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Health services research is underpinned by partnerships between researchers and health services. Partnership-based research is increasingly needed to deal with the uncertainty of global pandemics, climate change induced severe weather events, and other disruptions. To date there is very little data on what has happened to health services research during the COVID-19 pandemic. This paper describes the establishment of an Australian multistate Decolonising Practice research project and charts its adaptation in the face of disruptions. The project used cooperative inquiry method, where partner health services contribute as coresearchers. When the COVID-19 pandemic hit, data collection needed to be immediately paused, and when restrictions started to lift, all research plans had to be renegotiated with services. Adapting the research surfaced health service, university, and staffing considerations. Our experience suggests that cooperative inquiry was invaluable in successfully navigating this uncertainty and negotiating the continuance of the research. Flexible, participatory methods such as cooperative inquiry will continue to be vital for successful health services research predicated on partnerships between researchers and health services into the future. They are also crucial for understanding local context and health services priorities and ways of working, and for decolonising Indigenous health research.

Several national governments are showing interest in policies to promote wellbeing. One common strategy is to devise systems to measure indictors of wellbeing, presuming that governments act on what they measure. This article will argue instead that formation of multisectoral policies to promote psychological wellbeing requires a different kind of theoretical and evidentiary basis. The article integrates ideas from literature on wellbeing, health in all policies, political science, mental health promotion, and social determinants of health to make a case for place‐based policy as the central feature of multi‐sectoral policy for psychological wellbeing. I argue that the required theoretical foundation for policy action on psychological wellbeing lies with understanding certain basic functions of human social psychology including the role of stress arousal. I then draw on policy theory to propose three steps to translate this theoretical understanding of psychological wellbeing into practicable, multi‐sectoral policies. Step one is concerned with adopting a thoroughly revised conception of psychological wellbeing as a policy problem. Step two involves uptake of a theory of change in policy, grounded on recognition of essential social conditions required to promote psychological wellbeing. Proceeding from these, I will argue that a necessary (but not sufficient) third step is to implement place‐based strategies involving government‐community partnerships, to generate essential conditions for psychological wellbeing on a universal basis. Finally, I examine implications of the proposed approach for current theory and practice in mental health promotion policy. Place‐based policy is foundational for effective multi‐sectoral policy to promote psychological wellbeing. Governments aiming to promote psychological wellbeing should position place‐based policy at the centre of their strategies.

Recently, roadway releases of N,N′-substituted p-phenylenediamine (PPD) antioxidants and their transformation products (TPs) received significant attention due to the highly toxic 6PPD-quinone. However, the occurrence of PPDs and TPs in recycled tire rubber products remains uncharacterized. Here, we analyzed tire wear particles (TWPs), recycled rubber doormats, and turf-field crumb rubbers for seven PPD antioxidants, five PPD-quinones (PPDQs), and five other 6PPD TPs using liquid chromatography-tandem mass spectrometry. PPD antioxidants, PPDQs, and other TPs were present in all samples with chemical profiles dominated by 6PPD, DTPD, DPPD, and their corresponding PPDQs. Interestingly, the individual [PPDQ]/[PPD] and [TP]/[PPD] ratios significantly increased as total concentrations of the PPD-derived chemical decreased, indicating that TPs (including PPDQs) dominated the PPD-derived compounds with increased environmental weathering. Furthermore, we quantified 15 other industrial rubber additives (including bonding agents, vulcanization accelerators, benzotriazole and benzothiazole derivatives, and diphenylamine antioxidants), observing that PPD-derived chemical concentrations were 0.5–6 times higher than these often-studied additives. We also screened various other elastomeric consumer products, consistently detecting PPD-derived compounds in lab stoppers, sneaker soles, and rubber garden hose samples. These data emphasize that PPD antioxidants, PPDQs, and related TPs are important, previously overlooked contaminant classes in tire rubbers and elastomeric consumer products.

Abstract:The Chancery clerk Richard Sotheworth (d. 1419) listed a copy of the Canterbury Tales and three other books in his will, making him the earliest named owner of Chaucer's poem. I identify here a manuscript owned and copied by Sotheworth, and also a number of Chancery documents in his hand. Considering the wills and manuscripts owned by individuals connected to Sotheworth, this essay recovers a network of the books and belongings of Chancery clerks. From this network, I demonstrate that a distinct discourse emerges from how Chancery clerks described the books that were their daily business and also occupied them as they imagined their own deaths. The recurring attention in these wills to who bought, copied, and owned books of every type reveals the ways in which Sotheworth and his colleagues conceived of books as things that themselves required narration—as objects that Chancery clerks conceptualized, described, and valued not only for their texts, but in terms of the social relationships they embodied and the personal memories they evoked.

The goal of tissue decellularization is to efficiently remove unwanted cellular components, such as DNA and cellular debris, while retaining the complex structural and molecular milieu within the extracellular matrix (ECM). Decellularization protocols to date are centered on customized tissue-specific and lab-specific protocols that involve consecutive manual steps which results in variable and protocol-specific ECM material. The differences that result from the inconsistent protocols between decellularized ECMs affect consistency across batches, limit comparisons between results obtained from different laboratories, and could limit the transferability of the material for consistent laboratory or clinical use. The present study is the first proof-of-concept towards the development of a standardized protocol that can be used to derive multiple ECM biomaterials (powders and hydrogels) viaa previously established automated system. The automated decellularization method developed by our group was used due to its short decellularization time (4 hours) and its ability to reduce batch-to-batch variability. The ECM obtained using this first iteration of a unified protocol was able to produce ECM hydrogels from skin, lung, muscle, tendons, cartilage, and laryngeal tissues. All hydrogels formed in this study were cytocompatible and showed gelation and rheological properties consistent with previous ECM hydrogels. The ECMs also showed unique proteomic composition. The present study represents the first step towards developing standardized protocols that can be used on multiple tissues in a fast, scalable, and reproducible manner.

