effect on student attitudes toward older adults. Student acceptance of the programs was strong, and mentor acceptance and support were extraordinary. Eight of the 10 programs were operating in 2008 and having considerable effect on medical school environments. Most of the operating programs expect to be continuing for 5 or more years into the future. CONCLUSIONS: The findings of the national evaluation point toward continuation and likely growth of the senior mentor phenomenon in U.S. medical education. [ABSTRACT FROM AUTHOR]

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, severe cutaneous adverse reactions that result in in-hospital death in 12-49% of cases. The severity-of-illness score for toxic epidermal necrolysis (SCORTEN) is the most widely used mortality prognosis score; however, it has been shown to have critical limitations. Other mortality predictors not incorporated in SCORTEN or other predictor tools are being increasingly reported. This systematic review and meta-analysis aimed to synthesize and evaluate the predictors of mortality in adults with Stevens-Johnson syndrome and toxic epidermal necrolysis not included in SCORTEN. It was registered with the International Platform of Registered Systematic Review and Meta-Analysis Protocols (INPLASY) and conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines. Potential bias was assessed using the National Institutes of Health (NIH) criteria. Forty articles describing results from 52,398 cases were included. Sixteen predictors were reported in five or more articles, and thirty-three were reported in two to four articles. Meta-analysis showed preexisting renal disease (odds ratio (OR): 3.14, 95% confidence interval (CI): 1.99-4.97, P < 0.0001, I 2  = 21%), renal involvement (OR: 5.62, 95% CI: 2.29-13.77, P = 0.0002, I 2  = 36%), respiratory involvement (OR: 3.14, 95% CI: 1.25-7.92, P = 0.015, I 2  = 66%), diabetes mellitus (OR: 1.87, 95% CI: 1.21-2.89, P = 0.005, I 2  = 19%), sepsis (OR: 5.64, 95% CI: 2.81-11.29, P < 0.0001, I 2  = 63%), comorbidity (OR: 9.13, 95% CI: 4.60-18.12, P < 0.0001, I 2  = 0%), and time to hospitalization (OR: 2.56, 95% CI: 1.15-5.65, P = 0.021, I 2  = 93) increased risk of mortality. This systematic review and meta-analysis support several clinical and laboratory parameters not included in SCORTEN (preexisting renal disease, renal involvement, respiratory involvement, diabetes mellitus, sepsis, comorbidities, and time to hospitalization) as predictors of mortality in adults with SJS/TEN. The future utilization of these factors may improve mortality prognostication in adults with SJS/TEN., (© 2024 the International Society of Dermatology.)

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare severe cutaneous adverse reactions to medications characterized by keratinocyte necrosis leading to loss of protective barrier function and increased susceptibility to infection. Infection is a major cause of morbidity, and septicemia is the leading cause of mortality in this population. This systematic review and meta-analysis aimed to determine infectious complications' prevalence and risk factors in adults with SJS and TEN. This review was registered with the International Platform of Registered Systematic Review and Meta-Analysis Protocols (INPLASY) and conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines. Thirty-six articles describing results from 1446 cases were included. Skin infection was the most commonly diagnosed infection. The pooled prevalence of sepsis, respiratory tract infection, skin infection, and urinary tract infection was 27.3%, 21.5%, 37.5%, and 21.8%, respectively. Staphylococcus aureus was the most commonly identified organism. The overall quality of the studies was suboptimal, and the level of heterogeneity was high. The skin, bloodstream, respiratory, and urinary tracts are most commonly infected in the course of adult SJS and TEN. During hospitalization, clinicians should closely monitor and promptly investigate for these as well as several other infectious complications. More research is needed, with greater attention to the risk factors and causative organisms that cause these infections., (© 2024 the International Society of Dermatology.)