Invasive fungal infections pose an important threat to public health and are an under-recognized component of antimicrobial resistance, an emerging crisis worldwide. Across a period of profound global environmental change and expanding at-risk populations, human-infecting pathogenic fungi are evolving resistance to all licensed systemic antifungal drugs. In this Review, we highlight the main mechanisms of antifungal resistance and explore the similarities and differences between bacterial and fungal resistance to antimicrobial control. We discuss the research and innovation topics that are needed for risk reduction strategies aimed at minimizing the emergence of resistance in pathogenic fungi. These topics include links between the environment and One Health, surveillance, diagnostics, routes of transmission, novel therapeutics and methods to mitigate hotspots for fungal adaptation. We emphasize the global efforts required to steward our existing antifungal armamentarium, and to direct the research and development of future therapies and interventions.

Enhancer of zeste homolog 2 (EZH2) and SET domain bifurcated 1 (SETDB1, also known as ESET) are oncogenic methyltransferases implicated in a number of human cancers. These enzymes typically function as epigenetic repressors of target genes by methylating histone H3 K27 and H3-K9 residues, respectively. Here, we show that EZH2 and SETDB1 are essential to proliferation in 3 SCC cell lines, HSC-5, FaDu, and Cal33. Additionally, we find both of these proteins highly expressed in an aggressive stem-like SCC sub-population. Depletion of either EZH2 or SETDB1 disrupts these stem-like cells and their associated phenotypes of spheroid formation, invasion, and tumor growth. We show that SETDB1 regulates this SCC stem cell phenotype through cooperation with ΔNp63α, an oncogenic isoform of the p53-related transcription factor p63. Furthermore, EZH2 is upstream of both SETDB1 and ΔNp63α, activating these targets via repression of the tumor suppressor RUNX3. We show that targeting this pathway with inhibitors of EZH2 results in activation of RUNX3 and repression of both SETDB1 and ΔNp63α, antagonizing the SCC cancer stem cell phenotype. This work highlights a novel pathway that drives an aggressive cancer stem cell phenotype and demonstrates a means of pharmacological intervention.

We sought to examine barriers to access to, use of, and benefits from digital health services in an area of socioeconomic disadvantage of Adelaide, Australia. We conducted waiting room surveys in two hospital diabetes clinics and one hospital antenatal clinic in South Australia, and follow‐up telephone interviews with 20 patients. We examined the extent of access to, use of and benefits from digital health services, and what barriers people encountered. We undertook mixed methods, with quantitative descriptive analysis and qualitative analysis. Thirty‐seven diabetes clinic patients (54% response rate) and 99 antenatal clinic patients (33% response rate) participated. Sixty‐two percent of the patients with diabetes and 27% of antenatal clinic patients had never used digital health services. Seventeen percent of patients with diabetes and 30% of antenatal clinic patients were hesitant users, and 22% of patients with diabetes and 44% of antenatal clinic patients were confident users. Barriers included struggling to afford the technology or to stay connected and a lack of trust in online health information. Potential benefits included feeling more empowered and complementing face‐to‐face care. There are socioeconomic barriers to access, use of, and ability to benefit from digital health strategies that mean not everyone will be able to benefit from digital health services. As COVID‐19 accelerates the shift towards digital health services, people experiencing socioeconomic disadvantage may be excluded. If barriers to access and use are not addressed, they will exacerbate already increasing health inequities.

Muscle and tendon injuries are prevalent and range from minor sprains and strains to traumatic, debilitating injuries. However, the interactions between these tissues during injury and recovery remain unclear. Three-dimensional tissue models that incorporate both tissues and a physiologically relevant junction between muscle and tendon may help understand how the two tissues interact. Here, we use tissue specific extracellular matrix (ECM) derived from muscle and tendon to determine how cells of each tissue interact with the microenvironment of the opposite tissue, resulting in junction-specific features. The ECM materials were derived from the Achilles tendon and gastrocnemius muscle, decellularized, and processed to form tissue-specific pre-hydrogel digests. The ECM materials were unique in respect to protein composition and included many types of ECM proteins, not just collagens. After digestion and gelation, ECM hydrogels had similar complex viscosities that were less than type I collagen hydrogels at the same concentration. C2C12 myoblasts and tendon fibroblasts were cultured in tissue-specific ECM conditioned media or encapsulated in tissue-specific ECM hydrogels to determine cell–matrix interactions and the effects on a muscle–tendon junction marker, paxillin. The ECM conditioned media had only a minor effect on the upregulation of paxillin in cells cultured in monolayer. However, cells cultured within ECM hydrogels had 50–70% higher paxillin expression than cells cultured in type I collagen hydrogels. Contraction of the ECM hydrogels varied by the type of ECM used. Subsequent experiments with a varying density of type I collagen (and thus contraction) showed no correlation between paxillin expression and the amount of gel contraction, suggesting that a constituent of the ECM was the driver of paxillin expression in the ECM hydrogels. In addition, another junction marker, type XXII collagen, had similar expression patterns as paxillin, with smaller effect sizes. Using tissue-specific ECM allowed for the de-construction of the cell–matrix interactions similar to muscle–tendon junctions to study the expression of myotendinous junction-specific proteins.Impact statementThe muscle–tendon junction is an important feature of muscle–tendon units; however, despite crosstalk between the two tissue types, the junction is often overlooked in current research. Deconstructing the cell–matrix interactions will provide the opportunity to study significant junction-specific features and markers that should be included in tissue models of the muscle–tendon unit, while gaining a deeper understanding of the natural junction. This research aims at informing future methods to engineer a more relevant multi-tissue platform to study the muscle–tendon unit.