The use of diagenetic alterations in bone microstructure ('histotaphonomy') as indicators of funerary treatment in the past and for post-mortem interval calculations in forensic cases has received increasing attention in the last decade. Studies have used histological changes to conclude in-situ decomposition, mummification, infanticide and post-mortem interval. There has been very little attempt to experimentally validate the links between decomposition, depositional conditions, time-since-death and microscopic changes in human bone so that meaningful interpretations of archaeological and forensic observations can be made. Here, we address this problem experimentally using the largest sample of human remains from anatomical donors and the longest-term deposition framework to date. This study tests one key assumption of histotaphonomy; that putrefaction during the early stages of decay is reflected in bone microanatomy and composition. Seventeen human donors and six pigs were deposited on the surface in a known Australian environment and left to decompose between 463 and 1238 days. All remains underwent all stages of decomposition reaching skeletonisation. Rib and femur samples were analysed using conventional histological methods and scanning electron microscopy, by applying the Oxford Histological Index, and examining collagen birefringence, microcracking and re- and de mineralisation. Biomolecular changes of the femoral samples were analysed using Fourier-transform infrared (FTIR) spectroscopy. The results indicate that bioerosion in human bone does not occur due to putrefaction. There were no correlations between bone histology and the following variables: human vs pigs, season, primary vs secondary deposition, position, fresh vs frozen and time-since-deposition. Furthermore, no trends were observed between biomolecular changes and time-since-deposition. The study also shows that pigs cannot be used as substitutes for human remains for bone biodegradation research. This is the first, controlled, larger scale study of human remains providing a lack of support for a long-assumed relationship between putrefaction and bone histology bioerosion. Using bone degradation as an argument to prove putrefaction, in-situ decomposition and early taphonomic processes cannot be supported based on the experimental human data presented., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Schotsmans et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions characterised by keratinocyte apoptosis, necroptosis and epidermal detachment. Several cytokines and cytotoxic proteins have been shown to be elevated in the blood and skin of SJS/TEN sufferers and biologics such as intravenous immune globulin and tumour necrosis factor (TNF)-alpha inhibitors have demonstrated good therapeutic potential. The exact pathogenic model of SJS/TEN however remains elusive. This systematic review aimed to evaluate the case-control studies of cytokines and cytotoxic proteins in the blister fluid and skin of adults with Stevens Johnson syndrome and/or toxic epidermal necrolysis. This review was registered with INPLASY and conducted in accordance with the PRISMA reporting guidelines. Potential bias was assessed using the NIH criteria. Eleven articles describing results from 96 cases and 170 controls were included. Fas, Fas ligand, Interleukin (IL)-8 and B-cell lymphoma (Bcl)-2 were elevated in SJS/TEN blister fluid and skin tissue, compared with healthy controls. IL-2, IL-6, TNF-alpha, tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), interferon-gamma and matrix metalloproteinase-2 were elevated in SJS/TEN blister fluid compared with fluid sampled from lesional controls. Granulysin, IL-33, TGF-beta-1 and IL-13 were elevated in SJS/TEN skin tissue compared with lesional lichen planus tissue, as was IL-13, IFN-gamma, IL-2 and IL-5, when compared with erythema multiforme tissue. A wide array of cytokines and cytotoxic proteins are present at higher concentrations in the blister fluid and skin tissue of SJS/TEN patients compared with healthy and lesional controls. Our findings suggest that these proteins may be pathogenic, as well as possibly markers for diagnosis, disease severity and course. They may also prove to be useful therapeutic targets. More research is needed., (© 2024 The Author(s). Australasian Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Australasian College of Dermatologists.)