Metacognition and self-regulated learning are skills that contribute to student success, but few studies have examined these topics within a community college context. We addressed this lack of understanding by asking community college biology students to metacognitively reflect on their learning strategies. We took a novel approach in our analysis by investigating how learning strategies potentially differed based on race, age, gender, and final course grade. With some exceptions, we found little evidence to suggest that such differences existed. Notably, we found that learning strategies did not differ between high-achieving and low-achieving students, which contradicts previous studies. We offer several possible explanations for these preliminary results, which include misrepresentation by students in their reflecctions, external and internal barriers to studying, potential flaws in our survey instrument, and students not effectively using learning strategies. We suggest replication of this study with methodological changes to further investigate any potential differences that may exist among these groups of students. Our research is an example of how classroom action research can provide insight into how students learn, which empowers us to make evidence-based changes in our teaching.

Engineered scaffolds used to regenerate mammalian tissues should recapitulate the underlying fibrous architecture of native tissue to achieve comparable function. Current fibrous scaffold fabrication processes, such as electrospinning and three-dimensional (3D) printing, possess application-specific advantages, but they are limited either by achievable fiber sizes and pore resolution, processing efficiency, or architectural control in three dimensions. As such, a gap exists in efficiently producing clinically relevant, anatomically sized scaffolds comprising fibers in the 1–100 μm range that are highly organized. This study introduces a new high-throughput, additive fibrous scaffold fabrication process, designated in this study as 3D melt blowing (3DMB). The 3DMB system described in this study is modified from larger nonwovens manufacturing machinery to accommodate the lower volume, high-cost polymers used for tissue engineering and implantable biomedical devices and has a fiber collection component that uses adaptable robotics to create scaffolds with predetermined geometries. The fundamental process principles, system design, and key parameters are described, and two examples of the capabilities to create scaffolds for biomedical engineering applications are demonstrated.Impact statementThree-dimensional melt blowing (3DMB) is a new, high-throughput, additive manufacturing process to produce scaffolds composed of highly organized fibers in the anatomically relevant 1–100 μm range. Unlike conventional melt-blowing systems, the 3DMB process is configured for efficient use with the relatively expensive polymers necessary for biomedical applications, decreasing the required amounts of material for processing while achieving high throughputs compared with 3D printing or electrospinning. The 3DMB is demonstrated to make scaffolds composed of multiple fiber materials and organized into complex shapes, including those typical of human body parts.

Discovering that chytrid fungi cause chytridiomycosis in amphibians represented a paradigm shift in our understanding of how emerging infectious diseases contribute to global patterns of biodiversity loss. In this Review we describe how the use of multidisciplinary biological approaches has been essential to pinpointing the origins of amphibian-parasitizing chytrid fungi, including Batrachochytrium dendrobatidisand Batrachochytrium salamandrivorans, as well as to timing their emergence, tracking their cycles of expansion and identifying the core mechanisms that underpin their pathogenicity. We discuss the development of the experimental methods and bioinformatics toolkits that have provided a fuller understanding of batrachochytrid biology and informed policy and control measures.

The recent calls to reorient chemistry education so that it explicitly incorporates a systems perspective offer the potential for learning environments where students not only learn how chemists think and do various tasks in the lab, but also learn about the relationship between chemistry and the larger society. This reorientation will more fully engage students in the three complementary dimensions central to their preparation to become members of a profession like chemistry. The pedagogical approach developed by SENCER (Science Education for New Civic Engagements and Responsibilities) is one way that faculty could reorient chemistry courses toward a systems perspective and provide increased emphasis on the ethical nature of chemistry’s impact on society. An undergraduate chemistry curriculum that educates “head, hands, and heart” offers great potential to prepare students to become chemists that are fully committed to the ACS vision of “improving people’s lives through the transforming power of chemistry”.

In this Tutorial, we introduce a tool that allows researchers to track subjects’ on- and off-task activity on Qualtrics’ online survey platform. Our TaskMaster tool uses JavaScript to create several arrayed variables representing the frequency with which subjects enter and leave an active survey window and how long they remain within a given window. We provide code and instructions that will allow researchers to both implement the TaskMaster and analyze its output. We detail several potential applications, such as in studies of persistence and cheating, and studies that require sustained attention to experimental outcomes. The TaskMaster is designed to be accessible to researchers who are comfortable designing studies in Qualtrics, but who may have limited experience using programming languages such as JavaScript.

Invasive fungal infections caused by multiazole-resistant Aspergillus fumigatusare associated with increasing rates of mortality in susceptible patients. Current methods of diagnosing infections caused by multiazole-resistant A. fumigatusare, however, not well suited for use in clinical point-of-care testing or in the field. Loop-mediated isothermal amplification (LAMP) is a widely used method of nucleic acid amplification with rapid and easy-to-use features, making it suitable for use in different resource settings. Here, we developed a LAMP assay to detect a 34 bp tandem repeat, named TR34-LAMP. TR34 is a high-prevalence allele that, in conjunction with the L98H single-nucleotide polymorphism, is associated with the occurrence of multiazole resistance in A. fumigatusin the environment and in patients. This process was validated with both synthetic double-stranded DNA and genomic DNA prepared from azole-resistant isolates of A. fumigatus. Use of our assay resulted in rapid and specific identification of the TR34 allele with high sensitivity, detecting down to 10 genomic copies per reaction within 25 minutes. Fluorescent and colorimetric detections were used for the analysis of 11 clinical isolates as cross validation. These results show that the TR34-LAMP assay has the potential to accelerate the screening of clinical and environmental A. fumigatusto provide a rapid and accurate diagnosis of azole resistance, which current methods struggle to achieve.

Two 2-aminoimidazole-based inhibitors, LY3031207 (1) and LY3023703 (2), of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme were found to cause drug-induced liver injury (DILI) in humans. We studied imidazole ring substitutions to successfully mitigate reactive metabolite (RM) formation. These studies support the conclusion that RM formation may play a role in the observations of DILI and the consideration of 2-aminoimidazoles as structure alerts, due to the high likelihood of bioactivation to generate RMs.