For American Indians and Alaska Native (AIAN) and other communities of color, experiences with discrimination and historical trauma may contribute to healthcare system distrust and negatively affect health care decisions, including vaccination. A saturated path analysis was conducted to examine the direct and indirect associations of thoughts regarding historical losses (of culture, language, and traditional ways) and AIAN racial discrimination with historical loss associated distress, healthcare system distrust, and COVID-19 vaccine hesitancy among AIAN college students (N = 391). Historical loss thoughts and experiences with racial discrimination were strongly associated with each other, and both were uniquely associated with greater historical loss associated distress. In turn, historical loss associated distress was associated with greater healthcare system distrust, which in turn was associated with greater likelihood of being COVID-19 vaccine hesitant. While further research is needed, the findings suggest that to address health disparities for AIAN people it is necessary to consider how to best overcome healthcare system distrust and factors that contribute to it, including historical trauma and contemporary experiences with discrimination., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: In the American Indian and Alaska Native (AIAN) population there is a discrepancy between high rates of mental health needs and low utilization rates of mental health services. This study sought to explore whether historical trauma and racial discrimination are associated with health care system (HCS) distrust and negative attitudes toward seeking mental health services., Method: Participants were AIAN college students ( n = 392) who completed a cross-sectional online survey. A sequential mediation analysis examined whether historical trauma (thoughts and associated symptoms) was associated with less favorable attitudes toward seeking mental health services, and whether distrust of the HCS mediated this association. A second mediation analysis examined whether perceived racial discrimination was associated with less favorable attitudes toward seeking mental health services, and whether distrust of the HCS mediated this association., Results: Greater reported historical trauma (thoughts and associated symptoms) and racial discrimination were associated with greater distrust of the HCS, which in turn was associated with less favorable attitudes toward seeking mental health services. Perceived racial discrimination was also directly associated with less favorable attitudes toward seeking mental health services., Conclusion: Historical trauma and perceived racial discrimination appear to contribute to less favorable attitudes toward seeking mental health services through their association with distrust of the HCS. This suggests that attempts to address the underutilization of mental health services in the AIAN population should consider the potential roles of historical trauma, racial discrimination, and distrust. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Introduction: Common variants in the SLC30A8 gene, encoding the secretory granule zinc transporter ZnT8 (expressed largely in pancreatic islet alpha and beta cells), are associated with altered risk of type 2 diabetes. Unexpectedly, rare loss-of-function (LoF) variants in the gene, described in heterozygous individuals only, are protective against the disease, even though knockout of the homologous SLC30A8 gene in mice leads to unchanged or impaired glucose tolerance. Here, we aimed to determine how one or two copies of the mutant R138X allele in the mouse SLC30A8 gene impacts the homeostasis of zinc at a whole-body (using non-invasive 62 Zn PET imaging to assess the acute dynamics of zinc handling) and tissue/cell level [using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) to map the long-term distribution of zinc and manganese in the pancreas]., Methods: Following intravenous administration of [ 62 Zn]Zn-citrate (~7 MBq, 150 μl) in wild-type (WT), heterozygous (R138X +/- ), and homozygous (R138X +/+ ) mutant mice (14-15 weeks old, n = 4 per genotype), zinc dynamics were measured over 60 min using PET. Histological, islet hormone immunohistochemistry, and elemental analysis with LA-ICP-MS (Zn, Mn, P) were performed on sequential pancreas sections. Bulk Zn and Mn concentration in the pancreas was determined by solution ICP-MS., Results: Our findings reveal that whereas uptake into organs, assessed using PET imaging of 62 Zn, is largely unaffected by the R138X variant, mice homozygous of the mutant allele show a substantial lowering (to 40% of WT) of total islet zinc, as anticipated. In contrast, mice heterozygous for this allele, thus mimicking human carriers of LoF alleles, show markedly increased endocrine and exocrine zinc content (1.6-fold increase for both compared to WT), as measured by LA-ICP-MS. Both endocrine and exocrine manganese contents were also sharply increased in R138X +/- mice, with smaller increases observed in R138X +/+ mice., Discussion: These data challenge the view that zinc depletion from the beta cell is the likely underlying driver for protection from type 2 diabetes development in carriers of LoF alleles. Instead, they suggest that heterozygous LoF may paradoxically increase pancreatic β-cell zinc and manganese content and impact the levels of these metals in the exocrine pancreas to improve insulin secretion., Competing Interests: Authors HO and DG are employees of the company Regeneron. GR has received grant funding from and is a consultant for Sun Pharmaceuticals Inc.; however, Sun Pharmaceuticals Inc. was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Firth, Georgiadou, Griffiths, Amrahli, Kim, Yu, Hu, Stewart, Leclerc, Okamoto, Gomez, Blower and Rutter.)

The bioavailability of metal complexes is poorly understood. To evaluate bioavailability and toxicity of neutral and charged complexes as well as free metal ions, Visual Minteq, a chemical equilibrium model, was used to design media containing different metal species. Two non-essential (silver and cadmium) and two essential (copper and zinc) metals were selected. The rainbow trout (Oncorhynchus mykiss) gut cell line (RTgutGC) was used to investigate bioavailability, bioreactivity and toxicity of the different metal species. Toxicity was measured using a multiple endpoint cytotoxicity assay, bioavailability by measuring intracellular metal concentration, and bioreactivity by quantification of mRNA level of the metal responsive genes, metallothionein (MT), glutathione reductase (GR) and zinc transporter 1 (ZnT1). Speciation calculations showed that silver and cadmium preferentially bind chloride, copper phosphate and bicarbonate, and zinc remained primarily as a free ion. Cysteine avidly complexed with all metals reducing toxicity, bioavailability and bioreactivity. Silver and copper toxicity was not affected by inorganic metal speciation, whereas cadmium and zinc toxicity was decreased by chloride complexation. Moreover, reduction of calcium concentration in the medium increased toxicity and bioavailability of cadmium and zinc. Bioavailability of silver and zinc was reduced by low chloride while cadmium bioavailability was increased by low chloride and in presence of bicarbonate. Copper bioavailability was not affected by the medium composition. Cadmium and silver were more bioreactive, independently from the medium composition, in comparison to copper and zinc (i.e., higher induction of MT and GR). Cadmium was the only metal able to induce MT in presence of cysteine. ZnT1 was induced by cadmium in low-chloride, by zinc in low-chloride low-calcium and by cadmium and copper in the bicarbonate media. Overall, this study demonstrates that metal complexation alone is not sufficient to explain metal toxicity, and that anion exchange mechanisms play a role in metal uptake and bioreactivity., Competing Interests: Declaration of Competing Interest The authors have no known conflict of interest that could have influenced the reporting of data in this article., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Molecular motors such as kinesin and myosin often work in groups to generate the directed movements and forces critical for many biological processes. Although much is known about how individual motors generate force and movement, surprisingly, little is known about the mechanisms underlying the macroscopic mechanics generated by multiple motors. For example, the observation that a saturating number, N, of myosin heads move an actin filament at a rate that is influenced by actin-myosin attachment and detachment kinetics is accounted for neither experimentally nor theoretically. To better understand the emergent mechanics of actin-myosin mechanochemistry, we use an in vitro motility assay to measure and correlate the N-dependence of actin sliding velocities, actin-activated ATPase activity, force generation against a mechanical load, and the calcium sensitivity of thin filament velocities. Our results show that both velocity and ATPase activity are strain dependent and that velocity becomes maximized with the saturation of myosin-binding sites on actin at a value that is 40% dependent on attachment kinetics and 60% dependent on detachment kinetics. These results support a chemical thermodynamic model for ensemble motor mechanochemistry and imply molecularly explicit mechanisms within this framework, challenging the assumption of independent force generation., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Metals and metalloids are integral to biological processes and play key roles in physiology and metabolism. Nonetheless, overexposure to some metals or lack of others can lead to serious health consequences. In this study, eight zebrafish facilities collaborated to generate a multielement analysis of their centralized recirculating water systems. We report a first set of average concentrations for 46 elements detected in zebrafish facilities. Our results help to establish an initial baseline for trouble-shooting purposes, and in general for safe ranges of metal concentrations in recirculating water systems, supporting reproducible scientific research outcomes with zebrafish.