The integrative environment-health sciences including One Health, Conservation Medicine, EcoHealth and Planetary Health embody the transdisciplinary synthesis needed to understand the multitude of factors that underpin emerging infections and their management. Future successes in confronting and resolving the complex causal basis of disease emergence to generate robust, systems-oriented risk reduction strategies that preserve both human health as well as promoting sustainable futures represent the ‘Moon Shot’ for the integrative environment-health sciences.

Invasive fungal diseases are on the increase globally. The World Health Organization fungal priority pathogens list highlights fungi of critical or high importance to human health and provides pathways for action. The report calls for improved surveillance (diagnostics and antifungal resistance monitoring), research and innovation (implementation research) and public-health interventions.

This study identifies current practices of private health funds (PHFs) in Australian primary health care (PHC), including areas where their involvement is increasing, and examines the risks and benefits of these practices for quality of, and equity of access to PHC. The paper draws on research to investigate equity implications of current PHFinvolvement in PHCin Australia. We reviewed literature, analysed documents relating to a Senate Committee inquiry and interviewed stakeholders and experts in private health insurance policy from government, private sector and nongovernment organisations. Involvement of PHFs in the PHCsector in Australia is increasing, presenting risk of increased inequities in access to PHCbased on insurance status, which could undermine the universality of PHCunder Medicare. However, some stakeholders think these risks can be managed within current policy arrangements. There are also risks for quality of PHCservices arising from greater involvement of PHFs in service delivery and “preferred provider” models. Differing stakeholder views on equity implications of PHFinvolvement in PHCare associated with different views on desirable policy action. We conclude that there is a risk of increased involvement of PHFs in PHCrisks exacerbating existing inequities in the health system, but this is moderated by public support for Medicare.

Objectives: 1) To report outcomes from a citizens’ jury examining regulatory responses to the health impacts of McDonald's Australia; 2) To determine the value of using citizens’ juries to develop policy recommendations based on the findings of health impact assessment of transnational corporations (TNCs). Methods: A citizens’ jury engaged 15 randomly selected and demographically representative jurors from metropolitan Adelaide to deliberate on the findings of a Corporate Health Impact Assessment, and to decide on appropriate policy actions. Results: Jurors unanimously called for government regulation to ensure that transnational fast food corporations pay taxes on profits in the country of income. A majority (two‐thirds) also recommended government regulation to reduce fast food advertising, and improve standards of consumer information including a star‐ratings system. A minority held the view that no further regulation is required of the corporate fast food industry in Australia. Conclusion: The jury's recommendations can help inform policy makers about the importance of ending the legal profit‐shifting strategies by TNCs that affect taxation revenue. They also endorse regulating the fast food industry to provide healthier food, and employing forms of community education and awareness‐raising. Implications for public health: Citizens’ juries can play an important role in providing feedback and policy recommendations in response to the findings of a health impact assessment of transnational corporations.

After cartilage injury and repair, the subchondral bone plate remodels. Skeletal maturity likely impacts both bone remodeling and inherent cartilage repair capacity. The objective of this study was to evaluate subchondral bone remodeling as a function of injury type, repair scenario, and skeletal maturity in a Yucatan minipig model. Cartilage defects (4 mm) were created bilaterally in the trochlear groove. Treatment conditions included a full thickness chondral defect (full chondral defect, n= 3 adult/3 juvenile), a partial thickness (∼50%) chondral defect (PCD, n= 3/3), and FCD treated with microfracture (MFX, n= 3/3). At 6 weeks postoperatively, osteochondral samples containing the lesion site were imaged by micro-computed tomography (CT) and analyzed by histology and immunohistochemistry. Via micro-CT, FCD and MFX groups showed increased bone loss in juveniles compared with adults. Quantification of histology using the ICRS II scoring system showed equal overall assessment for the FCD groups and better overall assessment in juvenile animals treated with MFX compared with adults. All FCD and MFX groups were inferior to control samples. For the PCD injury, both age groups had values close to the control values. For the FCD groups, there were greater alterations in the subchondral bone in juveniles compared with adults. Staining for collagen II showed more intense signals in juvenile FCD and MFX groups compared with adults. This large animal study of cartilage repair shows the significant impact of skeletal maturity on the propensity of subchondral bone to remodel as a result of chondral injury. This will improve selection criteria for animal models for studying cartilage injury, repair, and treatment.

Large animal models play an essential role in the study of tissue engineering and regenerative medicine (TERM), as well as biomechanics. The porcine model has been increasingly used to study the musculoskeletal system, including specific joints, such as the knee and temporomandibular joints, and tissues, such as bone, cartilage, and ligaments. In particular, pigs have been utilized to evaluate the role of skeletal growth on the biomechanics and engineered replacements of these joints and tissues. In this review, we explore the publication history of the use of pig models in biomechanics and TERM discuss interspecies comparative studies, highlight studies on the effect of skeletal growth and other biological considerations in the porcine model, and present challenges and emerging opportunities for using this model to study functional TERM.

Subcutaneously implanted experimental tumors in mice are commonly used in cancer research. Despite their superficial location, they remain a challenge to image non-invasively at sufficient spatial resolution for microvascular studies. Here we evaluate the capabilities of optical coherence tomography (OCT) angiography for imaging such tumors directly through the murine skin in-vivo. Data sets were collected from mouse tumors derived from fibrosarcoma cells genetically engineered to express only single splice variant isoforms of vascular endothelial growth factor A (VEGF); either VEGF120 or VEGF188 (fs120 and fs188 tumors respectively). Measured vessel diameter was found to be significantly (p<0.001) higher for fs120 tumors (60.7 ± 4.9μm) compared to fs188 tumors (45.0 ± 4.0μm). The fs120 tumors also displayed significantly higher vessel tortuosity, fractal dimension and density. The ability to differentiate between tumor types with OCT suggests that the visible abnormal vasculature is representative of the tumor microcirculation, providing a robust, non-invasive method for observing the longitudinal dynamics of the subcutaneous tumor microcirculation.