Succinate dehydrogenase is a key enzyme in the tricarboxylic acid cycle and the electron transport chain. All four subunits of succinate dehydrogenase are tumor suppressor genes predisposing to paraganglioma, but only mutations in the SDHB subunit are associated with increased risk of metastasis. Here we generated an Sdhd knockout chromaffin cell line and compared it with Sdhb- deficient cells. Both cell types exhibited similar SDH loss of function, metabolic adaptation, and succinate accumulation. In contrast, Sdhb -/- cells showed hallmarks of mesenchymal transition associated with increased DNA hypermethylation and a stronger pseudo-hypoxic phenotype compared with Sdhd -/- cells. Loss of SDHB specifically led to increased oxidative stress associated with dysregulated iron and copper homeostasis in the absence of NRF2 activation. High-dose ascorbate exacerbated the increase in mitochondrial reactive oxygen species, leading to cell death in Sdhb -/- cells. These data establish a mechanism linking oxidative stress to iron homeostasis that specifically occurs in Sdhb -deficient cells and may promote metastasis. They also highlight high-dose ascorbate as a promising therapeutic strategy for SDHB-related cancers. SIGNIFICANCE: Loss of different succinate dehydrogenase subunits can lead to different cell and tumor phenotypes, linking stronger 2-OG-dependent dioxygenases inhibition, iron overload, and ROS accumulation following SDHB mutation., (©2021 American Association for Cancer Research.)

Mucin-type O-glycosylation occurs on many proteins that transit the Golgi apparatus. These glycans impact structure and function of many proteins and have important roles in cellular biosynthetic processes, signaling and differentiation. Although recent technological advances have enhanced our ability to profile glycosylation of glycoproteins, limitations in the understanding of the biosynthesis of these glycan structures remain. Some of these limitations stem from the difficulty to track the biosynthetic process of mucin-type O-glycosylation, especially when glycans occur in dense clusters in repeat regions of proteins, such as the mucins or immunoglobulin A1 (IgA1). Here, we describe a series of nano-liquid chromatography (LC)-mass spectrometry (MS) analyses that demonstrate the range of glycosyltransferase enzymatic activities involved in the biosynthesis of clustered O-glycans on IgA1. By utilizing nano-LC-MS relative quantitation of in vitro reaction products, our results provide unique insights into the biosynthesis of clustered IgA1 O-glycans. We have developed a workflow to determine glycoform-specific apparent rates of a human UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltrasnfersase (GalNAc-T EC 2.4.1.41) and demonstrated how pre-existing glycans affect subsequent activity of glycosyltransferases, such as core 1 galactosyltransferase and α2,3- and α2,6-specific sialyltransferases, in successive additions in the biosynthesis of clustered O-glycans. In the context of IgA1, these results have potential to provide insight into the molecular mechanisms implicated in the pathogenesis of IgA nephropathy, an autoimmune renal disease involving aberrant IgA1 O-glycosylation. In a broader sense, these methods and workflows are applicable to the studies of the concerted and competing functions of other glycosyltransferases that initiate and extend mucin-type core 1 clustered O-glycosylation., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Human ribs are thought to be less affected by mechanical strain at the microscopic level than limb bones, implying that rib remodelling better reflects bone physiological homeostasis. Here, we test the hypothesis that rib tissue will be well vascularized and thus enhance susceptibility to metabolic influence. An intra-skeletal comparison of bone vascular canal density was conducted using a macropod animal model adapted to bipedal habitual hopping. The right humerus, ulna, radius, femur, tibia, fibula, a mid-thoracic and upper-thoracic rib of an eastern grey kangaroo (Macropus giganteus) were sectioned at the midshaft, from which histological sections were prepared. Bone vascularity from a maximum of 12 mm 2  of sub-periosteal parallel-fibred and lamellar bone was recorded, resulting in a total of 2047 counted vessels. Vascular canal density data were corrected by cortical width, maximum length, and midshaft circumference robusticity indices computed for each bone. The fibula consistently had the highest vascular canal density, even when corrected for maximum length, cortical width and midshaft circumference robusticities. This was followed by the mid- and upper-thoracic ribs. Vascularity differences between bones were relatively consistent whether vascular canal density was controlled for by cortical width or midshaft circumference robusticities. Vascular canal density and robusticity indices were also positively and negatively correlated (p < 0.05). Results confirm that the ribs are well vascularized, which facilitates bone metabolic processes such as remodelling, but the fibula also appears to be a well vascularized bone. Future research investigating human bone metabolism will benefit from examining thoracic rib or fibula samples.