Cartilage tissue engineering is emerging as a promising treatment for osteoarthritis, and the field has progressed toward utilizing large animal models for proof of concept and preclinical studies. Mechanical testing of the regenerative tissue is an essential outcome for functional evaluation. However, testing modalities and constitutive frameworks used to evaluate in vitrogrown samples differ substantially from those used to evaluate in vivoderived samples. To address this, we developed finite element (FE) models (using FEBio) of unconfined compression and indentation testing, modalities commonly used for such samples. We determined the model sensitivity to tissue radius and subchondral bone modulus, as well as its ability to estimate material parameters using the built-in parameter optimization tool in FEBio. We then sequentially tested agarose gels of 4%, 6%, 8%, and 10% weight/weight using a custom indentation platform, followed by unconfined compression. Similarly, we evaluated the ability of the model to generate material parameters for living constructs by evaluating engineered cartilage. Juvenile bovine mesenchymal stem cells were seeded (2 × 107cells/mL) in 1% weight/volume hyaluronic acid hydrogels and cultured in a chondrogenic medium for 3, 6, and 9 weeks. Samples were planed and tested sequentially in indentation and unconfined compression. The model successfully completed parameter optimization routines for each testing modality for both acellular and cell-based constructs. Traditional outcome measures and the FE-derived outcomes showed significant changes in material properties during the maturation of engineered cartilage tissue, capturing dynamic changes in functional tissue mechanics. These outcomes were significantly correlated with one another, establishing this FE modeling approach as a singular method for the evaluation of functional engineered and native tissue regeneration, both in vitroand in vivo.

HIV-associated cryptococcal meningitis is by far the most common cause of adult meningitis in many areas of the world that have high HIV seroprevalence. In most areas in Sub-Saharan Africa, the incidence of cryptococcal meningitis is not decreasing despite availability of antiretroviral therapy, because of issues of adherence and retention in HIV care. In addition, cryptococcal meningitis in HIV-seronegative individuals is a substantial problem: the risk of cryptococcal infection is increased in transplant recipients and other individuals with defects in cell-mediated immunity, and cryptococcosis is also reported in the apparently immunocompetent. Despite therapy, mortality rates in these groups are high. Over the past 5 years, advances have been made in rapid point-of-care diagnosis and early detection of cryptococcal antigen in the blood. These advances have enabled development of screening and pre-emptive treatment strategies aimed at preventing the development of clinical infection in patients with late-stage HIV infection. Progress in optimizing antifungal combinations has been aided by evaluation of the clearance rate of infection by using serial quantitative cultures of cerebrospinal fluid (CSF). Measurement and management of raised CSF pressure, a common complication, is a vital component of care. In addition, we now better understand protective immune responses in HIV-associated cases, immunogenetic predisposition to infection, and the role of immune-mediated pathology in patients with non-HIV associated infection and in the context of HIV-associated immune reconstitution reactions.

AbstractThe Atlantic Sturgeon Acipenser oxyrinchus oxyrinchushistorically supported a significant commercial fishery along the eastern coast of North America. However, overfishing led to substantial population declines with contributions from other anthropogenic impacts, including vessel strikes and contaminants that continue to impede recovery. Our work is the first to estimate the abundance of early juvenile (age 0–1), resident Atlantic Sturgeon in the Delaware River estuary. Using the Schumacher and Eschmeyer mark–recapture estimator for multiple censuses, we estimated 3,656 (95% CI = 1,935–33,041) individuals used the Delaware River estuary as a nursery in 2014. We found no significant change in mean length during the course of our study (November–December), and lengths of age 0–1 Atlantic Sturgeon ranged from 220 to 515 mm TL. Further, using a passive acoustic receiver array, we identified significant habitat areas where age-0–1 juveniles spend considerable amounts of time; this included the Marcus Hook area and some habitat use downriver and upriver of Marcus Hook at Cherry Island and the Chester Range. Our results support the idea that a spawning population of Atlantic Sturgeon exists in the Delaware River and that some level of early juvenile recruitment is continuing to persist despite current depressed population levels. Understanding trends in abundance, habitat use, and other population metrics for natal river Atlantic Sturgeon will allow for better conservation and management of the species.Received March 24, 2016; accepted July 10, 2016Published online September 26, 2016

Bioinks play a central role in 3D-bioprinting by providing the supporting environment within which encapsulated cells can endure the stresses encountered during the digitally driven fabrication process and continue to mature, proliferate, and eventually form extracellular matrix (ECM). In order to be most effective, it is important that bioprinted constructs recapitulate the native tissue milieu as closely as possible. As such, musculoskeletal soft tissue constructs can benefit from bioinks that mimic their nanofibrous matrix constitution, which is also critical to their function. This study focuses on the development and proof-of-concept assessment of a fibrous bioink composed of alginate hydrogel, polylactic acid nanofibers, and human adipose-derived stem cells (hASC) for bioprinting such tissue constructs. First, hASC proliferation and viability were assessed in 3D-bioplotted strands over 16 days in vitro.Then, a human medial knee meniscus digitally modeled using magnetic resonance images was bioprinted and evaluated over 8 weeks in vitro. Results show that the nanofiber-reinforced bioink allowed higher levels of cell proliferation within bioprinted strands, with a peak at day 7, while still maintaining a vast majority of viable cells at day 16. The cell metabolic activity on day 7 was 28.5% higher in this bioink compared to the bioink without nanofibers. Histology of the bioprinted meniscus at both 4 and 8 weeks showed 54% and 147% higher cell density, respectively, in external versus internal regions of the construct. The presence of collagen and proteoglycans was also noted in areas surrounding the hASC, indicating ECM secretion and chondrogenic differentiation.

Objective We have recently shown that mesenchymal stem cells (MSCs) embedded in a hyaluronic acid (HA) hydrogel and exposed to chondrogenic factors (transforming growth factor–β3 [TGF-β3]) produce a cartilage-like tissue in vitro. The current objective was to determine if these same factors could be combined immediately prior to implantation to induce a superior healing response in vivorelative to the hydrogel alone.Design Trochlear chondral defects were created in Yucatan mini-pigs (6 months old). Treatment groups included an HA hydrogel alone and hydrogels containing allogeneic MSCs, TGF-β3, or both. Six weeks after surgery, micro-computed tomography was used to quantitatively assess defect fill and subchondral bone remodeling. The quality of cartilage repair was assessed using the ICRS-II histological scoring system and immunohistochemistry for type II collagen.Results Treatment with TGF-β3 led to a marked increase in positive staining for collagen type II within defects (P< 0.05), while delivery of MSCs did not (P> 0.05). Neither condition had an impact on other histological semiquantitative scores (P> 0.05), and inclusion of MSCs led to significantly less defect fill (P< 0.05). For all measurements, no synergistic interaction was found between TGF-β3 and MSC treatment when they were delivered together (P> 0.05).Conclusions At this early healing time point, treatment with TGF-β3 promoted the formation of collagen type II within the defect, while allogeneic MSCs had little benefit. Combination of TGF-β3 and MSCs at the time of surgery did not produce a synergistic effect. An in vitroprecultured construct made of these components may be required to enhance in vivorepair in this model system.

Prostaglandin (PG) E2plays a critical role in eliciting inflammation. Nonsteroidal anti-inflammatory drugs and selective inhibitors of cyclooxygenase, which block PGE2production, have been used as key agents in treating inflammation and pain associated with arthritis and other conditions. However, these agents have significant side effects such as gastrointestinal bleeding and myocardial infarction, since they also block the production of prostanoids that are critical for other normal physiologic functions. Microsomal prostaglandin E2synthase-1 is a membrane-bound terminal enzyme in the prostanoid pathway, which acts downstream of cyclooxygenase 2 and is responsible for PGE2production during inflammation. Thus, inhibition of this enzyme would be expected to block PGE2production without inhibiting other prostanoids and would provide analgesic efficacy without the side effects. In this report, we describe novel microsomal prostaglandin E2synthase-1 inhibitors that are potent in blocking PGE2production and are efficacious in a guinea pig monoiodoacetate model of arthralgia. These molecules may be useful in treating the signs and symptoms associated with arthritis.

Accurate estimates of age and growth of fishes are important in the management and conservation of species and for the development of modeling approaches. Assessments of endangered or rare species typically are limited by poor or inadequate data owing to low abundance, unrepresentative sampling, and/or restrictions on sampling. Atlantic Sturgeon Acipenser oxyrinchus oxyrinchus, which occurs along the east coast of North America, has five distinct population segments (DPSs) listed under the U.S. Endangered Species Act. The New York Bight (NYB) DPS is listed as endangered and represents the largest DPS in the United States. Coastal trawl surveys from 2005 to 2012 were used to evaluate the current age structure of the NYB DPS. A total of 21 year-classes (mean age = 8.89 years, n= 742 fish) were observed. Age data for the NYB DPS were combined with other available age estimates from multiple research laboratories and sources (n= 2,774) in the Hudson River and Delaware River as well from the coastal regions of New York, New Jersey, and Delaware from 1975 to 2012. Collectively, the combined data set captured much of the age range of the species, minimizing age biases and resulting in improved von Bertalanffy parameter estimates (L8= 278.87, K= 0.057, t0= -1.27) with high overall model fit (r2= 0.87). We assessed the effects of individual data sets through a series of leave-one-out bootstrap routines that evaluated the influence of each data set on growth parameter estimates. The parameter estimates of the von Bertalanffy growth function were influenced by sampling location and/or researcher effects. Despite these differences, the combined data set approach used here represents the most comprehensive study on the age-and-growth relationship of Atlantic Sturgeon and provides parameter estimates for the development of population dynamics models and valuable information for future management. Received February 23, 2015; accepted September 24, 2015

Current clinically approved methods for cartilage repair are generally based on either endogenous cell recruitment (e.g., microfracture) or chondrocyte delivery (e.g., autologous chondrocyte implantation). However, both methods culminate in repair tissue with inferior mechanical properties and the addition of biomaterials to these clinical interventions may improve their efficacy. To this end, the objective of this study was to investigate the ability of multipolymer acellular fibrous scaffolds to improve cartilage repair when combined with microfracture in a large animal (i.e., minipig) model. Composite scaffolds were formulated from a combination of hyaluronic acid (HA) fibers and poly(ɛ-caprolactone) (PCL) fibers, either with or without transforming growth factor-β3 (TGFβ3). After 12 weeks in vivo, material choice and TGFβ3 delivery had a significant impact on outcomes; specifically, PCL scaffolds without TGFβ3 had inferior gross appearance and reduced mechanical properties, whereas HA scaffolds that released TGFβ3 resulted in improved histological scores and increased type 2 collagen content. Importantly, analysis of the overall dataset revealed that histology, but not gross appearance, was a better predictor of mechanical properties. This study highlights the importance of scaffold properties on in vivocartilage repair as well as the need for numerous quantitative outcome measures to fully evaluate treatment methods.