Background: As the availability of Mohs micrographic surgery (MMS) continues to expand in Australia and incidence of keratinocyte cancer increases in adolescents and young adults, there has been rising interest in the use of MMS in this population., Objective: This study aimed to evaluate the characteristics of MMS cases in patients younger than 40 years., Methods: A review was performed of all MMS cases in patients younger than 40 years at the time of their surgery from 2012 to 2017 at the Skin and Cancer Foundation Australia, with comparison to a control group, aged older than 40 years. Patient, tumor and management characteristics were analyzed., Results: Four hundred ninety-three cases were eligible. Study and control groups differed significantly regarding gender (p < .001), tumor pathology (p < .001), anatomic site of tumor (p < .001), Mohs surgery stages (p = .039), defect size (p < .001), and repair method (p < .001)., Limitations: Retrospective study at a single institution., Conclusion: Mohs micrographic surgery cases in patients younger than 40 years exhibit unique patient and tumor characteristics influencing choice of repair method.

Background: The availability of Mohs micrographic surgery (MMS) in Australia has increased dramatically since its inception in the 1980s., Objective: This study aimed to describe the evolution of MMS practices at the Skin and Cancer Foundation Australia (SCFA) over the past 20 years (1997-2017)., Methods: Retrospective analysis of Mohs surgery cases at SCFA in 2017, 2007, and 1997, comparing data on sex, age, tumor type and site, initial tumor and final defect size, number of surgical stages and sections, and closure management. The present study is limited by being a retrospective analysis from a single institution., Results: There was a 415% increase in the number of Mohs surgery cases from 1997 to 2017, and a significant increase in Mohs surgery-treated squamous cell carcinoma. The preoperative tumor and final defect size have decreased. More side-to-side closures and fewer grafts are being performed over time., Limitations: Retrospective analysis from a single institution., Conclusion: Over the last 20 years, MMS has remained appropriate in its application and is being increasingly used for treatment of squamous cell carcinoma suggesting improved access.