Many-body quantum eigenstates of generic Hamiltonians at finite-energy density typically satisfy the "volume law" of entanglement entropy: the von Neumann entanglement entropy and the Renyi entropies for a subregion scale in proportion to its volume. Here we provide a connection between the volume law and the sign structure of eigenstates. In particular, we ask the following question: Can a positive wave function support a volume law entanglement? Remarkably, we find that a typical random positive wave function exhibits a constant law for Renyi entanglement entropies S" for n > 1, despite arbitrary large-amplitude fluctuations. We also provide evidence that the modulus of the finite-energy density eigenstates of generic local Hamiltonians shows similar behavior. [ABSTRACT FROM AUTHOR]

Objective:Preclinical large animal models are essential for evaluating new tissue engineering (TE) technologies and refining surgical approaches for cartilage repair. Some preclinical animal studies, including the commonly used minipig model, have noted marked remodeling of the subchondral bone. However, the mechanisms underlying this response have not been well characterized. Thus, our objective was to compare in-vivooutcomes of chondral defects with varied injury depths and treatments.Design:Trochlear chondral defects were created in 11 Yucatan minipigs (6 months old). Groups included an untreated partial-thickness defect (PTD), an untreated full-thickness defect (FTD), and FTDs treated with microfracture, autologous cartilage transfer (FTD-ACT), or an acellular hyaluronic acid hydrogel. Six weeks after surgery, micro-computed tomography (μCT) was used to quantitatively assess defect fill and subchondral bone remodeling. The quality of cartilage repair was assessed using the ICRS-II histological scoring system and immunohistochemistry for type II collagen. A finite element model (FEM) was developed to assess load transmission.Results:Using μCT, substantial bone remodeling was observed for all FTDs, but not for the PTD group. The best overall histological scores and greatest type II collagen staining was found for the FTD-ACT and PTD groups. The FEM confirmed that only the FTD-ACT group could initially restore appropriate transfer of compressive loads to the underlying bone.Conclusions:The bony remodeling observed in this model system appears to be a biological phenomena and not a result of altered mechanical loading, with the depth of the focal chondral defect (partial vs. full thickness) dictating the bony remodeling response. The type of cartilage injury should be carefully controlled in studies utilizing this model to evaluate TE approaches for cartilage repair.

The field of tissue engineering and regenerative medicine (TERM) has exploded in the last decade. In this Year (or so) in Review, we highlight some of the high impact advances within the field over the past several years. Using the past as our guide and starting with an objective premise, we attempt so to identify recent “hot topics” and transformative publications within the field. Through this process, several key themes emerged: (1) tissue engineering: grafts and materials, (2) regenerative medicine: scaffolds and factors that control endogenous tissue formation, (3) clinical trials, and (4) novel cell sources: induced pluripotent stem cells. Within these focus areas, we summarize the highly impactful articles that emerged from our objective analysis and review additional recent publications to augment and expand upon these key themes. Finally, we discuss where the TERM field may be headed and how to monitor such a broad-based and ever-expanding community.

The article discusses the dynamics of individual and social well-being, social behaviour and social cohesion in Australian society. It translates the theory and evidence back into relevant terms in interpreting real-world social events. It concludes that Australian political culture lacks depth and coherence in its analyses of what is going on in Australian politics.

Slurry health has been shown to impact defectivity in the chemical mechanical planarization (CMP) process. Improper mechanical handling is known to form large agglomerates in CMP slurries that can lead to increased scratching of the surface. The foremost cause of slurry damage occurs from shear stresses placed on the slurry particles as they pass through the motive force in a distribution system. This paper is a study of two common slurry pumping methods and their contribution to post CMP micro-scratch defects measured on TEOS, Black Diamond l (BD l), Cu blanket wafers, and low-k/Cu integrated patterned wafers. The two specific slurry handling methods studied were the recirculation of slurry in a distribution system by positive displacement (diaphragm) pumps and bearingless centrifugal pump systems.

Abstract: The practice of orthopaedic sports medicine, specifically the management of ligament and tendon injuries, will experience dramatic changes in the near future. Rapid technological advancements, especially in imaging, will greatly increase the speed and accuracy of diagnosing musculoskeletal injuries. On the contrary, effective treatment strategies will lag behind. This widening gap will offer huge opportunities for clinicians, basic scientists, and bioengineers to collaborate and work jointly on in depth basic science and bioengineering research. Together with appropriately designed clinical outcome studies, scientifically based treatment strategies can be designed in order to reduce the gap and to improve patient outcome. In this review, we will focus on the subject of orthopaedic biomechanics and its importance in the treatment of ligament and tendon injuries. We will detail the history of fundamental work done to characterize their biomechanical properties and highlight some recent advances using functional tissue engineering strategies, including the use of bioscaffolds, to improve the healing of medial collateral ligament, patellar tendon, and anterior cruciate ligament. To conclude, we will turn toward the future and highlight a few exciting areas of research as well as emphasize collaborative strategies to solve complex biological and biomechanical problems in ligaments and tendons.

The melanocortin family of receptors (MC 1 - 5R) and their endogenous peptide ligands (, , - MSH and ACTH) have been implicated in the control of a wide variety of behavioral and physiological functions including the homeostatic control of food intake and body weight. In rodent models, melanocortin agonists including the nonselective peptide MTII have been shown to decrease food intake and body weight while antagonists such as SHU9119 and AGRP have been shown to stimulate food intake and increase body weight. Deletion of either the MC3R or MC4R in mice was found to be associated with obesity although hyperphagia was only observed in the MC4R deficient mice. Similarly in humans, inactivating mutations of the MC4R have been found in as many as six percent of obese individuals. The suggestion from these findings that activation of MC4Rs would have an anorectic effect in humans has resulted in efforts to produce selective agonists for the treatment of obesity. Over the past decade, efforts to develop MC4R selective small molecule and peptide agonists have been met with fractional success. Many small molecule agonists have been identified; however, few have been shown to have activity in vivo. While their use as therapeutics may have limitations, selective and potent peptide agonists have been shown by several investigators to decrease food intake and body weight in rodent models. The subject of the current review is to examine the progress made to date on producing both small molecule and peptide MC4R agonists as potential therapeutics for obesity.

Batrachochytrium dendrobatidisis the chytridiomycete fungus which has been implicated in global amphibian declines and numerous species extinctions. Here, we show that introduced North American bullfrogs (Rana catesbeiana) consistently carry this emerging pathogenic fungus. We detected infections by this fungus on introduced bullfrogs from seven of eight countries using both PCR and microscopic techniques. Only native bullfrogs from eastern Canada and introduced bullfrogs from Japan showed no sign of infection. The bullfrog is the most commonly farmed amphibian, and escapes and subsequent establishment of feral populations regularly occur. These factors taken together with our study suggest that the global threat of B. dendrobatidisdisease transmission posed by bullfrogs is significant.

The synthesis of bis(triazine) molecules capable of acting as synthetic receptors for barbiturate guest molecules is described. The binding properties are also reported illustrating the modulation of the binding properties of these species by the modification of the hydrogen-bonding patterns of the receptor molecule, namely 1,3-N,N′-bis[4-(dibenzylamino)-6-(butylamino)-1,3,5-triazin-2-yl]xylylenediamine (1). Thus 1,3-O,O′-bis[4-(dibenzylamino)-6-(butylamino)-1,3,5-triazin-2-yl]benzenedimethanol (3) and 1,3-O,O′-bis[4-(dibenzylamino)-6-(diethylamino)-1,3,5-triazin-2-yl]benzenedimethanol (5) have been prepared, and their binding constants compared to those observed for 1. In the case of compounds 3 and 5 the hydrogen-bonding secondary amines at the apex of the receptor 1 are substituted by non-hydrogen-bonding ether links. The hydrogen-bonding ability is further modified in the case of 5 by the removal of all hydrogen-bond donors from the receptor site, replacing secondary amines by tertiary amines. NMR binding studies illustrate how these simple modifications of the hydrogen-bonding patterns of these receptors influences the overall strength of binding demonstrating a simple mechanism for controlling host-guest complex formation. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Penicillium marneffei infection is an important emerging public health problem, especially among patients infected with human immunodeficiency virus in the areas of endemicity in southeast Asia, India, and China. Within these regions, P. marneffei infection is regarded as an AIDS-defining illness, and the severity of the disease depends on the immunological status of the infected individual. Early diagnosis by serologic and molecular assay-based methods have been developed and are proving to be important in diagnosing infection. The occurrence of natural reservoirs and the molecular epidemiology of P. marneffei have been studied; however, the natural history and mode of transmission of the organism remain unclear. Soil exposure, especially during the rainy season, has been suggested to be a critical risk factor. Using a highly discriminatory molecular technique, multilocus microsatellite typing, to characterize this fungus, several isolates from bamboo rats and humans were shown to share identical multilocus genotypes. These data suggest either that transmission of P. marneffei may occur from rodents to humans or that rodents and humans are coinfected from common environmental sources. These putative natural cycles of P. marneffei infection need further investigation. Studies on the fungal genetics of P. marneffei have been focused on the characterization of genetic determinants that may play important roles in asexual development, mycelial-to-yeast phase transition, and the expression of antigenic determinants. Molecular studies have identified several genes involved in germination, hyphal development, conidiogenesis, and yeast cell polarity. A number of functionally important genes, such as the malate synthase- and catalase-peroxidase protein-encoding genes, have been identified as being upregulated in the yeast phase. Future investigations pertaining to the roles of these genes in host-fungus interactions may provide the key knowledge to understanding the pathogenicity of P. marneffei.

SUMMARYPenicillium marneffei infection is an important emerging public health problem, especially among patients infected with human immunodeficiency virus in the areas of endemicity in southeast Asia, India, and China. Within these regions, P. marneffei infection is regarded as an AIDS-defining illness, and the severity of the disease depends on the immunological status of the infected individual. Early diagnosis by serologic and molecular assay-based methods have been developed and are proving to be important in diagnosing infection. The occurrence of natural reservoirs and the molecular epidemiology of P. marneffei have been studied; however, the natural history and mode of transmission of the organism remain unclear. Soil exposure, especially during the rainy season, has been suggested to be a critical risk factor. Using a highly discriminatory molecular technique, multilocus microsatellite typing, to characterize this fungus, several isolates from bamboo rats and humans were shown to share identical multilocus genotypes. These data suggest either that transmission of P. marneffei may occur from rodents to humans or that rodents and humans are coinfected from common environmental sources. These putative natural cycles of P. marneffei infection need further investigation. Studies on the fungal genetics of P. marneffei have been focused on the characterization of genetic determinants that may play important roles in asexual development, mycelial-to-yeast phase transition, and the expression of antigenic determinants. Molecular studies have identified several genes involved in germination, hyphal development, conidiogenesis, and yeast cell polarity. A number of functionally important genes, such as the malate synthase- and catalase-peroxidase protein-encoding genes, have been identified as being upregulated in the yeast phase. Future investigations pertaining to the roles of these genes in host-fungus interactions may provide the key knowledge to understanding the pathogenicity of P. marneffei.

ABSTRACTInfection by Penicillium marneffeiin human immunodeficiency virus-positive patients in India has recently been described; the aim of our study was to survey wild rodents and their associated environment in order to identify the natural populations of this fungus. Surveys recovered P. marneffeifrom the internal organs of 10 (9.1%) of 110 bamboo rats (Cannomys badius) examined from Manipur state, India, an area endemic for penicilliosis marneffei. Identification of the isolates was based on a detailed study of their morphological characteristics, in vitro conversion to fission yeast form, and exoantigen tests. Multilocus microsatellite typing (MLMT) of the isolates revealed five genotypes. No genotypes were shared between sample sites, and all bamboo rats were infected with a single genotype within sample sites, demonstrating spatial genetic heterogeneity. One MLMT genotype was identical to that seen in a human isolate, suggesting that either coinfection from a common source or host-to-host transmission had occurred. This demonstrates the utility of an MLMT-based approach to elucidating the epidemiology of P. marneffei.