GalNAc-type O-glycans are often added to proteins post-translationally in a clustered manner in repeat regions of proteins, such as mucins and IgA1. Observed IgA1 glycosylation patterns show that glycans occur at similar sites with similar structures. It is not clear how the sites and number of glycans added to IgA1, or other proteins, can follow a conservative process. GalNAc-transferases initiate GalNAc-type glycosylation. In IgA nephropathy, an autoimmune disease, the sites and O-glycan structures of IgA1 hinge-region are altered, giving rise to a glycan autoantigen. To better understand how GalNAc-transferases determine sites and densities of clustered O-glycans, we used IgA1 hinge-region (HR) segment as a probe. Using LC-MS, we demonstrated a semi-ordered process of glycosylation by GalNAc-T2 towards the IgA1 HR. The catalytic domain was responsible for selection of four initial sites based on amino-acid sequence recognition. Both catalytic and lectin domains were involved in multiple second site-selections, each dependent on initial site-selection. Our data demonstrated that multiple start-sites and follow-up pathways were key to increasing the number of glycans added. The lectin domain predominately enhanced IgA1 HR glycan density by increasing synthesis pathway exploration by GalNAc-T2. Our data indicated a link between site-specific glycan addition and clustered glycan density that defines a mechanism of how conserved clustered O-glycosylation patterns and glycoform populations of IgA1 can be controlled by GalNAc-T2. Together, these findings characterized a correlation between glycosylation pathway diversity and glycosylation density, revealing mechanisms by which a single GalNAc-T isozyme can limit and define glycan heterogeneity in a disease-relevant context., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The glycome describes the complete repertoire of glycoconjugates composed of carbohydrate chains, or glycans, that are covalently linked to lipid or protein molecules. Glycoconjugates are formed through a process called glycosylation and can differ in their glycan sequences, the connections between them and their length. Glycoconjugate synthesis is a dynamic process that depends on the local milieu of enzymes, sugar precursors and organelle structures as well as the cell types involved and cellular signals. Studies of rare genetic disorders that affect glycosylation first highlighted the biological importance of the glycome, and technological advances have improved our understanding of its heterogeneity and complexity. Researchers can now routinely assess how the secreted and cell-surface glycomes reflect overall cellular status in health and disease. In fact, changes in glycosylation can modulate inflammatory responses, enable viral immune escape, promote cancer cell metastasis or regulate apoptosis; the composition of the glycome also affects kidney function in health and disease. New insights into the structure and function of the glycome can now be applied to therapy development and could improve our ability to fine-tune immunological responses and inflammation, optimize the performance of therapeutic antibodies and boost immune responses to cancer. These examples illustrate the potential of the emerging field of 'glycomedicine'.

This chapter explores the concept of bridge leadership within the context of student activism and student activist leadership on college campuses. This work seeks to uncover certain types of leadership that can often be rendered invisible in social movement spaces., (© 2019 Wiley Periodicals, Inc.)

To know how much of a metal species is in a particular location within a biological context at any given time is essential for understanding the intricate roles of metals in biology and is the fundamental question upon which the field of metallomics was born. Simply put, seeing is powerful. With the combination of spectroscopy and microscopy, we can now see metals within complex biological matrices complemented by information about associated molecules and their structures. With the addition of mass spectrometry and particle beam based techniques, the field of view grows to cover greater sensitivities and spatial resolutions, addressing structural, functional and quantitative metallomic questions from the atomic level to whole body processes. In this perspective, I present a paradigm shift in the way we relate to and integrate current and developing metallomic analytics, highlighting both familiar and perhaps less well-known state of the art techniques for in situ metallomic imaging, specific biological applications, and their use in correlative studies. There is a genuine need to abandon scientific silos and, through the establishment of a metallomic scientific platform for further development of multidimensional analytics for in situ metallomic imaging, we have an incredible opportunity to enhance the field of metallomics and demonstrate how discovery research can be done more effectively.

Psoriasis is estimated to affect around 2-3% of the general population. More than one-third of Australians report having a significant level of distress in their daily lives. Psychological stress has long been shown to play an important role in the natural history of psoriasis, but the details of this relationship remain to be clearly defined. We performed a systematic review of the literature with the aim of determining whether there is a temporal association between psychological stress as the predictor and onset and/or exacerbation of psoriasis as the outcome measure. Our secondary aim was to establish whether there is a relationship between the degree of psychological stress and clinical severity of psoriasis. Our systematic review demonstrates a probable temporal association between different measures of psychological stress and onset, recurrence, and severity of psoriasis. In the light of this, we suggest clinicians include "stress" as a trigger factor in their psoriasis assessment and consider psychological interventions as adjuncts, particularly in those who identify as "stress-responders"., (© 2018 The International Society of Dermatology.)

Background and Objectives: The standard treatment for cutaneous squamous cell carcinoma (cSCC) is wide local excision (WLE). Incomplete tumor excision is associated with increased recurrence rates and mortality risk. Risk factors for positive margins after WLE of cSCC has been examined in only a few studies. We sought to assess the influence of several clinicopathological factors on margin status in the largest cSCC population to date., Methods: We performed a retrospective review of records at two skin cancer clinics identifying patients with biopsy-proven cSCC who underwent WLE. We mined clinicopathological information for eligible subjects including age, gender, lesion location, immunosuppression, previous treatment, lesion size, biopsy type, tumor subtype, tumor thickness, degree of differentiation, ulceration and perineural invasion., Results: A total of 1468 patients were eligible and 117 (8%) had positive margins after WLE. Older age at diagnosis (p = .011), lesion location on the head and neck (p < .001), previous treatment (p < .001), increased lesion diameter (p < .001), invasive subtype (p = .020) or increased tumor thickness (p < .001) were statistically significant risk factors for positive surgical margins., Conclusions: Our results present an opportunity to stratify cSCC patients into low- or high-risk for incomplete tumor clearance after WLE based on several clinicopathological factors. These findings should educate and inform the dermatologic surgeon's choice of primary management of cSCC.

Early identification of treatment needs in incarcerated individuals with serious mental illness has significant implications. Validated assessment instruments to guide treatment are lacking in correctional settings. Hierarchical linear modeling was used to examine the predictive validity of the Level of Care Index (LOCI) in 35 inmates admitted to a specialized treatment unit. The LOCI score was predictive of levels of depressogenic psychopathology and psychological well-being as well as changes in these constructs over time. These results validate the use of the LOCI in a correctional setting and demonstrate the utility of the LOCI to identify treatment trajectories.

Background : Acne vulgaris is an inflammatory skin disorder with not as yet fully understood pathogenesis. In this controlled study, we assessed acne vulgaris patients for several possible pathogenic factors such as vitamin D deficiency, vegan diet, increased body mass index (BMI) and positive anti-transglutaminase antibody. Methods : We screened 10 years of records at a family medicine clinic for patients diagnosed with acne vulgaris. In eligible subjects, we collected data regarding 25-hydroxylvitamin D levels, BMI, dietary preference and serum IgA tissue transglutaminase levels. Controls were age- (+/- 12 months) and sex-matched patients seen during the study period without a diagnosis of acne vulgaris. Results : 453 patients were given a diagnosis of acne vulgaris during the study period. Compared with controls, we found significant associations between vitamin D deficiency (<50nmol/L), and/or positive transglutaminase antibody level (>4.0U/mL) and a diagnosis of acne vulgaris. Conclusions : Our study adds important information to the current body of literature in pursuit of elucidating the pathogenesis of this complex multifactorial disease.

Evidence of a periodic biorhythm is retained in tooth enamel in the form of Retzius lines. The periodicity of Retzius lines (RP) correlates with body mass and the scheduling of life history events when compared between some mammalian species. The correlation has led to the development of the inter-specific Havers-Halberg oscillation (HHO) hypothesis, which holds great potential for studying aspects of a fossil species biology from teeth. Yet, our understanding of if, or how, the HHO relates to human skeletal growth is limited. The goal here is to explore associations between the biorhythm and two hard tissues that form at different times during human ontogeny, within the context of the HHO. First, we investigate the relationship of RP to permanent molar enamel thickness and the underlying daily rate that ameloblasts secrete enamel during childhood. Following this, we develop preliminary research conducted on small samples of adult human bone by testing associations between RP, adult femoral length (as a proxy for attained adult stature) and cortical osteocyte lacunae density (as a proxy for the rate of osteocyte proliferation). Results reveal RP is positively correlated with enamel thickness, negatively correlated with femoral length, but weakly associated with the rate of enamel secretion and osteocyte proliferation. These new data imply that a slower biorhythm predicts thicker enamel for children but shorter stature for adults. Our results develop the intra-specific HHO hypothesis suggesting that there is a common underlying systemic biorhythm that has a role in the final products of human enamel and bone growth., (© 2017 Anatomical Society.)